WO2024107615A1 - Orexin receptor agonists - Google Patents

Orexin receptor agonists Download PDF

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WO2024107615A1
WO2024107615A1 PCT/US2023/079457 US2023079457W WO2024107615A1 WO 2024107615 A1 WO2024107615 A1 WO 2024107615A1 US 2023079457 W US2023079457 W US 2023079457W WO 2024107615 A1 WO2024107615 A1 WO 2024107615A1
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methyl
carboxamide
piperazine
phenyl
methylpropanoyl
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PCT/US2023/079457
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French (fr)
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Maria Irina CHIRIAC
Danielle M. Hurzy
Jeffrey C. Kern
Peter J. Manley
Michael T. Rudd
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Merck Sharp & Dohme Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: orexin A (OX-A) (a 33 amino acid peptide) and the orexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcolepsy, idiopathic hypersomnia, excessive daytime sleepiness, shift work disorder, obstructive sleep apnea and insomnia (Chemelli R.M.
  • Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins have also been indicated as playing a role in arousal, emotion, energy homeostasis, reward, learning and memory (Peyron, et al., Journal Neurosci., 1998,18(23):9996-100150, Harris, et al., Trends Neurosci., 2006, 29 (10), 571-577). Two orexin receptors have been cloned and characterized in mammals.
  • the orexin-1 receptor (OX or OX1R) is partially selective for OX-A and the orexin-2 receptor (OX2 or OX2R) is capable of binding OX-A as well as OX-B with similar affinity.
  • OX1R the orexin-1 receptor
  • OX2 or OX2R the orexin-2 receptor
  • the physiological actions in which orexins are presumed to participate are thought to be expressed via one or both of the OX1 receptor and the OX2 receptor as the two subtypes of orexin receptors.
  • the present invention is directed to agonists of orexin receptors.
  • the present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved.
  • the present invention is also directed to compositions comprising these compounds.
  • the present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
  • Ring A is selected from aryl and heteroaryl
  • R is independently selected from H, -C 1-6 alkyl, O-C 1-6 alkyl, CF 3 , CHF 2 , CH 2 F, and C 3-6 cycloalkyl
  • Ra is selected from -C 1-6 alkyl and -C 3-6 cycloalkyl
  • R 1 is independently selected from: (1) -(CR 2 ) n -heteroaryl, where the heteroaryl is unsubstituted or substituted with one to s ix substituents independently selected from R 4 , (2) -(CR 2 ) n -heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , ( 3) -(CR2)n- C 3-6 cycloalkyl, where the cycloalkyl is unsubstit
  • the instant invention is directed to compounds of the formula 1, wherein: Ring A is selected from pyrazinyl, naphthyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, imidazolyl, quinolinyl, pyradazinyl, phenyl and pyridinyl; Ra is -C 1-6 alkyl; R 1 is independently selected from: (1) H, (2) -(CR 2 ) n -heteroaryl, where the heteroaryl is unsubstituted or substituted with one to s ix substituents independently selected from R 4 , (3) -(CR 2 ) n -heterocyclyl, where the heterocyclyl is unsubstituted or substituted with o ne to six substituents independently selected from R 4 , (4) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six s
  • the instant invention is directed to compounds of the formula 1, wherein: Ring A is selected from phenyl and pyridinyl; Ra is -C 1-6 alkyl; R 1 is independently selected from: ( 1) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six s ubstituents independently selected from R 4 , (2) -O(CR2)pR 4 , (3) -OR, and (4) Halo; R 2 is selected from: (1) H, ( 2) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three s ubstituents selected from R 5 , (3) -(CR 2 ) s OR, and (4) -(CR2)sC(O)OR; R 3 is independently selected from: (1) Heteroaryl which is selected from pyrimidinyl, pyridinyl, or oxazolyl, where the heteroaryl is unsubsti
  • Ring A is selected from aryl and heteroaryl
  • 25608 R is independently selected from H, -C 1-6 alkyl, -O-C 1-6 alkyl, -CF 3 , -CHF 2 , -CH 2 F, and -C 3-6 cycloalkyl
  • R 1 is independently selected from: (1) -(CR2)n-heteroaryl, where the heteroaryl is unsubstituted or substituted with one to s ix substituents independently selected from R 4 , (2) -(CR 2 ) n -heterocyclyl, where the heterocyclyl is unsubstituted or substituted with o ne to six substituents independently selected from R 4 , ( 3) -(CR 2 ) n - C 3-6 cycloalkyl, where the cycloalky
  • Certain embodiments of the present invention include a compound which is selected from: cis-4-benzyl-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (1-1); (2R,6R)-N- ⁇ [4-(furan-2-yl)phenyl]methyl ⁇ -6-methyl-1-(2-methylpropanoyl)-4- ⁇ [2-(morpholin- 4-yl)phenyl]methyl ⁇ piperazine-2-carboxamide (1-2); N- ⁇ [4-(furan-2-yl)phenyl]methyl ⁇ -6-methyl-1-(2-methylpropanoyl)-4-[(2- phenoxyphenyl)methyl]piperazine-2-carboxamide (1-3); 4-[(2,6-difluorophenyl)methyl]-N- ⁇ [4-(furan-2-yl)phenyl]methyl ⁇ -6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide
  • FIG. 1 For embodiments of the present invention, a compound which is selected from 2R,6R)-4-(2-fluoro-6-(2-methoxyphenoxy)benzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (13-1); (2R,6R)-4-( ⁇ 2-[(2-ethyl-5-methylpyridin-3-yl)oxy]-6-fluorophenyl ⁇ methyl)-6-methyl-1-(2- methylpropanoyl)-N- ⁇ [4-(pyrimidin-2-yl)phenyl]methyl ⁇ piperazine-2-carboxamide (13-2); 25608 (2R,6R)-4-( ⁇ 2-[2-(dimethylamino)phenoxy]-6-fluorophenyl ⁇ methyl)-6-methyl-1-(2- methylpropanoyl)-N- ⁇ [4-(pyrimidin-2-yl)phenyl]methyl ⁇ piperaz
  • Further embodiments of the present invention include a compound which is selected from (2R,6R)-N- ⁇ [4-(1,1-difluoroethoxy)phenyl]methyl ⁇ -4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)- 3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (16-3); (2R,6R)-4-[(1R)-1-(3-fluoro-6-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N- ⁇ [4-(pyrimidin-2-yl)phenyl]methyl ⁇ piperazine-2-carboxamide (16-11); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(6- meth
  • An embodiment of the present invention includes compounds of Formula I wherein Ring A is selected from: pyrazinyl, naphthyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl, 25608 triazolyl, imidazolyl, quinolinyl, pyradazinyl, phenyl and pyridinyl.
  • a further embodiment of the present invention includes compounds wherein Ring A is selected from: pyrazinyl, naphthyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, imidazolyl, quinolinyl, pyradazinyl, phenyl and pyridinyl.
  • Ring A is phenyl. In an embodiment, Ring A is pyridinyl.
  • An embodiment of the present invention includes compounds of Formula I wherein R 1 is selected from: (1) -(CR2)n-heteroaryl, where the heteroaryl is unsubstituted or substituted with one to s ix substituents independently selected from R 4 , (2) -(CR2)n-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with o ne to six substituents independently selected from R 4 , ( 3) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six s ubstituents independently selected from R 4 , (4) -O(CR2)pR 4 , (5) -OR, (6) halo, (7) -OCR 2 C(O)NR 2 , (8) -OCR2CF3, (9) -O(CR 2 ) t OCR 3 , (
  • the present invention includes compounds of Formula I wherein R 1 is selected from: C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , -O(CR2)pR 4 , halo, -OR, ,-OCR2C(O)NR2, and -OCR 2 CF 3 .
  • R1 is selected from halo, -O(CR 2 ) p R4 or C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R4.
  • R1 is C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 .
  • R 1 is halo.
  • R 1 is -O(CR2)pR 4 .
  • R 1 is -CF3.
  • An embodiment of the present invention includes compounds of Formula I wherein R2 is selected from H, -(CR 2 ) s OR, -C 1-6 alkyl, where the alkyl is unsubstituted or 25608 substituted with one to three substituents selected from R 5 , and -(CR2)sC(O)OR.
  • An embodiment of the present invention includes compounds of Formula I wherein R 3 is selected from ( 1) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to four s ubstituents independently selected from R 7 , (2) aryl, where the aryl is unsubstituted or substituted with one to four substituents i ndependently selected from R 7 , (3) heteroaryl, where the heteroaryl is unsubstituted or substituted with one to four s ubstituents independently selected from R 7 , (4) -OCF2CH3.
  • the present invention includes compounds of Formula I wherein R 3 is selected from unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted furanyl or -OCF2CH3, wherein pyrimidinyl, pyridinyl, furanyl or oxazolyl is optionally substituted with one to four substituents independently selected from R 7 .
  • An embodiment of the present invention includes compounds of Formula I wherein R 4 is selected from -OR, halo, -C 1-6 alkyl, aryl, heteroaryl, and heterocyclyl, where said alkyl, aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R 6 .
  • the present invention includes compounds of Formula I wherein R 4 is selected from aryl, heteroaryl, and heterocyclyl, where said aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R 6 .
  • R 4 is selected from phenyl or pyridinyl, 25608 where said phenyl or pyridinyl is unsubstituted or substituted with one to six substituents independently selected from R 6 .
  • An embodiment of the present invention includes compounds of Formula I wherein m is selected from 0, 1, 2 or 3.
  • An embodiment of the present invention includes compounds of Formula I wherein m is 2.
  • An embodiment of the present invention includes compounds of Formula I wherein m is 1.
  • An embodiment of the present invention includes compounds of Formula I wherein n is selected from 0 or 1.
  • An embodiment of the present invention includes compounds of Formula I wherein n is 0.
  • An embodiment of the present invention includes compounds of Formula I wherein n is 1.
  • An embodiment of the present invention includes compounds of Formula I wherein p is selected from 0 or 1. In an embodiment, the present invention includes compounds of Formula I wherein p is 0. In an embodiment, the present invention includes compounds of Formula I wherein p is 1. An embodiment of the present invention includes compounds of Formula I wherein s is selected from 0, 1, 2 or 3. An embodiment of the present invention includes compounds of Formula I wherein s is 2. An embodiment of the present invention includes compounds of Formula I wherein s is 1.
  • the present invention includes compounds that may contain one or more asymmetric centers. Thus, compounds of the present invention include those that can occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. Likewise, the present invention includes tautomeric forms of the compounds disclosed herein. Formula I shows the structure of the class of compounds without specific stereochemistry. At least some of the chemical names of compounds of the invention as set forth in this application may have been generated on an automated basis by use of commercially available chemical naming software programs, and have not been independently verified.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • Compounds of the present invention may also be separated by supercritical fluid chromatography (SFC). Furthermore, some separations required multiple rounds of purifications by the same method of purification and/or an alternative purification system to resolve mixtures into single isomers. Additionally, a mixture may be a mixture of 2 to 4 stereoisomers. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. As appreciated by those of skill in the art, halogen or halo as used herein are intended to include fluoro, chloro, bromo and iodo.
  • C 1-6 as in C 1-6 alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that C 1-6 alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert- butyl, pentyl, and hexyl.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
  • aryl elements examples include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • aryl is phenyl or naphthyl. In a further embodiment, aryl is phenyl.
  • heterocyclyl, heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclyl, heterocycle or heterocyclic can include heteroaryl moieties when two rings are fused together.
  • heterocyclic elements include, but are not limited to, azabicyclo[2.2.1]heptanyl, azepanyl, azetidinyl, benzodioxolyl, chromanyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydro-pyrrolo[1,2-b]pyrazolyl, 1,3-dioxolanyl, 1,4-dioxanyl, imidazolidinyl, indolinyl, isochromanyl, isoindolinyl, morpholinyl, oxa-5-azabicyclo[2.2.1]heptanyl, oxetanyl, 2- oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperidinyl, piperazinyl,
  • heterocyclyl is selected from azabicyclo[2.2.1]heptanyl, azepanyl, azetidinyl, dihydro-pyrrolo[1,2-b]pyrazolyl, morpholinyl, oxa-5- azabicyclo[2.2.1]heptanyl, piperidyl, piperazinyl, pyrazolidinyl, pyrrolidinyl, pyrrolyl, and tetrahydrofuryl.
  • heterocyclyl is selected from azabicyclo[2.2.1]heptanyl, azepanyl, azetidinyl, dihydro-pyrrolo[1,2-b]pyrazolyl, oxa-5-azabicyclo[2.2.1]heptanyl, piperazinyl, and pyrrolidinyl.
  • Heteroaryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S.
  • heterocyclic elements include, but are not limited to, azepinyl, furanyl, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, 5H-pyrrolo[2,3-b]pyrazinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiazolyl, thienofuryl, thiophenyl, thienothienyl, thien
  • heteroaryl is selected 25608 from furyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, 5H-pyrrolo[2,3-b]pyrazinyl, tetrazolyl, thiazolyl, thienyl, triazolyl and the like.
  • the present invention also includes all pharmaceutically acceptable isotopic variations of a compound of the Formula I in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Such compounds are identical to those disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2 H and 3 H, carbon such as 11 C, 13 C and 14 C, nitrogen such as 13 N and 15 N, oxygen such as 15 O, 17 O and 18 O, phosphorus such as 32 P, sulfur such as 35 S, fluorine such as 18 F, iodine such as 123 I and 125 I, and chlorine such as 36 Cl.
  • isotopically-labelled compounds of Formula I for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • An embodiment of the present invention includes compounds that are substituted with a positron emitting isotope.
  • An embodiment of the present invention includes compounds that are substituted with a 11 C isotope.
  • An embodiment of the present invention includes compounds that are substituted with an 18 F isotope.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of the invention.
  • different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H).
  • Protium is the predominant hydrogen isotope found in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or 25608 reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • a “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).
  • the compounds of the present invention are limited to stable compounds embraced by Formula I.
  • a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the present invention.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates or solvates.
  • Salts derived from pharmaceutically acceptable organic non- toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including 25608 naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N ' -dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • Particular embodiments include the citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
  • Salts of the compounds of the invention may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Exemplifying the invention is the use of the compounds disclosed in the Examples and herein.
  • Specific compounds within the present invention include a compound which is selected from the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual enantiomers or diastereomers thereof.
  • the present invention is also directed to the use of the compounds disclosed herein as agonists of orexin receptor activity.
  • the subject compounds and pharmaceutically acceptable salts thereof are useful in a method of agonizing orexin receptor activity in a subject such as a mammal comprising the administration of an amount of the compound.
  • a variety of other mammals may be administered with a compound of the present invention.
  • the present invention is directed to a compound of the present invention or a pharmaceutically acceptable salt thereof that could be useful in therapy.
  • the present invention may further be directed to a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for agonizing 25608 orexin receptor activity or treating the disorders and diseases noted herein in humans and animals.
  • a subject administered with a compound of the present invention, or a pharmaceutically acceptable salt thereof is generally a mammal, such as a human being, male or female.
  • the amount of compound administered to the subject is an amount sufficient to agonize the orexin receptor in the subject.
  • the amount of compound can be an “effective amount”, wherein the subject compound is administered in an amount that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • An effective amount does not necessarily include considerations of toxicity and safety related to the administration of the compound. It is recognized that one skilled in the art may affect neurological and psychiatric disorders associated with orexin receptor activation by treating a subject presently afflicted with the disorders, or by prophylactically treating a subject likely to be afflicted with the disorders, with an effective amount of a compound of the present invention.
  • treatment and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a subject that is predisposed to such disease or disorder.
  • administration of and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to to the subject.
  • compositions as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • IP-3 inositol monophosphate
  • IP-1 inositol monophosphate
  • IP-One Cisbio; cat# 621PAPEC
  • OX1R and/or OX2R agonists may be determined utilizing this assay.
  • OX1 and OX2 receptor agonist activity is determined in accordance with the following general experimental method.
  • CHO cells expressing human OX1R and/or the human OX2R were grown in Iscove’s modified DMEM containing glutaMAX TM , 1% G418, 100 U/mL penicillin, 100 ⁇ g /mL streptomycin and 10 % heat-inactivated qualified fetal bovine serum (FBS).
  • the OX2R cells were seeded at 10,000 cells/well/50 ⁇ L and the OX1R cells were seeded at 20,000 cells/well/50 ⁇ L into 384-well white tissue culture plates (Greiner; cat# 781080). All cell/media reagents were from GIBCO- Invitrogen Corp.
  • the seeded cell plate(s) were incubated at 37 o C with 5% CO 2 and 85% humidity for 20-24 hours.
  • assay-ready compound plates were prepared using an acoustic liquid handler (ECHO; Labcyte), which dispensed sufficient volume of test compound stock (10 mM in DMSO) or 100% DMSO to prepare 10 point, 1 ⁇ 2-log dilutions in a final volume of 202.5 nL/well in all test wells of a 384-well diamond plate (Labcyte).
  • ECHO acoustic liquid handler
  • IP-one detection reagents were prepared (38:1:1 lysis buffer:D2:AB-cryptate reagents).
  • Six ⁇ L of mixed detection reagents were added to the cell plate using a Multidrop Combi (small cassette, Thermo Fisher Scientific cat #24073290) and incubated 60 minutes at room temperature in the dark. Fluorescence signal was 25608 detected using an Envision plate reader (Perkin Elmer) [LANCE/DELFIA Dual Enh (Em: APC 665; Ex: Cy5620)].
  • Envision plate reader Perkin Elmer
  • Em APC 665; Ex: Cy5620
  • Percent effect for each test compound was determined as the percentage of sample raw value/mean max effect, where the mean max effect was derived from the mean raw value of 32 control wells per assay plate (using Orexin A (cat# 003-30) at 1 ⁇ M for human OX1R and a reference compound at 1 uM with 100% activity previously established by comparison to Orexin A for human OX2R).
  • the intrinsic orexin receptor agonist activity of a compound which may be used in the present invention may be determined by these assays. All of the final compounds of the following examples had activity in agonizing the human orexin-2 receptor in the aforementioned IPOne assay with an EC 50 of about 0.01 nM to 5000 nM. Additional data is provided in the following Examples.
  • Such a result is indicative of the intrinsic activity of the compounds in use as agonists of orexin-1 receptor and/or the orexin-2 receptor.
  • a substance is considered to effectively agonize the orexin receptor if it has an EC 50 in the IPOne assay of less than about 50 ⁇ M, or more specifically less than about 1000 nM.
  • the orexin receptors have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species.
  • the compounds of the present invention could therefore potentially have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with orexin receptors, including one or more of the following conditions or diseases: narcolepsy, narcolepsy syndrome accompanied by narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, repeatability hypersomnia, intrinsic hypersomnia, hypersomnia accompanied by daytime hypersomnia, interrupted sleep, sleep apnea, wakefulness, nocturnal myoclonus, disturbances of consciousness, such as coma, REM sleep interruptions, jet-lag, excessive daytime sleepiness, shift workers' sleep disturbances, dyssomnias, sleep disorders, sleep disturbances, hypersomnia associated with depression, emotional/mood disorders, Alzheimer's disease or cognitive impairment, Parkinson’s disease, Guillain-
  • the present invention may provide methods for: treating or controlling narcolepsy, narcolepsy syndrome accompanied by narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, repeatability hypersomnia, intrinsic hypersomnia, hypersomnia accompanied by daytime hypersomnia, interrupted sleep, sleep apnea, disturbances of consciousness, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dyssomnias, night terror, insomnias associated with depression, emotional/mood disorders, Alzheimer's disease or cognitive impairment; treating or controlling sleep disturbances associated with diseases such as neurological disorders including neuropathic pain and restless leg syndrome; treating or controlling addiction disorders; treating or controlling psychoactive substance use and abuse; enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling diabetes and appetite, taste, eating, or drinking disorders; treating or controlling insulin resistance syndrome
  • EDS day
  • the compounds of the present invention may also potentially have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of other disorders associated with orexin receptors, including one or more of the following conditions or diseases including enhancing sleep quality, improving sleep quality, increasing sleep efficiency, augmenting sleep maintenance; increasing the value which is calculated from the time that a 25608 subject sleeps divided by the time that a subject is attempting to sleep; improving sleep initiation; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing intermittent wakings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency or duration of REM sleep bouts; altering the timing, frequency or duration of slow wave (i.e., stages 3 or 4) sleep bouts; increasing the amount and percentage of stage 2 sleep; promoting slow wave sleep; enhancing EEG-delta activity during
  • the subject compounds could further be of potential use in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
  • the dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the active ingredient may be administered to subjects (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
  • the dose will vary from subject to subject depending upon the nature and severity of disease, the subject's weight, special diets then being followed by a subject, concurrent medication, and other factors which those skilled in the art will recognize.
  • dosage levels of between 0.0001 to 100 mg/kg. of body weight daily are administered to the subject, e.g., humans, adolescent humans and elderly humans, to obtain effective agonism of orexin receptors.
  • the dosage range will generally be about 0.5 mg to 10.0 g. per subject per day which may be administered in single or multiple doses. In one embodiment, the dosage range will be about 0.5 mg to 500 mg per subject per day; in another embodiment about 0.5 mg to 200 mg per subject per day; and in yet another embodiment about 5 mg to 50 mg per subject per day.
  • Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient.
  • the pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient.
  • the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.
  • the compounds may be administered once or multiple times during the day.
  • the compounds may be administered upon awakening or 25608 otherwise in the morning, or during waking hours.
  • the compounds may be administered about 1 hour after awakening, about 30 minutes after awakening or immediately after awakening.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is contemplated.
  • the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules.
  • the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention.
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, such as about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of the present invention may be administered in combination with compounds which are known in the art to be useful for treating or controlling narcolepsy, 25608 including e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, gamma- hydroxybutyric acid, sodium oxybate, or other oxybate salts, modafinil, armodafinil, caffeine, and salts thereof, and combinations thereof, and the like,
  • the compounds of the present invention may be administered in combination with compounds which are known in the art to be useful for preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists, histamine antagonist
  • the subject compound may be employed in combination with other compounds which are known in the art, either administered separately or in the same 25608 pharmaceutical compositions, including, but are not limited to: insulin sensitizers including (i) PPAR ⁇ antagonists such as glitazones (e.g.
  • ciglitazone darglitazone; englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone; troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY-300512, and the like);
  • biguanides such as metformin and phenformin
  • insulin or insulin mimetics such as biota, LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7) (insulintropin); and GLP-1 (7-36)-NH 2 );
  • sulfonylureas such as acetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide; glybur
  • PTP-1B protein tyrosine phosphatase-1B
  • cannabinoid receptor ligands such as cannabinoid CB 1 receptor antagonists or inverse agonists, such as rimonabant, taranabant, AMT-251, and
  • neuropeptide Y1 antagonists such as BIBP3226, J-115814, BIBO 3304, LY- 357897, CP-671906, GI-264879A, and those disclosed in U.S. Patent No.6,001,836, and PCT Patent Publication Nos.
  • neuropeptide Y5 antagonists such as GW- 569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, and those disclosed in U.S.
  • WO 97/19682 WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO 98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO 99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO 02/094825; WO 03/0140
  • CCK agonists such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and those discribed in U.S.
  • Patent No.5,739,106 (21) GLP-1 agonists; (22) corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3) modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists, such as hioperamide, 3- (1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and O-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25) ⁇ -hydroxy steroid dehydrogenase-1 inhibitors ( ⁇ -HSD-1); (26) PDE (phosphodiesterase) inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast;
  • leptin including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (31) leptin derivatives; (32) BRS3 (bombesin receptor subtype 3) agonists such as [D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and [D-Phe6,Phe13]Bn(6- 13)propylamide, and those compounds disclosed in Pept.
  • leptin including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (31) leptin derivatives; (32) BRS3 (bombesin receptor subtype 3) agonists such as [D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and [D-Phe6,Phe13]Bn(6
  • CNTF Central neurotrophic factors
  • GI-181771 Gaxo-SmithKline
  • SR146131 Sanofi Synthelabo
  • butabindide PD170,292, and PD 149164 (Pfizer)
  • CNTF derivatives such as axokine (Regeneron);
  • monoamine reuptake inhibitors such as sibutramine;
  • UCP-1 uncoupling protein-1
  • activators such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoic acid (TTNPB), retinoic acid;
  • thyroid hormone ⁇ agonists such as KB-2611 (KaroBioBMS)
  • FAS fatty acid synthase inhibitors, such as Cerulenin and C
  • dipeptidyl peptidase IV (DP- 25608 IV) inhibitors such as isoleucine thiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, sitagliptin; and the compounds disclosed in US 6,699,871, WO 03/004498; WO 03/004496; EP 1 258476; WO 02/083128; WO 02/062764; WO 03/000250; WO 03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; and WO 03/000181; (46) dicarboxylate transporter inhibitors; (47) glucose transporter inhibitors; (48) phosphate IV (DP- 25608 IV) inhibitors, such as isoleucine
  • Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, and cyclo-(28/32)-Ac-[Lys28-Glu32]- (25-36)-pNPY;
  • Neuropeptide Y4 (NPY4) agonists such as pancreatic peptide (PP), and other Y4 agonists such as 1229U91;
  • cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib, valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522, ABT963, CS502 and GW406381;
  • Neuropeptide Y1 (NPY1) antagonists such as BIBP3226, J-115814, BIBO 3304,
  • the subject compound may be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine 25608 oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, ⁇ -adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT 1A agonists or antagonists,
  • norepinephrine reuptake inhibitors including tertiary amine tricyclics and secondary amine tricyclics
  • SSRIs selective serotonin reuptake inhibitors
  • MAOIs mono
  • Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
  • the subject compound may be employed in combination with anti-Alzheimer's agents; beta-secretase inhibitors, such as verubecestat; gamma-secretase inhibitors; growth hormone secretagogues; recombinant growth hormone; HMG-CoA reductase inhibitors; NSAID's including ibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonists or CB-1 receptor inverse agonists; antibiotics such as doxycycline and rifampin; N- methyl-D-aspartate (NMDA) receptor antagonists, such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H 3 antagonists; AMPA agonists; PDE IV inhibitors; GABA A inverse agonists; or neuropeptide inhibitor
  • the subject compound may be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate
  • the subject compound may be employed in combination with acetophenazine, alentemol, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene or trifluoperazine.
  • the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent.
  • phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine.
  • Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
  • An example of a dibenzazepine is clozapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other neuroleptic agents include loxapine, sulpiride and risperidone.
  • the subject compound may be employed in combination with a nicotine agonist or a nicotine receptor partial agonist such as varenicline, opioid antagonists (e.g., naltrexone (including naltrexone depot), antabuse, and nalmefene), dopaminergic agents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidate hydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g., Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g., Adderall®)) and anti-obesity agents, such as apo- B/MTP inhibitors, 11Beta-hydroxy steroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors, peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists, monoamine renicline,
  • the subject compound may be employed in combination with an agent such as aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and
  • the subject compound may be employed in combination with an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like.
  • a lipoxygenase inhibitor such as an inhibitor of 5-lipoxy
  • the subject compound may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine.
  • a pain reliever such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide
  • a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinep
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
  • inhalation spray nasal, vaginal, rectal, sublingual, or topical routes of administration
  • nasal, vaginal, rectal, sublingual, or topical routes of administration may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention may be effective
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Oily suspensions may be formulated by suspending the active ingredient in a suitable oil. Oil-in-water emulsions may also be employed.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Pharmaceutical compositions of the present compounds may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed.
  • the compounds of the present invention may also be formulated for administered by inhalation.
  • the compounds of the present invention may also be administered by a transdermal patch by methods known in the art.
  • Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein. The following abbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl; ACN: acetonitrile; DAST: Diethylaminosulfur trifluoride; DCM (CH 2 Cl 2 ): dichloromethane; DIPEA: N,N-diisopropylethylamine; DMA: N,N-dimethylacetamide; DMAP: 4-dimethylaminopyridine; DMF: N,N-dimethylformamide; DMSO: dimethylsulfoxide; DPPF: 1,1′- Bis(dip
  • the compounds of the present invention can be prepared in a variety of fashions.
  • the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • the following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
  • Step 1 Preparation of methyl 6-methylpyrazine-2-carboxylate (1b) To 2-chloro-6- methylpyrazine (1a, 50.0 g, 388.9 mmol) in MeOH (750 mL) was added triethylamine (81.2 mL, 583 mmol), DPPF (6.50 g, 11.7 mmol), and Pd(OAc)2 (2.60 g, 11.7 mmol). The reaction vessel was charged with carbon monoxide and heated to 80°C for 16 hrs at 50PSI CO. The reactions were combined and the mixture was filtered through celite and concentrated.
  • Step 2 Preparation of cis-methyl 6-methylpiperazine-2-carboxylate (1c) To methyl 6- methylpyrazine-2-carboxylate (1b, 50.0 g, 328 mmol) and PtO2 (5.0 g, 22 mmol) in MeOH (500 mL) was added 4M HCl in methanol (205 mL). The reaction vessel was charged with hydrogen and heated to 50°C for 16 hrs at 50PSI hydrogen.
  • Step 3 Preparation of cis-1-(tert-butyl) 3-methyl 5-methylpiperazine-1,3-dicarboxylate (1d)
  • a solution of cis-methyl 6-methylpiperazine-2-carboxylate (1c, 160 g, 692 mmol) in MeOH/H2O (0.8/0.8 L) was added tert-butoxycarbonyl tert-butyl carbonate (151.1 g, 692 mmol) and triethylamine (96.4 mL, 692 mmol) and the resulting mixture was stirred 16hrs at room temperature.
  • Step 4 Preparation of cis-1-(tert-butyl) 3-methyl 4-isobutyryl-5-methylpiperazine-1,3- dicarboxylate (1e)
  • DCM dimethylethylamine
  • isobutyryl chloride 1.34 mL, 12.78 mmol
  • Step 5 Preparation of cis-4-(tert-butoxycarbonyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid
  • Step 6 Preparation of cis-tert-butyl 3-((4-(furan-2-yl)benzyl)carbamoyl)-4-isobutyryl-5- methylpiperazine-1-carboxylate (1g) To a stirred solution of cis-4-(tert-butoxycarbonyl)-1- isobutyryl-6-methylpiperazine-2-carboxylic acid (1f, 1.0 g, 3.18 mmol) and (4-(furan-2- yl)phenyl)methanamine (0.72 g, 4.14 mmol) in DCM (9.0 mL) was added HABT (0.48 g, 3.50 mmol) and EDC (0.73 g, 3.82 mmol).
  • Step 7 Preparation of cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (1h)
  • cis-tert-butyl 3-((4-(furan-2-yl)benzyl)carbamoyl)-4- isobutyryl-5-methylpiperazine-1-carboxylate (1g, 1.49 g, 3.18 mmol)
  • Ethyl acetate (15.0 mL) was chilled in an ice bath to 0°C and saturated with HCl gas.
  • Step 8 Preparation of cis-4-benzyl-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (1-1)
  • benzaldehyde 0.011 g, 0.10 mmol
  • sodium triacetoxyborohydride 0.037 g, 0.17 mmol
  • Step 1 Preparation of 2-fluoro-6-phenoxybenzaldehyde (3b) To a stirred solution of 2,6- difluorobenzaldehyde (3a, 0.200 g, 1.407 mmol) and phenol (0.146 g, 1.548 mmol) in DMF (5 mL), K 2 CO 3 (0.39 g, 2.81 mmol) was added and the mixture was stirred at 15 °C for 12 h. The reaction mixture was brought to room temperature and partitioned between H2O and CH2Cl2.
  • Step 2 Preparation of cis-4-(2-fluoro-6-phenoxybenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl- 6-methylpiperazine-2-carboxamide (3) To the mixture of cis-N-(4-(furan-2-yl)benzyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (1h, 0.020 g, 0.054 mmol) in MeOH (10 mL) was added AcOH (3.10 ⁇ L, 0.054 mmol), the mixture was stirred for 5 min.
  • Step 1 Preparation of 2-ethoxy-6-fluorobenzaldehyde (5b) To a mixture of 2,6- difluorobenzaldehyde (3a, 0.200 g, 1.407 mmol) and NaOH (0.113 g, 2.81 mmol) was added EtOH (10 mL), and the solution was stirred at 15 °C for 12 hours.
  • Step 2 Preparation of (2-(pyridin-4-yloxy)phenyl)methanol (7c)
  • the mixture of NaBH4 (0.233 g, 6.17 mmol), calcium chloride (0.684 g, 6.17 mmol) in THF (5 mL) was stirred at 15 °C for 1 hour under N2, then ethyl 2-(pyridin-4-yloxy)benzoate (7b, 0.10 g, 0.411 mmol) was added to the mixture and then was stirred at 15 °C for 16 hours under N 2 .
  • the mixture was poured into water (10 mL), extracted with DCM, the organic layer were dried over sodium sulfate and then filtered. The filtrate was concentrated in vacuo.
  • Step 3 Preparation of 2-(pyridin-4-yloxy)benzaldehyde (7d) DMSO (0.042 mL, 0.596 mmol) in DCM (5 mL) was added to oxalyl chloride (0.026 mL, 0.298 mmol) in DCM (5 mL) at -78 °C. Then the mixture was stirred at -78 °C for 30 min.
  • Step 4 In an analogous manner to example 3, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-(pyridin-4-yloxy)benzaldehyde (7d) were used to prepare cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(pyridin-4- yloxy)benzyl)piperazine-2-carboxamide (7).
  • Step 2 Preparation of 2-(pyridin-3-ylmethyl)benzaldehyde (8c) (2-formylphenyl)boronic acid (0.20 g, 1.334 mmol), pyridin-3-ylmethyl acetate (8b, 0.202 g, 1.334 mmol), Pd(OAc) 2 (0.006 g, 0.027 mmol) and Ru-phos (0.025 mg, 0.053 mmol) in 2-Propanol (5 mL) and water (0.5 mL) were stirred for 5 min at N2 atmosphere. K 2 CO 3 (0.461 g, 3.33 mmol) was added under N2 atmosphere and stirred for 5 minutes. The suspention was heated to 80 °C for 24 hours.
  • Step 3 In an analogous manner to example 3, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-(pyridin-3-ylmethyl)benzaldehyde (8c) were used to prepare cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(pyridin-4- yloxy)benzyl)piperazine-2-carboxamide (8).
  • Step 2 Preparation of 2-(2-bromobenzyl)oxazole (9c)
  • a mixture of 2-(2-bromophenyl)acetamide (9b, 9.6 g, 44.8 mmol) and 1,3-dioxol-2-one (4.63 g, 53.8 mmol) in polyphosphoric acid (40 mL) was stirred at 170 °C for 3 h.
  • the reaction mixture was added to water (100 mL) and extracted with EtOAc (50 mL x 3). The organic layers were washed with brine (20 mL), dried over Na 2 SO 4 .
  • Step 3 Preparation of 2-(2-vinylbenzyl)oxazole (9d) 25608 To a solution of 2-(2-bromobenzyl)oxazole (9c, 1.0 g, 4.20 mmol), potassium trifluoro(vinyl)borate (1.125 g, 8.40 mmol) and K2CO3 (1.741 g, 12.60 mmol) in Dioxane (15 mL) and H 2 O (5 mL) were added PdCl 2 (dppf) (0.307 g, 0.420 mmol) under N2 protection. The mixture was stirred at 100 °C for 3 hours. The reaction mixture was poured into water (30 mL), and extracted with EtOAc (20 mL x 3).
  • Step 4 Preparation of 2-(oxazol-2-ylmethyl)benzaldehyde (9e) To a solution of 2-(2- vinylbenzyl)oxazole (9d, 0.20 g, 1.08 mmol) in Dioxane (4 mL) was added NaIO4 (0.924 g, 4.32 mmol) in Water (4 mL) and OsO 4 (0.0028 g, 10.80 ⁇ mol) in turn. The reaction mixture was stirred at 16 °C for 15 minutes. To the mixture was added water (10 mL), which was extracted with EtOAc (10 mL x 3).
  • Step 5 In an analogous manner to example 3, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-(oxazol-2-ylmethyl)benzaldehyde (9e) were used to prepare cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(oxazol-2- ylmethyl)benzyl)piperazine-2-carboxamide (9).
  • Step 2 In an analogous manner to example 1-1, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-((4H-1,2,4-triazol-4-yl)methyl)benzaldehyde (10b) were used to prepare cis-4-(2-((4H-1,2,4-triazol-4-yl)methyl)benzyl)-N-(4-(furan-2-yl)benzyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (10).
  • Step 2 In an analogous manner to example 1-1, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-(tetrahydro-2H-pyran-4-yl)benzaldehyde (11b) were used to prepare cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(tetrahydro-2H-pyran-4- yl)benzyl)piperazine-2-carboxamide (11).
  • Step 2 Preparation of 1-(tert-butyl) 3-methyl (3R,5R)-4-benzyl-5-methylpiperazine-1,3- dicarboxylate (12b)
  • Compound 1-(tert-butyl) 3-methyl 4-benzyl-5-methylpiperazine-1,3- dicarboxylate (12a) was seperated by SFC using a Thar 200 preparative SFC (SFC-7) with a ChiralPak IC, 300 ⁇ 50 mm I.D., 10 ⁇ m. column using a 15% IPA/CO2 gradient with a flow rate of 180 mL/min.
  • Step 5 In an analogous manner to example 1f, 1-(tert-butyl) 3-methyl (3R,5R)-4-isobutyryl-5- methylpiperazine-1,3-dicarboxylate (12d) and potassium trimethylsilanolate were used to prepare (2R,6R)-4-(tert-butoxycarbonyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (12e).
  • Step 6 Preparation of tert-butyl (3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazine-1-carboxylate
  • (2R,6R)-4-(tert- butoxycarbonyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (12e, 0.15 g, 0.47 mmol) and (4-(pyrimidin-2-yl)phenyl)methanamine, HCl (0.125 g, 0.56 mmol) in DMF (1.34 mL) was added HATU (0.197 g, 0.52 mmol) and triethylamine (0.196 mL, 1.41 mmol).
  • Step 7 Preparation of (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (12g) To a stirred solution of tert-butyl (3R,5R)-4-isobutyryl-3-methyl-5-((4- (pyrimidin-2-yl)benzyl)carbamoyl)piperazine-1-carboxylate (12f, 0.47 mmol) in EtOAc (3 mL) chilled to 0°C in an ice bath was added HCl gas until saturated.
  • Step 2 In an analogous manner to example 1-1, (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin- 2-yl)benzyl)piperazine-2-carboxamide (12g) and 2-fluoro-6-(2-methoxyphenoxy)benzaldehyde (13a) were used to prepare (2R,6R)-4-(2-fluoro-6-(2-methoxyphenoxy)benzyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (13-1).
  • Step 2 In an analogous manner to example 1-1, (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin- 2-yl)benzyl)piperazine-2-carboxamide (12g) and 3-(2-methoxyphenoxy)picolinaldehyde (14b) were used to prepare (2R,6R)-1-isobutyryl-4-((3-(2-methoxyphenoxy)pyridin-2-yl)methyl)-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (14).
  • Step 2 Preparation of 1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropan-1-ol (16c) To a stirred solution of 2-bromo-3-fluoro-4-methylpyridine (16b, 1.00 g, 5.26 mmol) in THF (13.2 mL) chilled in an ice bath to 0°C under nitrogen was added a 1.3M isopropyl magnesium chloride lithium chloride solution (4.05 mL, 5.26 mmol) dropwise over 5 minutes. The resulting solution 25608 was allowed to warm to room temperature and stirred 3.5 hours.
  • Step 3 Preparation of 2-(1-chloro-3-methoxypropyl)-3-fluoro-4-methylpyridine (16d)
  • thionyl chloride 1.0 mL, 13.70 mmol
  • the resulting solution was heated to 80°C for 1 hour.
  • the mixture was allowed to cool to room temperature and concentrated.
  • the concentrate was taken up in ethyl ether and concentrated to dryness several times.
  • the crude material 2-(1-chloro-3-methoxypropyl)-3-fluoro-4-methylpyridine (16d).
  • Step 4 Preparation of (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1- isobutyryl-6-methylpiperazine-2-carboxylic acid (16e)
  • 2-(1-chloro-3- methoxypropyl)-3-fluoro-4-methylpyridine 16d, 0.223mmol
  • potassium iodide (0.36 g, 2.20 mmol
  • potassium carbonate (0.91 g, 6.58 mmol
  • Step 5 Preparation of (2R,6R)-4-(1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (16-1)
  • the following compounds were prepared in an analogous manner to example 16-1 using the appropriately substituted bromopyridine.
  • Step 1 Preparation of tert-butyl (4-(5-chloro-6-methoxypyridin-2-yl)benzyl)carbamate (17b) To a vial containing (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (17a, 0.20 g, 0.80 mmol), 6-bromo-3-chloro-2-methoxypyridine (0.266 g, 1.195 mmol), Potassium phosphate (0.254 g, 1.195 mmol), and Tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.08 mmol) under nitrogen was added Dioxane (2 mL) and water (2 mL) and the resulting mixture was heated overnight at 80°C.
  • Step 2 In an analogous manner to example 12g, tert-butyl (4-(5-chloro-6-methoxypyridin-2- yl)benzyl)carbamate (17b) and HCl were used to prepare (4-(5-chloro-6-methoxypyridin-2- yl)phenyl)methanamine (17c, 98%).
  • Step 3 In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(5-chloro- 6-methoxypyridin-2-yl)phenyl)methanamine (17c) were used to prepare (2R,6R)-N-(4-(5-chloro- 6-methoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (17).
  • Step 2 In an analogous manner to example 12g, tert-butyl (4-(5-cyclopropyl-6-methoxypyridin- 2-yl)benzyl)carbamate (18a) and HCl were used to prepare (4-(5-cyclopropyl-6-methoxypyridin- 2-yl)phenyl)methanamine (18b).
  • Step 3 In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(5- cyclopropyl-6-methoxypyridin-2-yl)phenyl)methanamine (18b) were used to prepare (2R,6R)-N- 25608 (4-(5-cyclopropyl-6-methoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (18).
  • Step 3 In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(6- methoxy-5-methylpyridin-2-yl)phenyl)methanamine (19b) were used to prepare (2R,6R)-4-((R)- 1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(6-methoxy-5- methylpyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (19).
  • Step 2 In an analogous manner to example 12g, tert-butyl (4-(5-fluoro-6-methoxypyridin-2- yl)benzyl)carbamate (20a) and HCl were used to prepare (4-(5-fluoro-6-methoxypyridin-2- yl)phenyl)methanamine (20b).
  • Step 3 In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(5-fluoro- 6-methoxypyridin-2-yl)phenyl)methanamine (20b) were used to prepare (2R,6R)-4-((R)-1-(3- fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-N-(4-(5-fluoro-6-methoxypyridin-2-yl)benzyl)- 25608 1-isobutyryl-6-methylpiperazine-2-carboxamide (20-1).
  • Step 2 In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(pyridin- 2-yl)phenyl)methanamine (21b) were used to prepare (2R,6R)-4-((R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyridin-2- yl)benzyl)piperazine-2-carboxamide (21).
  • Step 2 In an analogous manner to example 18a, tert-butyl (4-(4-chloro-6-methoxypyridin-2- yl)benzyl)carbamate (22b) and cyclopropyl boronic acid were used to prepare tert-butyl (4-(4- cyclopropyl-6-methoxypyridin-2-yl)benzyl)carbamate (22c).
  • Step 3 In an analogous manner to example 12g, tert-butyl (4-(4-cyclopropyl-6-methoxypyridin- 2-yl)benzyl)carbamate (22c) and HCl were used to prepare (4-(4-cyclopropyl-6-methoxypyridin- 2-yl)phenyl)methanamine (22d).
  • Step 2 In an analogous manner to example 12g, tert-butyl ((2'-fluoro-5'-methoxy-[1,1'-biphenyl]- 4-yl)methyl)carbamate (23a) and HCl were used to prepare (2'-fluoro-5'-methoxy-[1,1'- biphenyl]-4-yl)methanamine (23b).
  • Step 3 In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (2'-fluoro-5'- methoxy-[1,1'-biphenyl]-4-yl)methanamine (23b) were used to prepare (2R,6R)-4-((R)-1-(3- fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-N-((2'-fluoro-5'-methoxy-[1,1'-biphenyl]-4- yl)methyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (23).
  • Step 2 In an analogous manner to example 12g, tert-butyl (4-(6-cyclopropoxypyridin-2- yl)benzyl)carbamate (24a) and HCl were used to prepare (4-(6-cyclopropoxypyridin-2- yl)phenyl)methanamine (24b).
  • Step 3 In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(6- cyclopropoxypyridin-2-yl)phenyl)methanamine (24b) were used to prepare (2R,6R)-N-(4-(6- cyclopropoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)- 1-isobutyryl-6-methylpiperazine-2-carboxamide (24).
  • Step 3 In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(6- methoxypyridin-2-yl)phenyl)methanamine (25b) were used to prepare (2R,6R)-4-((R)-1-(3- fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(6-methoxypyridin-2- yl)benzyl)-6-methylpiperazine-2-carboxamide (25).
  • Step 2 In an analogous manner to example 12g, tert-butyl (4-(3-methoxypyridin-2- yl)benzyl)carbamate (26a) and HCl were used to prepare (4-(3-methoxypyridin-2- yl)phenyl)methanamine (26b).
  • Step 3 In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(3- methoxypyridin-2-yl)phenyl)methanamine (26b) were used to prepare (2R,6R)-4-((R)-1-(3- 25608 fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(3-methoxypyridin-2- yl)benzyl)-6-methylpiperazine-2-carboxamide (26).
  • Step 2 Preparation of tert-butyl 3-((4-(furan-2-yl)benzyl)carbamoyl)-5-methylpiperazine-1- carboxylate (27b)
  • 4-(tert-butoxycarbonyl)-6-methylpiperazine-2- carboxylic acid (27a, 0.47 g, 1.93 mmol) and (4-(furan-2-yl)phenyl)methanamine (0.40 g, 2.32 mmol) in DCM (8.7 mL) and DMSO (0.96 mL) was added HATU (0.88 g, 2.32 mmol) and N- methyl morpholine (0.85 mL, 7.74 mmol).
  • Step 3 In an analogous manner to example 1h, tert-butyl 3-((4-(furan-2-yl)benzyl)carbamoyl)-5- methylpiperazine-1-carboxylate (27b) and HCl in DCM were used to prepare N-(4-(furan-2- yl)benzyl)-6-methylpiperazine-2-carboxamide (27c, Quant.).
  • Step 3 In an analogous manner to example 2-1 N-(4-(furan-2-yl)benzyl)-6-methylpiperazine-2- carboxamide (27c) and 2-(bromomethyl)-1,3-difluorobenzene were used to prepare 4-(2,6- difluorobenzyl)-N-(4-(furan-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (27d, 63%).
  • Step 4 In an analogous manner to example 1e, 4-(2,6-difluorobenzyl)-N-(4-(furan-2-yl)benzyl)- 6-methylpiperazine-2-carboxamide (27d) and cyclopropanecarbonyl chloride in DCM were used to prepare 1-(cyclopropanecarbonyl)-4-(2,6-difluorobenzyl)-N-(4-(furan-2-yl)benzyl)-6- methylpiperazine-2-carboxamide (27).
  • EXAMPLE 28 1-isobutyryl- 6-methyl-N-(4-(prop-1-yn-1-yl)benzyl)piperazine-2-carboxamide (28) Step 1: Preparation of tert-butyl (4-(prop-1-yn-1-yl)benzyl)carbamate (28b) To a vial containing tert-butyl (4-bromobenzyl)carbamate (28a, 0.30 g, 1.05 mmol) and 25608 Tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) under nitrogen was added Dioxane (3.5 mL) and tributyl(prop-1-yn-1-yl)stannane (0.48 ml, 1.57 mmol) and the resulting solution was microwave irradiated at 120°C for 1 hour.
  • Step 3 In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(prop-1- yn-1-yl)phenyl)methanamine (28c) were used to prepare (2R,6R)-4-((R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(prop-1-yn-1- yl)benzyl)piperazine-2-carboxamide (28).
  • Step 3 In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4- (cyclopropylethynyl)phenyl)methanamine (29b) were used to prepare (2R,6R)-N-(4- (cyclopropylethynyl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (29).
  • Step 2 In an analogous manner to example 12g tert-butyl (4-(3,3,3-trifluoroprop-1-yn-1- yl)benzyl)carbamate (30a) and HCl were used to prepare (4-(3,3,3-trifluoroprop-1-yn-1- yl)phenyl)methanamine (30b).
  • Step 2 Preparation of (4-(but-2-yn-1-yl)phenyl)methanamine (31c)
  • tert- butyl (4-(1-hydroxybut-2-yn-1-yl)benzyl)carbamate (31b, 0.106 g, 0.385 mmol) in DCM (4.4 mL) was added triethylsilane (0.12 mL, 0.77 mmol).
  • Trifluoroacetic acid (0.27 ml, 3.46 mmol) was then added dropwise.
  • the resulting mixture was stirred at room temperature for 3 hours, poured into sat. sodium bicarbonate solution and extracted several times with dichloromethane.
  • Step 3 In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(but-2-yn- 1-yl)phenyl)methanamine (31c) were used to prepare (2R,6R)-N-(4-(but-2-yn-1-yl)benzyl)-4- ((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (31).
  • Step 2 Preparation of 2-(4-bromophenyl)-4-methyl-2H-1,2,3-triazole 1-oxide (32c)
  • 2-(2-(4-bromophenyl)hydrazono)propanal oxime (32b, 4.80 g, 18.74 mmol) in Pyridine (200 mL) was added a solution of CuSO4 (5.98 g, 37.5 mmol) in Water (50 mL).
  • the resulting mixture was stirred at 120 °C under N 2 protection for 1.5 hours.
  • the mixture reaction was poured into ice- water (500 mL) and extracted with EtOAc (100 mL ⁇ 3).
  • Step 4 Preparation of 4-(4-methyl-2H-1,2,3-triazol-2-yl)benzonitrile (32e)
  • 2-(4- bromophenyl)-4-methyl-2H-1,2,3-triazole (32d, 1.40 g, 5.88 mmol) and zinc cyanide (1.38 g, 11.76 mmol) in DMF (20 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.68 g, 0.59 mmol).
  • the resulting mixture was stirred at 140 °C under MW for 30 minutes.
  • the reaction mixture was poured into water (100 mL) and extracted with EtOAc (30 mL ⁇ 3).
  • Step 5 Preparation of (4-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanamine (32f)
  • 4-(4-methyl-2H-1,2,3-triazol-2-yl)benzonitrile 32e, 0.85 g, 4.61 mmol
  • MeOH MeOH
  • ammonium hydroxide 1 mL, 4.61 mmol
  • nickel 0.135 g, 2.31 mmol
  • Step 3 In an analogous manner to example 32c, 3-(2-(4-bromophenyl)hydrazono)butan-2-one oxime (33b) was used to prepare 2-(4-bromophenyl)-4,5-dimethyl-2H-1,2,3-triazole 1-oxide (33c).
  • Step 4 In an analogous manner to example 32d, 2-(4-bromophenyl)-4,5-dimethyl-2H-1,2,3- triazole 1-oxide (33c) and triethyl phosphite were used to prepare 2-(4-bromophenyl)-4,5- dimethyl-2H-1,2,3-triazole (33d).
  • Step 5 In an analogous manner to example 32e, 2-(4-bromophenyl)-4,5-dimethyl-2H-1,2,3- triazole (33d) and zinc cyanide were used to prepare 4-(4,5-dimethyl-2H-1,2,3-triazol-2- yl)benzonitrile (33e, 38%).
  • Step 6 In an analogous manner to example 32f, 4-(4,5-dimethyl-2H-1,2,3-triazol-2- yl)benzonitrile (33e) was used to prepare (4-(4,5-dimethyl-2H-1,2,3-triazol-2- yl)phenyl)methanamine (33f).
  • Step 2 Preparation of 1-(3-fluoro-4,6-dimethylpyridin-2-yl)-3-methoxypropan-1-ol (35c)
  • 2-bromo-3-fluoro-4,6-dimethylpyridine 35b, 0.28 g, 1.37 mmol
  • DCM 3.4 mL
  • n-butyl lithium 2.5M, 0.55 mL, 1.37 mmol
  • 3-methoxypropanal (0.12 g, 1.37 mmol) dropwise at -78°C.
  • Step 2 Preparation of 2-(1-bromo-3-methoxypropyl)-1,3,5-trifluorobenzene (36c)
  • a stirred solution of 3-methoxy-1-(2,4,6-trifluorophenyl)propan-1-ol (36b, 0.92 g, 4.18 mmol) in ethyl ether (1 mL) was added pyridine (0.135 mL, 1.67 mmol).
  • PBr3 0.59 mL, 6.27 mmol
  • Step 1 Preparation of 1-(3,5-difluoropyridin-4-yl)-3-methoxypropan-1-ol (37b) To a stirred solution of 3,5-difluoropyridine (37a, 0.5 mL, 5.47 mmol) in THF (15.6 mL) chilled to -78°C was added LDA (2.0M, 3.01 mL, 6.02 mmol). The resulting solution was stirred 1 hour.
  • Trimethylsilyl trifluoromethanesulfonate (0.69 mL, 3.79 mmol) dropwise and the resulting solution was stirred 15 minutes at 0°C, then dimethoxylmethane (0.264 mL, 2.98 mmol) was added and the mixture was allowed to warm to room temperature for 3 hours.
  • the reaction was partitioned between water and dichloromethane. The organic phase was concentrated and extracted several times with ethyl acetate.
  • Step 2 Preparation of 1-(6-chloro-3-fluoropyridin-2-yl)-3-methoxypropan-1-ol (39c) To a stirred solution of 1-(6-chloro-3-fluoropyridin-2-yl)-3-methoxypropan-1-one (39b, 0.47 g, 2.16 mmol) 25608 in THF (4 ml) and MeOH (0.5 mL) chilled to 0°C, was added sodium borohydride (0.08 g, 2.16 mmol) and the resulting mixture was stirred for 1 hour. Brine was added to the solution and the mixture was extracted with ethyl acetate.
  • EXAMPLE 42 isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (42)
  • Step 1 In an analogous manner to example 18a, 1-(6-chloro-3-fluoropyridin-2-yl)-3- methoxypropan-1-ol (39c) and cyclopropyl boronic acid were used to prepare 1-(6-cyclopropyl- 3-fluoropyridin-2-yl)-3-methoxypropan-1-ol (42a, 43%).
  • Step 2 In an analogous manner to example 18a, 1-(4-chloro-3-fluoropyridin-2-yl)-3- methoxypropan-1-ol (45b) and cyclopropyl boronic acid were used to prepare 1-(4-cyclopropyl- 3-fluoropyridin-2-yl)-3-methoxypropan-1-ol (45c, 26%).
  • Step 2 In an analogous manner to example 28b, 1-(2-chloro-5-fluoropyridin-4-yl)-3- methoxypropan-1-ol (47b) and tributyl(prop-1-yn-1-yl)stannane were used to prepare 1-(5- fluoro-2-(prop-1-yn-1-yl)pyridin-4-yl)-3-methoxypropan-1-ol (47c, 91%).
  • Step 2 Preparation of 2-chloro-5-fluoro-4-(3-methoxyprop-1-en-1-yl)pyrimidine (50c) To a solution of 2,4-dichloro-5-fluoropyrimidine (2.0 g, 11.98 mmol) in Dioxane (50 mL) and Water (10 mL) were added 2-(3-methoxyprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50b, 2.97 g, 11.98 mmol), K 2 CO 3 (3.31 g, 23.96 mmol) and PdCl 2 (dppf) (0.175 g, 0.240 mmol).
  • Step 3 Preparation of 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methoxypropan-1-ol (50d)
  • a mixture of 2-chloro-5-fluoro-4-(3-methoxyprop-1-en-1-yl)pyrimidine (50c, 2.3 g, 11.35 mmol), cobalt(ii) acetylacetonate hydrate (0.312 g, 1.135 mmol) and phenylsilane (2.457 g, 22.70 mmol) in THF (20 mL) was stirred at 25 °C under N 2 protection for 15 hours. The reaction was filtered and concentrated.
  • Step 4 Preparation of 1-(5-fluoro-2-methylpyrimidin-4-yl)-3-methoxypropan-1-ol (50e) Na2CO3 (0.60 g, 5.67 mmol) and 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methoxypropan-1-ol (50d, 0.50 g, 2.27 mmol) were combined in a flask, 4-Dioxane (4 mL) / Water (1 mL).2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (341 mg, 2.72 mmol) and PdCl 2 (dppf) (166 mg, 0.227 mmol) were added at 25 °C.
  • 4-Dioxane (4 mL) / Water (1 mL).2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (341 mg, 2.72 mmol) and PdCl 2
  • Step 2 Preparation of (2R,6R)-1-isobutyryl-4-(3-methoxy-1-phenylpropyl)-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (51)
  • (2R,6R)-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (12g, 0.024 g, 0.063 mmol) and 3-methoxy-1-phenylpropan-1-one (51b, 0.041 g, 0.252 mmol) in dichloroethane (0.42 mL) was added solid supported sodium cyanoborohydride 2.51 mmol/g (0.
  • Step 2 Preparation of (bromo(1-(methoxymethyl)cyclobutyl)methyl)benzene (53c)
  • a stirred solution of (1-(methoxymethyl)cyclobutyl)(phenyl)methanol (53b, 0.540 g, 2.62 mmol) in ethyl ether (4 mL) was added pyridine (0.085 mL, 1.05 mmol) and the resulting mixture was chilled in an ice bath.
  • PBr3 (0.37 mL, 3.93 mmol
  • the resulting solution was stirred 30 minutes and allowed to warm to room temperature.
  • Step 1 Preparation of 3-methoxy-1-phenylpropan-1-one (54b) To a stirred solution of propiophenone (54a, 0.66 g, 4.93 mmol) in methanol (3 mL) was added potassium carbonate (0.068 g, 0.493 mmol) and formaldehyde (0.367 mL, 4.93 mmol) and the resulting mixture was stirred 10 days at room temperature.
  • Step 2 Preparation of 3-methoxy-2-methyl-1-phenylpropan-1-ol (54c) To a stirred solution of 3- methoxy-1-phenylpropan-1-one (54b, 0.818 g, 4.59 mmol) in THF (15 mL) and Methanol (1 mL) chilled in an ice bath was added sodium borohydride (0.174 g, 4.59 mmol) and the mixture was stirred for 3 hours.
  • Step 3 In an analogous manner to example 53c, 3-methoxy-2-methyl-1-phenylpropan-1-ol (54c) was used to prepare (1-bromo-3-methoxy-2-methylpropyl)benzene (54d).
  • Step 1 Preparation of N-methoxy-N-methyl-1,4-dioxane-2-carboxamide (60b) To a stirred solution of 1,4-dioxane-2-carboxylic acid (60a, 3.0 g, 22.71 mmol), N,O-dimethylhydroxylamine HCl (2.66 g, 27.2 mmol) and DMAP (0.277 g, 2.27 mmol) in Dichloromethane (65 mL) was added EDC (5.22 g, 27.2 mmol) and triethylamine (3.8 mL, 27.2 mmol).
  • Step 2 In an analogous manner to example 1-1, (2R,6R)-1-isobutyryl-6-methylpiperazine-2- carboxylic acid (16a) and 2-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)benzaldehyde (63a) were used to prepare (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxylic acid (63b, 76%).
  • Step 3 In an analogous manner to example 16-1, (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoropropan- 2-yl)oxy)benzyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (63b) and (4-(pyrimidin-2- yl)phenyl)methanamine, HCl were used to prepare (2R,6R)-4-(2-fluoro-6-((1,1,1- trifluoropropan-2-yl)oxy)benzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine- 2-carboxamide (63, 68%).
  • Step 2 Preparation of (2R,6R)-1-isobutyryl-6-methyl-4-(1-phenylpropyl)-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (68).
  • a catalyst solution prepared by combining Cu(OAc) 2 (1 mg, 5.51 uM), DTBM-SEGPHOS (6.5 mg, 5.51 uM) in THF (0.3 mL) under nitrogen followed by addition of methyldiethoxysilane (29uL, 0.181 mmol). After addition of the catalyst solution, the reaction was heated overnight at 40°C.
  • Step 2 In an analogous manner to example 68, (3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin- 2-yl)benzyl)carbamoyl)piperazin-1-yl benzoate (68a), tert-butyl(cinnamyloxy)dimethylsilane (69b) and R-DTBM-SEGPHOS were used to prepare (2R,6R)-4-((R)-3-((tert- butyldimethylsilyl)oxy)-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (69c) LRMS (
  • Step 3 Preparation of (2R,6R)-4-((R)-3-hydroxy-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (69).
  • Step 2 Preparation of (E)-2-(2,6-difluorostyryl)tetrahydrofuran (74c) A solution of diethyl (2,6- difluorobenzyl)phosphonate (74b, 165 mg, 0.624 mmol) in 4 mL THF was cooled to 0 °C. To this was added 1M NaHMDS (0.625 ml, 0.625 mmol) in THF slowly.
  • Step 4 In an analogous manner to example 68, methyl (2R,6R)-4-(benzoyloxy)-1-isobutyryl-6- methylpiperazine-2-carboxylate (74d), (E)-2-(2,6-difluorostyryl)tetrahydrofuran.
  • Step 5 In an analogous manner to example 1f, methyl (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-2- (tetrahydrofuran-2-yl)ethyl)-1-isobutyryl-6-methylpiperazine-2-carboxylate (74e) and potassium trimethylsilanolate were used to prepare (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-2- (tetrahydrofuran-2-yl)ethyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (74f).
  • Step 3 In an analogous manner to example 1f, methyl (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3- hydroxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylate (75c) and potassium trimethylsilanolate were used to prepare (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3- hydroxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (75d).
  • Step 4 In an analogous manner to example 12f, (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3- hydroxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (75d) and (4-(pyrimidin-2- yl)phenyl)methanamine were used to prepare (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3- hydroxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (75).
  • Step 3 In an analogous manner to example 1f, methyl (2R,6R)-1-isobutyryl-6-methyl-4-((1R)- 4,4,4-trifluoro-3-methyl-1-phenyl-3-((trimethylsilyl)oxy)butyl)piperazine-2-carboxylate (76c) 25608 and potassium trimethylsilanolate were used to prepare (2R,6R)-1-isobutyryl-6-methyl-4-((1R)- 4,4,4-trifluoro-3-hydroxy-3-methyl-1-phenylbutyl)piperazine-2-carboxylic acid (76d).
  • Step 4 In an analogous manner to example 12f, (2R,6R)-1-isobutyryl-6-methyl-4-((1R)-4,4,4- trifluoro-3-hydroxy-3-methyl-1-phenylbutyl)piperazine-2-carboxylic acid (76d) and (4- (pyrimidin-2-yl)phenyl)methanamine were used to prepare (2R,6R)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)-4-((1R)-4,4,4-trifluoro-3-hydroxy-3-methyl-1-phenylbutyl)piperazine-2- carboxamide (76).
  • Step 3 In an analogous manner to example 1f, methyl (2R,6R)-4-((1R)-3-((tert- butyldimethylsilyl)oxy)-1-(2,6-difluorophenyl)butyl)-1-isobutyryl-6-methylpiperazine-2- carboxylate (77b) and potassium trimethylsilanolate were used to prepare (2R,6R)-4-((1R)-1- (2,6-difluorophenyl)-3-hydroxybutyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (77c).
  • Step 4 In an analogous manner to example 12f, (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-3- hydroxybutyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (77c) and (4-(pyrimidin-2- yl)phenyl)methanamine were used to prepare (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-3- hydroxybutyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (77).
  • Step 3 In an analogous manner to example 1f, methyl (2R,6R)-1-isobutyryl-6-methyl-4-((1R)- 4,4,4-trifluoro-1-phenyl-3-((trimethylsilyl)oxy)butyl)piperazine-2-carboxylate (78c) and potassium trimethylsilanolate were used to prepare (2R,6R)-1-isobutyryl-6-methyl-4-((1R)-4,4,4- trifluoro-3-hydroxy-1-phenylbutyl)piperazine-2-carboxylic acid (78d).
  • Step 4 In an analogous manner to example 12f, (2R,6R)-1-isobutyryl-6-methyl-4-((1R)-4,4,4- trifluoro-3-hydroxy-1-phenylbutyl)piperazine-2-carboxylic acid (78d) and (4-(pyrimidin-2- yl)phenyl)methanamine were used to prepare (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)-4-((1R)-4,4,4-trifluoro-3-hydroxy-1-phenylbutyl)piperazine-2-carboxamide (78).
  • Step 2 Preparation of (E)-tert-butyl((4-(2,6-difluorophenyl)-2-methylbut-3-en-2- yl)oxy)dimethylsilane (79b)
  • a solution of (E)-4-(2,6-difluorophenyl)-2-methylbut-3-en-2-ol (79a, 156 mg, 0.787 mmol) in DCM (4 mL) was cooled to 0 °C. To this was added 2,6-lutidine (0.37 mL, 3.18 mmol) then tert-butyldimethylsillyl trifluoromethanesulfonate (0.365 mL, 1.588 mmol).
  • Step 4 In an analogous manner to example 1f, methyl (2R,6R)-4-((R)-3-((tert- butyldimethylsilyl)oxy)-1-(2,6-difluorophenyl)-3-methylbutyl)-1-isobutyryl-6-methylpiperazine- 2-carboxylate (79c) and potassium trimethylsilanolate were used to prepare (2R,6R)-4-((R)-3- ((tert-butyldimethylsilyl)oxy)-1-(2,6-difluorophenyl)-3-methylbutyl)-1-isobutyryl-6- methylpiperazine-2-carboxylic acid (79d).
  • Step 2 Preparation of methyl (S)-2-(2,6-difluorophenyl)-2-((3R,5R)-4-isobutyryl-3-methyl-5- ((4-(pyrimidin-2-yl)benzyl)carbamoyl)piperazin-1-yl)acetate (80b) (S)-2-(2,6-difluorophenyl)-2- ((3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin-2-yl)benzyl)carbamoyl)piperazin-1-yl)acetic acid (80a, 12 mg, 0.022 mmol) was dissolved in DCM (290 ⁇ l) and MeOH (145 ⁇ l).
  • Step 3 Preparation of (2R,6R)-4-((S)-1-(2,6-difluorophenyl)-2-hydroxyethyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (80) methyl 2-(2,6- difluorophenyl)-2-((3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazin-1-yl)acetate (80b, 12 mg, 0.021 mmol) was dissolved in THF (450 ⁇ l) and MeOH (50 ⁇ l).
  • Step 3 In an analogous manner to example 13-5, (2R,6R)-1-isobutyryl-6-methyl-N-(4-(oxazol-2- yl)benzyl)piperazine-2-carboxamide (81b) was used to prepare (2R,6R)-4-(2-((2-ethylpyridin-3- yl)oxy)-6-fluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(oxazol-2-yl)benzyl)piperazine-2- carboxamide (81).
  • Step 2 In an analogous manner to example 1e, tert-butyl 3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazine-1-carboxylate (82a) and acetic anhydride were used to prepare tert-butyl 4-acetyl-3-methyl-5-((4-(pyrimidin-2-yl)benzyl)carbamoyl)piperazine-1-carboxylate (82b).
  • Step 4 In an analogous manner to example 13-1, 1-acetyl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (82c) was used to prepare 1-acetyl-4-(2-(2-ethylphenoxy)-6- fluorobenzyl)-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (82).
  • Step 3 In an analogous manner to example 13-5, (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyridin- 2-yl)benzyl)piperazine-2-carboxamide (83b) was used to prepare (2R,6R)-4-(2-((2-ethylpyridin- 3-yl)oxy)-6-fluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(pyridin-2-yl)benzyl)piperazine-2- carboxamide (83).
  • Example hOX2R_IP IC 50 (nM) Emax (%) 25608 1-7 362.2 99.67 1-8 401.4 99.35 25608 1-38 2969 61.9 1-39 3128 51.65 25608 1-69 16340 47.71 1-70 18210 84.3 25608 10 835.2 101.7 11 871.7 102.2 25608 13-29 112.3 98.87 13-30 114.8 100.7 25608 20-6 9.251 101.3 20-7 12.91 100.3 25608 37 464 100.3 38 454.4 100.2 25608 68 6260 93.41 69 26.2 99.42 While th e invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention.

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Abstract

The present invention is directed to compounds of Formula I which are agonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.

Description

OREXIN RECEPTOR AGONISTS BACKGROUND OF THE INVENTION The orexins (hypocretins) comprise two neuropeptides produced in the hypothalamus: orexin A (OX-A) (a 33 amino acid peptide) and the orexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches for narcolepsy, idiopathic hypersomnia, excessive daytime sleepiness, shift work disorder, obstructive sleep apnea and insomnia (Chemelli R.M. et al., Cell, 1999, 98, 437-451). Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behavior (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins have also been indicated as playing a role in arousal, emotion, energy homeostasis, reward, learning and memory (Peyron, et al., Journal Neurosci., 1998,18(23):9996-100150, Harris, et al., Trends Neurosci., 2006, 29 (10), 571-577). Two orexin receptors have been cloned and characterized in mammals. They belong to the super family of G-protein coupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): the orexin-1 receptor (OX or OX1R) is partially selective for OX-A and the orexin-2 receptor (OX2 or OX2R) is capable of binding OX-A as well as OX-B with similar affinity. The physiological actions in which orexins are presumed to participate are thought to be expressed via one or both of the OX1 receptor and the OX2 receptor as the two subtypes of orexin receptors. SUMMARY OF THE INVENTION The present invention is directed to agonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved. DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to compounds of the formula I: wherein:
Figure imgf000003_0001
Ring A is selected from aryl and heteroaryl; R is independently selected from H, -C 1-6 alkyl, O-C 1-6 alkyl, CF 3 , CHF 2 , CH 2 F, and C 3-6 cycloalkyl; Ra is selected from -C 1-6 alkyl and -C 3-6 cycloalkyl; R 1 is independently selected from: (1) -(CR2)n-heteroaryl, where the heteroaryl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (2) -(CR2)n-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R4, (3) -(CR2)n- C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (4) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (5) -O(CR2)pR 4 , (6) -OR, (7) halo, (8) -OCR2C(O)NR2, (9) -OCR2CF3, (10) -O(CR2)tOCR3, (11) -(CR2)nCN (12) -(CR2)nNR2, (13) -O(CR2)tNR2 (14) -C2-C6 alkenyl, where the alkenyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , and (15) -C2-C6 alkynyl, where the alkynyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ; R 2 is selected from: (1) H, (2) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three substituents selected from R 5 , (3) halo, (4) -(CR2)sOR, (5) -(CR2)sCN (6) -(CR2)sS(O)zR, (7) -(CR2)sC(O)OR, (8) aryl, where the aryl is unsubstituted or substituted with one to three substituents selected from R 5 ; and (9) -(CR2)s-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to three substituents selected from R 5 ; R 3 is independently selected from: (1) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (2) -C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to four substituents independently selected from R7, 25608 (3) aryl, where the aryl is unsubstituted or substituted with one to four substituents independently selected from R7, (4) heteroaryl, where the heteroaryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (5) -(CH2)x-C2-C6 alkenyl, where the alkenyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (6) -(CH2)x-C2-C6 alkynyl, where the alkynyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , and (7) -OCF2CH3; R 4 is independently selected from: (1) H, (2) -C 1-6 alkyl, which is unsubstituted or substituted with one to six substituents independently selected from R6, (3) aryl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (4) heteroaryl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (5) heterocyclyl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (6) halo, (7) -OR, (8) -CN, (9) -S(O)zR, and (10) -C(O)OR; R 5 is independently selected from: (1) halo, (2) -OR, (3) -CN, (4) -S(O)zR, (5) -C(O)OR, (6) -CF3, (7) heterocyclyl, and (8) -C 1-6 alkyl; R6 is independently selected from: H, halo, -OR, -NR2, -CF3, and -C 1-6 alkyl; R7 is independently selected from: halo, -OR, C 3 -C 6 cycloalkyl, -CF 3 , -CHF 2 , -CH 2 F, and -C 1-6 alkyl; m is independently selected from 0, 1, 2, 3 and 4; n is independently selected from 0, 1 and 2; p is independently selected from 0, 1 and 2; s is independently selected from 0, 1, 2 and 3; t is independently selected from 1, 2, 3 and 4; x is independently selected from 0, 1, and 2; and z is independently selected from 0, 1 and 2; or a pharmaceutically acceptable salt thereof. In another embodiment, the instant invention is directed to compounds of the formula 1, wherein: Ring A is selected from pyrazinyl, naphthyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, imidazolyl, quinolinyl, pyradazinyl, phenyl and pyridinyl; Ra is -C 1-6 alkyl; R1 is independently selected from: (1) H, (2) -(CR2)n-heteroaryl, where the heteroaryl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (3) -(CR2)n-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (4) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (5) -O(CR2)pR 4 , (6) -OR, (7) halo, (8) -OCR2C(O)NR2, (9) -OCR2CF3, (10) -O(CR2)tOCR3, (11) -(CR2)nCN (12) -(CR2)nNR2, and (13) -O(CR2)tNR2; R 2 is selected from: (1) H, (2) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three substituents selected from R 5 , (3) halo, (4) -(CR2)sOR, and (5) -(CR2)sC(O)OR; R 3 is independently selected from: (1) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to four substituents independently selected from R7, (2) aryl, where the aryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (3) heteroaryl, where the heteroaryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , and (4) -OCF2CH3; R4 is independently selected from: (1) -C 1-6 alkyl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (2) aryl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (3) heteroaryl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (4) heterocyclyl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 (5) halo, and (6) -OR; R 5 is independently selected from: (1) halo, (2) -OR, (3) -CN, (4) -S(O)zR, (5) -C(O)OR, (6) -CF3, (7) heterocyclyl, and (8) -C 1-6 alkyl; R6 is independently selected from: H, halo, -OR, -NR2, -CF3, and -C 1-6 alkyl; R7 is independently selected from: halo, -OR, C3-C6 cycloalkyl, -CF3, -CHF2, -CH2F, and -C 1-6 alkyl; m is independently selected from 0, 1, 2 and 3; n is independently selected from 0, 1 and 2; p is independently selected from 0, 1 and 2; s is independently selected from 0, 1, 2 and 3; t is independently selected from 1, 2, 3 and 4; x is independently selected from 0, 1, and 2; and z is independently selected from 0, 1 and 2; or a pharmaceutically acceptable salt thereof. In a further embodiment, the instant invention is directed to compounds of the formula 1, wherein: Ring A is selected from phenyl and pyridinyl; Ra is -C 1-6 alkyl; R 1 is independently selected from: (1) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (2) -O(CR2)pR 4 , (3) -OR, and (4) Halo; R 2 is selected from: (1) H, (2) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three substituents selected from R 5 , (3) -(CR2)sOR, and (4) -(CR2)sC(O)OR; R 3 is independently selected from: (1) Heteroaryl which is selected from pyrimidinyl, pyridinyl, or oxazolyl, where the heteroaryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , and (2) -OCF2CH3; or a pharmaceutically acceptable salt thereof. Another embodiment of the instant invention is directed to compounds of the formula IA: and all substituents are as defined
Figure imgf000010_0001
Another embodiment of the instant invention is directed to compounds of the formula IB:
Figure imgf000010_0002
wherein: Ring A is selected from aryl and heteroaryl; 25608 R is independently selected from H, -C 1-6 alkyl, -O-C 1-6 alkyl, -CF 3 , -CHF 2 , -CH 2 F, and -C 3-6 cycloalkyl; R 1 is independently selected from: (1) -(CR2)n-heteroaryl, where the heteroaryl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (2) -(CR2)n-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (3) -(CR 2 ) n - C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (4) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (5) -O(CR2)pR 4 , (6) -OR, (7) halo, (8) -OCR2C(O)NR2, (9) -OCR2CF3, (10) -O(CR2)tOCR3, (11) -(CR2)nCN (12) -(CR2)nNR2, (13) -O(CR2)tNR2 (14) C2-C6 alkenyl, where the alkenyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , and (15) C2-C6 alkynyl, where the alkynyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ; R 2 is selected from: (1) H, (2) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three substituents selected from R 5 , (3) halo, 25608 (4) -(CR2)sOR, (5) -(CR2)sCN (6) -(CR2)sS(O)zR, (7) -(CR2)sC(O)OR, (8) aryl, where the aryl is unsubstituted or substituted with one to three substituents selected from R 5 ; and (9) -(CR2)s-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to three substituents selected from R 5 ; R 3 is independently selected from: (1) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (2) -C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to four substituents independently selected from R7, (3) aryl, where the aryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (4) heteroaryl, where the heteroaryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (5) -(CH2)x-C2-C6 alkenyl, where the alkenyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (6) -(CH2)x-C2-C6 alkynyl, where the alkynyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , and (7) -OCF2CH3; R 4 is independently selected from: (1) hydrogen, (2) -C 1-6 alkyl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (3) aryl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , 25608 (4) heteroaryl, which is unsubstituted or substituted with one to six substituents independently selected from R6, (5) heterocyclyl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (6) halo, (7) -OR, (8) -CN, (9) -S(O)zR, and (10) -C(O)OR; R 5 is independently selected from: (1) halo, (2) -OR, (3) -CN, (4) -S(O)zR, (5) -C(O)OR, (6) -CF3, (7) heterocyclyl, and (8) -C 1-6 alkyl; R6 is independently selected from: H, halo, -OR, -NR2, -CF3, and -C 1-6 alkyl; R7 is independently selected from: halo, -OR, C3-C6 cycloalkyl, -CF3, -CHF2, -CH2F, and -C 1-6 alkyl; m is independently selected from 0, 1, 2, 3 and 4; n is independently selected from 0, 1 and 2; p is independently selected from 0, 1 and 2; s is independently selected from 0, 1, 2 and 3; t is independently selected from 1, 2, 3 and 4; x is independently selected from 0, 1, and 2; and z is independently selected from 0, 1 and 2; 25608 or a pharmaceutically acceptable salt thereof. It is understood that reference herein to “compounds of Formula I” also encompasses compounds of Formula IA and Formula IB, unless otherwise indicated. Certain embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein or a pharmaceutically acceptable salt thereof. Certain embodiments of the present invention include a compound which is selected from: cis-4-benzyl-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (1-1); (2R,6R)-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(morpholin- 4-yl)phenyl]methyl}piperazine-2-carboxamide (1-2); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(2- phenoxyphenyl)methyl]piperazine-2-carboxamide (1-3); 4-[(2,6-difluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-4); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-({2-[(pyridin-3- yl)oxy]phenyl}methyl)piperazine-2-carboxamide (1-5); 4-{[2-(2-amino-2-oxoethoxy)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-6); 4-{[2-fluoro-6-(morpholin-4-yl)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1- (2-methylpropanoyl)piperazine-2-carboxamide (1-7); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(morpholin-4- yl)phenyl]methyl}piperazine-2-carboxamide (1-8); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-({2-[(1H-pyrazol-1- yl)methyl]phenyl}methyl)piperazine-2-carboxamide (1-9); 4-[(3-fluoropyridin-2-yl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-10); 4-[(2-fluoro-6-methoxyphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-11); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-({2-[(pyrazin-2- yl)oxy]phenyl}methyl)piperazine-2-carboxamide (1-12); 25608 4-[(2-fluoro-5-methylphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-13); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-({2-[(pyridin-2- yl)oxy]phenyl}methyl)piperazine-2-carboxamide (1-14); 4-[(2-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-15); N-{[4-(furan-2-yl)phenyl]methyl}-4-{[2-(2-methoxyethoxy)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-16); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(2,2,2- trifluoroethoxy)phenyl]methyl}piperazine-2-carboxamide (1-17); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-({2-[(oxolan-2- yl)methoxy]phenyl}methyl)piperazine-2-carboxamide (1-18); 4-[(2-chloro-6-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-19); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(pyrimidin-2- yl)methyl]piperazine-2-carboxamide (1-20); N-{[4-(furan-2-yl)phenyl]methyl}-4-{[2-(4-hydroxypiperidin-1-yl)phenyl]methyl}-6-methyl-1- (2-methylpropanoyl)piperazine-2-carboxamide (1-21); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(4-methyl-1,3-thiazol-2- yl)methyl]piperazine-2-carboxamide (1-22); N-{[4-(furan-2-yl)phenyl]methyl}-4-[(2-methoxyphenyl)methyl]-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-23); 4-{[2-(difluoromethoxy)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-24); 4-[(2-ethoxyphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-25); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[4-(propan-2-yl)-1,3- thiazol-2-yl]methyl}piperazine-2-carboxamide (1-26); 4-[(2-cyanophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-27); 4-[(3-cyanophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-28); 25608 N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(pyridin-4- yl)phenyl]methyl}piperazine-2-carboxamide (1-29); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(pyridin-2- yl)methyl]piperazine-2-carboxamide (1-30); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(pyridin-3- yl)methyl]piperazine-2-carboxamide (1-31); 4-[(2,3-difluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-32); 4-[(2-fluoro-3-methoxyphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-33); 4-[(2-fluoro-5-methoxyphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-34); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(3-methylphenyl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-35); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(1H-1,2,4-triazol-1- yl)phenyl]methyl}piperazine-2-carboxamide (1-36); N-{[4-(furan-2-yl)phenyl]methyl}-4-[(3-methoxyphenyl)methyl]-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-37); 4-[(3-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-38); 4-[(4-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-39); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2- (trifluoromethoxy)phenyl]methyl}piperazine-2-carboxamide (1-40); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(pyridin-3- yl)phenyl]methyl}piperazine-2-carboxamide (1-41); 4-[(2-fluoro-6-hydroxyphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-42); 4-[(3-chloro-2-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-43); 4-[(2-cyclopropylphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-44); 25608 4-{[2-(cyanomethyl)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-45); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(pyrimidin-5- yl)phenyl]methyl}piperazine-2-carboxamide (1-46); N-{[4-(furan-2-yl)phenyl]methyl}-4-[(2-hydroxyphenyl)methyl]-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-47); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(5-methyl-1,3-thiazol-2- yl)methyl]piperazine-2-carboxamide (1-48); 4-{[3-(dimethylamino)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-49); 4-[(3-fluoropyridin-4-yl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-50); 4-{[2-fluoro-5-(trifluoromethyl)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1- (2-methylpropanoyl)piperazine-2-carboxamide (1-51); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(1H-pyrazol-1- yl)phenyl]methyl}piperazine-2-carboxamide (1-52); 4-{[2-(difluoromethyl)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-53); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(piperidin-1- yl)phenyl]methyl}piperazine-2-carboxamide (1-54); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(pyrrolidin-1- yl)phenyl]methyl}piperazine-2-carboxamide (1-55); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(3-methyl-1,2-oxazol-5-yl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-56); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(5-methyl-1H-pyrazol-3- yl)methyl]piperazine-2-carboxamide (1-57); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(2-methylphenyl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-58); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-({2-[(morpholin-4- yl)methyl]phenyl}methyl)piperazine-2-carboxamide (1-59); 4-({2-[2-(dimethylamino)ethoxy]phenyl}methyl)-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1- (2-methylpropanoyl)piperazine-2-carboxamide (1-60); 25608 N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(2-methyl-1,3-thiazol-5- yl)methyl]piperazine-2-carboxamide (1-61); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(1H-1,2,3-triazol-1- yl)phenyl]methyl}piperazine-2-carboxamide (1-62); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-{[2-(4-methylpiperazin-1-yl)phenyl]methyl}-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-63); 4-[(2-ethylphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-64); 4-{[2-fluoro-3-(trifluoromethyl)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1- (2-methylpropanoyl)piperazine-2-carboxamide (1-65); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2- (trifluoromethyl)phenyl]methyl}piperazine-2-carboxamide (1-66); N-{[4-(furan-2-yl)phenyl]methyl}-4-[(3-hydroxypyridin-2-yl)methyl]-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-67); 4-[(5-cyano-2-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-68); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(pyridin-4- yl)methyl]piperazine-2-carboxamide (1-69); 4-{[2-(dimethylamino)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-70); 4-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-71); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(1-methyl-1H-pyrazol-5- yl)methyl]piperazine-2-carboxamide (1-72); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-73); 4-[(4-cyanophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-74); 4-({2-[(dimethylamino)methyl]phenyl}methyl)-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1- (2-methylpropanoyl)piperazine-2-carboxamide (1-75); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(4-methyl-1H-imidazol-2-yl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-76); 25608 N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(2-methyl-1H-imidazol-4-yl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-77); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(4-methyl-4H-1,2,4- triazol-3-yl)methyl]piperazine-2-carboxamide (1-78); 4-{[4-(dimethylamino)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-79); N-{[4-(furan-2-yl)phenyl]methyl}-4-[(4-methoxyphenyl)methyl]-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-80); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(4-methylphenyl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-81); cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(quinolin-8-ylmethyl)piperazine-2- carboxamide (2-1); 4-[(2,6-difluoro-3-methylphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (2-2); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(2,4,6- trifluorophenyl)methyl]piperazine-2-carboxamide (2-3); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(2,3,5,6- tetrafluorophenyl)methyl]piperazine-2-carboxamide (2-4); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(1,3-thiazol-2- yl)methyl]piperazine-2-carboxamide (2-5); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-(pent-2-yn-1- yl)piperazine-2-carboxamide (2-6); 4-(but-2-yn-1-yl)-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)piperazine- 2-carboxamide (2-7); 4-[(2-bromo-6-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (2-8); 4-[(2-chlorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (2-9); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(pyridazin-3- yl)methyl]piperazine-2-carboxamide (2-10); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(naphthalen-1- yl)methyl]piperazine-2-carboxamide (2-11); 25608 cis-4-(2-fluoro-6-phenoxybenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (3); cis-4-(2-(benzyloxy)-6-fluorobenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine- 2-carboxamide (4); cis-4-(2-ethoxy-6-fluorobenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (5); cis-4-(2-fluoro-6-hydroxybenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (6); cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(pyridin-4-yloxy)benzyl)piperazine-2- carboxamide (7); cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(pyridin-4-yloxy)benzyl)piperazine-2- carboxamide (8); cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(oxazol-2-ylmethyl)benzyl)piperazine- 2-carboxamide (9); cis-4-(2-((4H-1,2,4-triazol-4-yl)methyl)benzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (10); cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(tetrahydro-2H-pyran-4- yl)benzyl)piperazine-2-carboxamide (11); (2R,6R)-4-(2,6-difluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine- 2-carboxamide (12); (2R,6R)-4-(2-fluoro-6-(2-methoxyphenoxy)benzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (13-1) (2R,6R)-4-({2-[(2-ethyl-5-methylpyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-2); (2R,6R)-4-({2-[2-(dimethylamino)phenoxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-3); (2R,6R)-4-{[2-(2-ethylphenoxy)-6-fluorophenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-4); (2R,6R)-4-({2-[(2-ethylpyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-5); (2R,6R)-4-({2-fluoro-6-[2-(trifluoromethyl)phenoxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-6); 25608 (2R,6R)-4-({2-fluoro-6-[(imidazo[1,2-a]pyridin-8-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-7); (2R,6R)-4-({2-[(2,6-dimethylpyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-8); (2R,6R)-4-{[2-(2,6-dimethylphenoxy)-6-fluorophenyl]methyl}-6-methyl-1-(2-methylpropanoyl)- N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-9); (2R,6R)-4-({2-fluoro-6-[(2-methylpyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-10); (2R,6R)-4-({2-fluoro-6-[(3-methoxy-2-methylpyridin-4-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-11); (2R,6R)-4-{[2-fluoro-6-(2-methylphenoxy)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-12); (2R,6R)-4-({2-fluoro-6-[2-(trifluoromethoxy)phenoxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-13); (2R,6R)-4-{[2-(2-chlorophenoxy)-6-fluorophenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-14); (2R,6R)-4-({2-[(6-ethylpyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-15); (2R,6R)-4-({2-[(2-chloro-6-methylpyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-16); (2R,6R)-4-({2-fluoro-6-[(4-methylpyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-17); (2R,6R)-4-{[2-fluoro-6-(2-methoxy-6-methylphenoxy)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-18); (2R,6R)-4-({2-[(6-chloropyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-19); (2R,6R)-4-[(2-fluoro-6-phenoxyphenyl)methyl]-6-methyl-1-(2-methylpropanoyl)-N-{[4- (pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-20); (2R,6R)-4-({2-[(2,6-dichloropyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-21); (2R,6R)-4-({2-fluoro-6-[(4-methoxypyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-22); 25608 (2R,6R)-4-({2-[(2-chloropyrimidin-5-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-23); (2R,6R)-4-({2-fluoro-6-[(6-methylpyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-24); (2R,6R)-4-({2-fluoro-6-[(6-fluoropyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-25); (2R,6R)-4-({2-fluoro-6-[(2-fluoropyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-26); (2R,6R)-4-({2-fluoro-6-[(2-fluoro-6-methylpyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-27); (2R,6R)-4-({2-fluoro-6-[(4-methylpyridin-2-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-28); (2R,6R)-4-({2-fluoro-6-[(5-methoxypyridin-2-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-29); (2R,6R)-4-({2-fluoro-6-[(2-methoxypyridin-4-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-30); (2R,6R)-4-({2-fluoro-6-[(pyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-31); (2R,6R)-4-({2-fluoro-6-[(6-methylpyridin-2-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-32); (2R,6R)-4-({2-fluoro-6-[(5-methylpyridin-2-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-33); (2R,6R)-4-({2-fluoro-6-[(5-methylpyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-34); (2R,6R)-4-({2-fluoro-6-[(2-methoxypyrimidin-5-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-35); (2R,6R)-4-({2-fluoro-6-[(pyridin-2-yl)oxy]phenyl}methyl)-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-36); (2R,6R)-4-(2-fluoro-6-(2-methoxyphenoxy)benzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (14); (2R,6R)-1-isobutyryl-6-methyl-4-(2-phenoxybenzyl)-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (15); 25608 (2R,6R)-4-(1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (16-1); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(1,3-thiazol-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-2); (2R,6R)-N-{[4-(1,1-difluoroethoxy)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)- 3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (16-3); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(1,3-oxazol-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-4); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(2H-1,2,3-triazol-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-5); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-[(4-propylphenyl)methyl]piperazine-2-carboxamide (16-6); (2R,6R)-N-[(4-cyclopropylphenyl)methyl]-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (16-7); (2R,6R)-N-[(4-tert-butylphenyl)methyl]-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (16-8); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(propan-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-9); (2R,6R)-N-[(4-ethylphenyl)methyl]-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (16-10); (2R,6R)-4-[(1R)-1-(3-fluoro-6-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-11); (2R,6R)-4-[(1R)-1-(3-fluoropyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-12); (2R,6R)-4-[(1R)-1-(3,5-difluoropyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-13); (2R,6R)-N-(4-(5-chloro-6-methoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (17); (2R,6R)-N-(4-(5-cyclopropyl-6-methoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (18); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(6- methoxy-5-methylpyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (19); 25608 (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-N-(4-(5-fluoro-6- methoxypyridin-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (20-1); (2R,6R)-N-{[4-(4,6-dimethoxypyridin-2-yl)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl) piperazine-2- carboxamide (20-2); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-N-{[4-(6-methoxy-4- methylpyridin-2-yl) phenyl]methyl}-6-methyl-1-(2-methylpropanoyl) piperazine-2-carboxamide (20-3); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-N-{[4-(4- methoxypyrimidin-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-4); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-N-({4-[6-methoxy-4- (trifluoromethyl)pyridin-2-yl]phenyl}methyl)-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-5); (2R,6R)-N-{[4-(6-ethoxypyridin-2-yl)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (20-6); (2R,6R)-N-{[4-(3,6-dimethoxypyridin-2-yl)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-7); (2R,6R)-N-({4-[6-(difluoromethyl)pyridin-2-yl]phenyl}methyl)-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-8); (2R,6R)-N-[(2'-fluoro-3'-methoxy[1,1'-biphenyl]-4-yl)methyl]-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-9); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-N-{[4-(5-fluoropyrimidin- 2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (20-10); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(thieno[2,3-b]pyridin-6-yl)phenyl]methyl}piperazine-2-carboxamide (20-11); (2R,6R)-N-({4-[6-(difluoromethoxy)pyridin-2-yl]phenyl}methyl)-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-12); 25608 (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-N-{[4-(6-methoxypyrazin- 2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (20-13); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl]methyl}piperazine-2- carboxamide (20-14); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-({4-[6-(trifluoromethoxy)pyridin-2-yl]phenyl}methyl)piperazine-2- carboxamide (20-15); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-N-{[4-(1- methyl-6-oxo-1,6-dihydropyridin-2-yl)phenyl]methyl}-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-16); (2R,6R)-N-{[4-(3-fluoro-6-methoxypyridin-2-yl)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-17); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N- (4-(pyridin-2-yl)benzyl)piperazine-2-carboxamide (21); (2R,6R)-N-(4-(4-cyclopropyl-6-methoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (22); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-N-((2'-fluoro-5'-methoxy- [1,1'-biphenyl]-4-yl)methyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (23); (2R,6R)-N-(4-(6-cyclopropoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (24); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(6- methoxypyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (25); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(3- methoxypyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (26); 1-(cyclopropanecarbonyl)-4-(2,6-difluorobenzyl)-N-(4-(furan-2-yl)benzyl)-6-methylpiperazine- 2-carboxamide (27); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N- (4-(prop-1-yn-1-yl)benzyl)piperazine-2-carboxamide (28); (2R,6R)-N-(4-(cyclopropylethynyl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (29); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N- (4-(3,3,3-trifluoroprop-1-yn-1-yl)benzyl)piperazine-2-carboxamide (30); (2R,6R)-N-(4-(but-2-yn-1-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (31); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N- (4-(4-methyl-2H-1,2,3-triazol-2-yl)benzyl)piperazine-2-carboxamide (32); (2R,6R)-N-(4-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (33); (2R,6R)-4-((R)-1-(3,5-difluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (34); (2R,6R)-4-((R)-1-(3-fluoro-4,6-dimethylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (35-1); (2R,6R)-4-[(1R)-3-methoxy-1-(2,4,6-trifluorophenyl)propyl]-6-methyl-1-(2-methylpropanoyl)- N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (35-2); (2R,6R)-4-{(1R)-1-[3-fluoro-6-(trifluoromethyl)pyridin-2-yl]-3-methoxypropyl}-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (35-3); (2R,6R)-4-[(1R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)- N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamid (35-4); (2R,6R)-4-[(1R)-3-methoxy-1-(pyrimidin-2-yl)propyl]-6-methyl-1-(2-methylpropanoyl)-N-{[4- (pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (35-5); (2R,6R)-1-isobutyryl-4-((R)-3-methoxy-1-(2,4,6-trifluorophenyl)propyl)-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (36); (2R,6R)-4-((R)-1-(3,5-difluoropyridin-4-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (37); (2R,6R)-4-((R)-1-(4-ethyl-3-fluoropyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (38); (2R,6R)-4-((R)-1-(6-chloro-3-fluoropyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (39); (2R,6R)-4-((R)-1-(3-fluoro-5-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N- (4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (40); (2R,6R)-4-((R)-1-(3-fluoro-6-(prop-1-yn-1-yl)pyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (41); (2R,6R)-4-((R)-1-(6-cyclopropyl-3-fluoropyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (42); (2R,6R)-4-((R)-1-(6-ethyl-3-fluoropyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (43); (2R,6R)-4-((R)-1-(3-fluoro-4,5-dimethylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (44); (2R,6R)-4-((R)-1-(4-cyclopropyl-3-fluoropyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (45); (2R,6R)-4-((R)-1-(3-fluoro-4-(prop-1-yn-1-yl)pyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (46); (2R,6R)-4-((R)-1-(5-fluoro-2-(prop-1-yn-1-yl)pyridin-4-yl)-3-methoxypropyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (47); (2R,6R)-4-((R)-1-(3,5-difluoro-2-methylpyridin-4-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (48); (2R,6R)-1-isobutyryl-4-((R)-3-methoxy-1-(pyrazin-2-yl)propyl)-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (49); (2R,6R)-4-((R)-1-(5-fluoro-2-methylpyrimidin-4-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (50); (2R,6R)-1-isobutyryl-4-(3-methoxy-1-phenylpropyl)-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (51); (2R,6R)-4-(3-ethoxy-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (52); (2R,6R)-1-isobutyryl-4-((S)-(1-(methoxymethyl)cyclobutyl)(phenyl)methyl)-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (53); (2R,6R)-1-isobutyryl-4-((1R)-3-methoxy-2-methyl-1-phenylpropyl)-6-methyl-N-(4-(pyrimidin- 2-yl)benzyl)piperazine-2-carboxamide (54); (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (55); (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-(methylthio)propyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (56); (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-3-(methylsulfinyl)propyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (57); 25608 (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-(methylsulfonyl)propyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (58); (2R,6R)-4-((R)-(2,6-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (59); (2R,6R)-4-((1S)-(2,6-difluorophenyl)(1,4-dioxan-2-yl)methyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (60); (2R,6R)-4-((R)-3-cyano-1-(2,6-difluorophenyl)propyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (61); methyl 3-(2,6-difluorophenyl)-3-((3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazin-1-yl)propanoate (62); (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)benzyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (63); (2R,6R)-4-(2-(1-cyclopropyl-2,2,2-trifluoroethoxy)-6-fluorobenzyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (64); (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoro-3,3-dimethylbutan-2-yl)oxy)benzyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (65); (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluorobutan-2-yl)oxy)benzyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (66); (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoro-3-methylbutan-2-yl)oxy)benzyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (67); (2R,6R)-1-isobutyryl-6-methyl-4-(1-phenylpropyl)-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (68); (2R,6R)-4-((R)-3-hydroxy-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (69); (2R,6R)-1-isobutyryl-6-methyl-4-((1R)-1-phenyl-2-(tetrahydrofuran-2-yl)ethyl)-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (70); (2R,6R)-4-((R)-3-(difluoromethoxy)-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (71); (2R,6R)-1-isobutyryl-6-methyl-4-((R)-1-phenyl-3-(trifluoromethoxy)propyl)-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (72); (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)-4-((R)-4,4,4-trifluoro-1- phenylbutyl)piperazine-2-carboxamide (73); 25608 (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-2-(tetrahydrofuran-2-yl)ethyl)-1-isobutyryl-6-methyl-N- (4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (74); (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-hydroxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (75); (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)-4-((1R)-4,4,4-trifluoro-3-hydroxy- 3-methyl-1-phenylbutyl)piperazine-2-carboxamide (76); (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-3-hydroxybutyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (77); (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)-4-((1R)-4,4,4-trifluoro-3-hydroxy- 1-phenylbutyl)piperazine-2-carboxamide (78); (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-hydroxy-3-methylbutyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (79); (2R,6R)-4-((S)-1-(2,6-difluorophenyl)-2-hydroxyethyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin- 2-yl)benzyl)piperazine-2-carboxamide (80); (2R,6R)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(oxazol-2- yl)benzyl)piperazine-2-carboxamide (81); 1-acetyl-4-(2-(2-ethylphenoxy)-6-fluorobenzyl)-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (82); (2R,6R)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(pyridin-2- yl)benzyl)piperazine-2-carboxamide (83); (2R,6R)-N-(4-(1,1-difluoroethoxy)benzyl)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (84); (2R,6R)-N-(4-(2H-1,2,3-triazol-2-yl)benzyl)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (85); and (2R,6R)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1-isobutyryl-N-(4-(6-methoxypyridin- 2-yl)benzyl)-6-methylpiperazine-2-carboxamide (86); or a pharmaceutically acceptable salt thereof. Further embodiments of the present invention include a compound which is selected from 2R,6R)-4-(2-fluoro-6-(2-methoxyphenoxy)benzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (13-1); (2R,6R)-4-({2-[(2-ethyl-5-methylpyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-2); 25608 (2R,6R)-4-({2-[2-(dimethylamino)phenoxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-3); (2R,6R)-4-{[2-(2-ethylphenoxy)-6-fluorophenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-4); (2R,6R)-N-{[4-(1,1-difluoroethoxy)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)- 3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (16-3); (2R,6R)-4-[(1R)-1-(3-fluoro-6-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-11); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(6- methoxy-5-methylpyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (19); (2R,6R)-N-{[4-(4,6-dimethoxypyridin-2-yl)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl) piperazine-2- carboxamide (20-2); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(6- methoxypyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (25); (2R,6R)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(oxazol-2- yl)benzyl)piperazine-2-carboxamide (81); or a pharmaceutically acceptable salt thereof. Further embodiments of the present invention include a compound which is selected from (2R,6R)-N-{[4-(1,1-difluoroethoxy)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)- 3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (16-3); (2R,6R)-4-[(1R)-1-(3-fluoro-6-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-11); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(6- methoxypyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (25); or a pharmaceutically acceptable salt thereof. An embodiment of the present invention includes compounds of Formula I wherein Ring A is selected from: pyrazinyl, naphthyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl, 25608 triazolyl, imidazolyl, quinolinyl, pyradazinyl, phenyl and pyridinyl. A further embodiment of the present invention includes compounds wherein Ring A is selected from: pyrazinyl, naphthyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, imidazolyl, quinolinyl, pyradazinyl, phenyl and pyridinyl. In an embodiment, Ring A is phenyl. In an embodiment, Ring A is pyridinyl. An embodiment of the present invention includes compounds of Formula I wherein R 1 is selected from: (1) -(CR2)n-heteroaryl, where the heteroaryl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (2) -(CR2)n-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (3) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (4) -O(CR2)pR 4 , (5) -OR, (6) halo, (7) -OCR2C(O)NR2, (8) -OCR2CF3, (9) -O(CR2)tOCR3, (10) -(CR2)nCN (11) -(CR2)nNR2, and (12) -O(CR2)tNR2. In a further embodiment, the present invention includes compounds of Formula I wherein R1 is selected from: C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , -O(CR2)pR 4 , halo, -OR, ,-OCR2C(O)NR2, and -OCR 2 CF 3 . In a further embodiment, R1 is selected from halo, -O(CR 2 ) p R4 or C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R4. In an embodiment, R1 is C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 . In an embodiment, R 1 is halo. In an embodiment, R 1 is -O(CR2)pR 4 . In an embodiment, R 1 is -CF3. An embodiment of the present invention includes compounds of Formula I wherein R2 is selected from H, -(CR 2 ) s OR, -C 1-6 alkyl, where the alkyl is unsubstituted or 25608 substituted with one to three substituents selected from R5, and -(CR2)sC(O)OR. In an embodiment, the present invention includes compounds of Formula I wherein R 2 is selected from H, -(CR2)sOR, and -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three substituents selected from R5. In a further embodiment, the present invention includes compounds of Formula I wherein R2 is H, -CF3, or -(CR2)sOR. In a further embodiment, the present invention includes compounds of Formula I wherein R 2 is H or -(CR2)sOR. In an embodiment, the present invention includes compounds of Formula I wherein R 2 is -(CR2)sOR. In an embodiment, the present invention includes compounds of Formula I wherein R2 is H. An embodiment of the present invention includes compounds of Formula I wherein R 3 is selected from (1) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (2) aryl, where the aryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (3) heteroaryl, where the heteroaryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (4) -OCF2CH3. In a further embodiment, the present invention includes compounds of Formula I wherein R 3 is selected from unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted furanyl or -OCF2CH3, wherein pyrimidinyl, pyridinyl, furanyl or oxazolyl is optionally substituted with one to four substituents independently selected from R 7 . An embodiment of the present invention includes compounds of Formula I wherein R4 is selected from -OR, halo, -C1-6alkyl, aryl, heteroaryl, and heterocyclyl, where said alkyl, aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R6. In a further embodiment, the present invention includes compounds of Formula I wherein R 4 is selected from aryl, heteroaryl, and heterocyclyl, where said aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R 6 . In an embodiment, R 4 is selected from phenyl or pyridinyl, 25608 where said phenyl or pyridinyl is unsubstituted or substituted with one to six substituents independently selected from R6. An embodiment of the present invention includes compounds of Formula I wherein m is selected from 0, 1, 2 or 3. An embodiment of the present invention includes compounds of Formula I wherein m is 2. An embodiment of the present invention includes compounds of Formula I wherein m is 1. An embodiment of the present invention includes compounds of Formula I wherein n is selected from 0 or 1. An embodiment of the present invention includes compounds of Formula I wherein n is 0. An embodiment of the present invention includes compounds of Formula I wherein n is 1. An embodiment of the present invention includes compounds of Formula I wherein p is selected from 0 or 1. In an embodiment, the present invention includes compounds of Formula I wherein p is 0. In an embodiment, the present invention includes compounds of Formula I wherein p is 1. An embodiment of the present invention includes compounds of Formula I wherein s is selected from 0, 1, 2 or 3. An embodiment of the present invention includes compounds of Formula I wherein s is 2. An embodiment of the present invention includes compounds of Formula I wherein s is 1. The present invention includes compounds that may contain one or more asymmetric centers. Thus, compounds of the present invention include those that can occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. Likewise, the present invention includes tautomeric forms of the compounds disclosed herein. Formula I shows the structure of the class of compounds without specific stereochemistry. At least some of the chemical names of compounds of the invention as set forth in this application may have been generated on an automated basis by use of commercially available chemical naming software programs, and have not been independently verified. 25608 The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Absolute stereochemistry may also be elucidated through other techniques known in the art, such as cryogenic electron microscopy. Relative stereochemistry may be determined using nuclear magnetic resonance with methods known in the art. Stereochemistry may be assigned by analogy to a set of isomers based on their relative biological activity following the same trend established by a similar stereochemically defined group of isomers. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Compounds of the present invention may also be separated by supercritical fluid chromatography (SFC). Furthermore, some separations required multiple rounds of purifications by the same method of purification and/or an alternative purification system to resolve mixtures into single isomers. Additionally, a mixture may be a mixture of 2 to 4 stereoisomers. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. As appreciated by those of skill in the art, halogen or halo as used herein are intended to include fluoro, chloro, bromo and iodo. Similarly, C 1-6 , as in C 1-6 alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that C 1-6 alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert- butyl, pentyl, and hexyl. As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of 25608 such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In an embodiment of the instant invention, aryl is phenyl or naphthyl. In a further embodiment, aryl is phenyl. The term heterocyclyl, heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The term heterocyclyl, heterocycle or heterocyclic can include heteroaryl moieties when two rings are fused together. Examples of heterocyclic elements include, but are not limited to, azabicyclo[2.2.1]heptanyl, azepanyl, azetidinyl, benzodioxolyl, chromanyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydro-pyrrolo[1,2-b]pyrazolyl, 1,3-dioxolanyl, 1,4-dioxanyl, imidazolidinyl, indolinyl, isochromanyl, isoindolinyl, morpholinyl, oxa-5-azabicyclo[2.2.1]heptanyl, oxetanyl, 2- oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperidinyl, piperazinyl, pyrazolidinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, thiomorpholinyl and the like. In an embodiment, heterocyclyl is selected from azabicyclo[2.2.1]heptanyl, azepanyl, azetidinyl, dihydro-pyrrolo[1,2-b]pyrazolyl, morpholinyl, oxa-5- azabicyclo[2.2.1]heptanyl, piperidyl, piperazinyl, pyrazolidinyl, pyrrolidinyl, pyrrolyl, and tetrahydrofuryl. In another embodiment, heterocyclyl is selected from azabicyclo[2.2.1]heptanyl, azepanyl, azetidinyl, dihydro-pyrrolo[1,2-b]pyrazolyl, oxa-5-azabicyclo[2.2.1]heptanyl, piperazinyl, and pyrrolidinyl. "Heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocyclic elements include, but are not limited to, azepinyl, furanyl, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, 5H-pyrrolo[2,3-b]pyrazinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiazolyl, thienofuryl, thiophenyl, thienothienyl, thienyl, triazinyl, triazolyl and the like. In an embodiment, heteroaryl is selected 25608 from furyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, 5H-pyrrolo[2,3-b]pyrazinyl, tetrazolyl, thiazolyl, thienyl, triazolyl and the like. The present invention also includes all pharmaceutically acceptable isotopic variations of a compound of the Formula I in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Such compounds are identical to those disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2 H and 3 H, carbon such as 11 C, 13 C and 14 C, nitrogen such as 13 N and 15 N, oxygen such as 15 O, 17 O and 18 O, phosphorus such as 32 P, sulfur such as 35 S, fluorine such as 18 F, iodine such as 123 I and 125 I, and chlorine such as 36 Cl. Certain isotopically-labelled compounds of Formula I, for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. An embodiment of the present invention includes compounds that are substituted with a positron emitting isotope. An embodiment of the present invention includes compounds that are substituted with a 11 C isotope. An embodiment of the present invention includes compounds that are substituted with an 18F isotope. In the compounds of the invention, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or 25608 reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically-enriched reagents and/or intermediates. When any variable (e.g., R 1 , R 5 etc.) occurs more than one time in any substituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence unless otherwise specified at the point of definition. One of ordinary skill in the art will recognize that choice of combinations of the various substituents defined in a structural representation, i.e., R1, R2, R5, etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability, and combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject). The compounds of the present invention are limited to stable compounds embraced by Formula I. Those skilled in the art will recognize those instances in which the compounds of the invention may form salts. In such instances, another embodiment provides pharmaceutically acceptable salts of the compounds of the invention. Thus, reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. In addition, when a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the present invention. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates or solvates. Salts derived from pharmaceutically acceptable organic non- toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including 25608 naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like. Particular embodiments include the citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts. Salts of the compounds of the invention may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Exemplifying the invention is the use of the compounds disclosed in the Examples and herein. Specific compounds within the present invention include a compound which is selected from the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual enantiomers or diastereomers thereof. The present invention is also directed to the use of the compounds disclosed herein as agonists of orexin receptor activity. The subject compounds and pharmaceutically acceptable salts thereof are useful in a method of agonizing orexin receptor activity in a subject such as a mammal comprising the administration of an amount of the compound. In addition to primates, especially humans, a variety of other mammals may be administered with a compound of the present invention. The present invention is directed to a compound of the present invention or a pharmaceutically acceptable salt thereof that could be useful in therapy. The present invention may further be directed to a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for agonizing 25608 orexin receptor activity or treating the disorders and diseases noted herein in humans and animals. A subject administered with a compound of the present invention, or a pharmaceutically acceptable salt thereof, is generally a mammal, such as a human being, male or female. The amount of compound administered to the subject is an amount sufficient to agonize the orexin receptor in the subject. In an embodiment, the amount of compound can be an “effective amount”, wherein the subject compound is administered in an amount that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. An effective amount does not necessarily include considerations of toxicity and safety related to the administration of the compound. It is recognized that one skilled in the art may affect neurological and psychiatric disorders associated with orexin receptor activation by treating a subject presently afflicted with the disorders, or by prophylactically treating a subject likely to be afflicted with the disorders, with an effective amount of a compound of the present invention. As used herein, the terms "treatment" and "treating" refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a subject that is predisposed to such disease or disorder. The terms "administration of" and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to to the subject. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. 25608 The utility of the compounds in accordance with the present invention as orexin receptor OX1R and/or OX2R agonists may be readily determined without undue experimentation by methodology well known in the art. Both the OX1R and/or OX2R G-coupled protein receptors (GPCRs) couple through the Gαq signaling pathway, which ultimately promotes calcium mobilization via inositol triphosphate (IP3) production. The half-life of IP-3 is relatively short, being rapidly metabolized to inositol monophosphate (IP-1), which can be readily detected using a commercially available assay kit (IP-One; Cisbio; cat# 621PAPEC) coupled with a cell line expressing the target receptor(s) of interest. The utility of the compounds in accordance with the present invention as orexin receptor OX1R and/or OX2R agonists may be determined utilizing this assay. In a typical experiment, the OX1 and OX2 receptor agonist activity is determined in accordance with the following general experimental method. Chinese hamster ovary (CHO) cells expressing human OX1R and/or the human OX2R were grown in Iscove’s modified DMEM containing glutaMAXTM, 1% G418, 100 U/mL penicillin, 100 μg /mL streptomycin and 10 % heat-inactivated qualified fetal bovine serum (FBS). The OX2R cells were seeded at 10,000 cells/well/50 µL and the OX1R cells were seeded at 20,000 cells/well/50 µL into 384-well white tissue culture plates (Greiner; cat# 781080). All cell/media reagents were from GIBCO- Invitrogen Corp. The seeded cell plate(s) were incubated at 37oC with 5% CO2 and 85% humidity for 20-24 hours. On the day of the assay, assay-ready compound plates were prepared using an acoustic liquid handler (ECHO; Labcyte), which dispensed sufficient volume of test compound stock (10 mM in DMSO) or 100% DMSO to prepare 10 point, ½-log dilutions in a final volume of 202.5 nL/well in all test wells of a 384-well diamond plate (Labcyte). Following completion of assay-ready plates, importantly, the next three steps were performed with minimal delay: 1) 20 µl of 1x stimulation buffer was added to the compound plate using a Multidrop Combi (small cassette, Thermo Fisher Scientific cat# 24073290); 2) culture medium was removed from the cell plate using the Bluewasher plate washer (gentle spin; BlueCatBio); 3) 14 µ l of compound/stimulation buffer mixture was added to the cell plate using a Bravo liquid handler (Agilent) prior to incubating cell plates at 37oC with 5% CO2 and 85% humidity for 1 or 2 hours (OX1R and OX2R, respectively). During this incubation, IP-one detection reagents were prepared (38:1:1 lysis buffer:D2:AB-cryptate reagents). Six µL of mixed detection reagents were added to the cell plate using a Multidrop Combi (small cassette, Thermo Fisher Scientific cat #24073290) and incubated 60 minutes at room temperature in the dark. Fluorescence signal was 25608 detected using an Envision plate reader (Perkin Elmer) [LANCE/DELFIA Dual Enh (Em: APC 665; Ex: Cy5620)]. For each compound, data were fit to a four parameter logistic fit (ActivityBase software) and the EC50 was reported as the inflection point of the resulting curve. Percent effect for each test compound was determined as the percentage of sample raw value/mean max effect, where the mean max effect was derived from the mean raw value of 32 control wells per assay plate (using Orexin A (cat# 003-30) at 1 µM for human OX1R and a reference compound at 1 uM with 100% activity previously established by comparison to Orexin A for human OX2R). The intrinsic orexin receptor agonist activity of a compound which may be used in the present invention may be determined by these assays. All of the final compounds of the following examples had activity in agonizing the human orexin-2 receptor in the aforementioned IPOne assay with an EC 50 of about 0.01 nM to 5000 nM. Additional data is provided in the following Examples. Such a result is indicative of the intrinsic activity of the compounds in use as agonists of orexin-1 receptor and/or the orexin-2 receptor. In general, one of ordinary skill in the art would appreciate that a substance is considered to effectively agonize the orexin receptor if it has an EC 50 in the IPOne assay of less than about 50 μM, or more specifically less than about 1000 nM. The orexin receptors have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species. The compounds of the present invention could therefore potentially have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with orexin receptors, including one or more of the following conditions or diseases: narcolepsy, narcolepsy syndrome accompanied by narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, repeatability hypersomnia, intrinsic hypersomnia, hypersomnia accompanied by daytime hypersomnia, interrupted sleep, sleep apnea, wakefulness, nocturnal myoclonus, disturbances of consciousness, such as coma, REM sleep interruptions, jet-lag, excessive daytime sleepiness, shift workers' sleep disturbances, dyssomnias, sleep disorders, sleep disturbances, hypersomnia associated with depression, emotional/mood disorders, Alzheimer's disease or cognitive impairment, Parkinson’s disease, Guillain-Barre syndrome, Kleine Levin syndrome, and sleep disorders which accompany aging; Alzheimer's sundowning; conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across 25608 time zones and with rotating shift-work schedules; fibromyalgia; cardiac failure; diseases related to bone loss; sepsis; syndromes which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep; conditions which result from a diminished quality of sleep; and other diseases related to general orexin system dysfunction. Thus, in certain embodiments the present invention may provide methods for: treating or controlling narcolepsy, narcolepsy syndrome accompanied by narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, repeatability hypersomnia, intrinsic hypersomnia, hypersomnia accompanied by daytime hypersomnia, interrupted sleep, sleep apnea, disturbances of consciousness, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dyssomnias, night terror, insomnias associated with depression, emotional/mood disorders, Alzheimer's disease or cognitive impairment; treating or controlling sleep disturbances associated with diseases such as neurological disorders including neuropathic pain and restless leg syndrome; treating or controlling addiction disorders; treating or controlling psychoactive substance use and abuse; enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling diabetes and appetite, taste, eating, or drinking disorders; treating or controlling insulin resistance syndrome; treating or controlling hypothalamic diseases; treating or controlling depression; treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling Guillain-Barre syndrome; treating or controlling Klein Levin syndrome; treating or controlling psychosis; treating or controlling dysthymic, mood, psychotic and anxiety disorders; treating side effects or complications due to anesthesia; reversal of anesthesia; reversal of anesthesia following surgery; treating or controlling depression, including major depression and major depression disorder; treating or controlling bipolar disorder; or treating, controlling, ameliorating or reducing the risk of schizophrenia, in a mammalian subject which comprises administering to the subject a compound of the present invention. The compounds of the present invention may also potentially have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of other disorders associated with orexin receptors, including one or more of the following conditions or diseases including enhancing sleep quality, improving sleep quality, increasing sleep efficiency, augmenting sleep maintenance; increasing the value which is calculated from the time that a 25608 subject sleeps divided by the time that a subject is attempting to sleep; improving sleep initiation; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing intermittent wakings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency or duration of REM sleep bouts; altering the timing, frequency or duration of slow wave (i.e., stages 3 or 4) sleep bouts; increasing the amount and percentage of stage 2 sleep; promoting slow wave sleep; enhancing EEG-delta activity during sleep; decreasing nocturnal arousals, especially early morning awakenings; increasing daytime alertness; reducing daytime drowsiness; treating or reducing excessive daytime sleepiness; increasing satisfaction with the intensity of sleep; increasing sleep maintenance; idiopathic insomnia; sleep problems; insomnia; night terror, insomnias associated with depression, emotional/mood disorders, Alzheimer's disease or cognitive impairment, as well as sleep walking and enuresis, and sleep disorders which accompany aging; Alzheimer's sundowning; conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules, conditions due to drugs which cause reductions in REM sleep as a side effect; fibromyalgia; syndromes which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep; conditions which result from a diminished quality of sleep; increasing learning; augmenting memory; increasing retention of memory; eating disorders associated with excessive food intake and complications associated therewith, compulsive eating disorders, obesity (due to any cause, whether genetic or environmental), obesity-related disorders overeating, anorexia, bulimia, cachexia, dysregulated appetite control, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, lung disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoid haemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; sudden death, polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich’s syndrome, GH-deficient subjects, normal variant short stature, Turner’s syndrome, and other pathological conditions showing 25608 reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g., children with acute lymphoblastic leukemia, metabolic syndrome, also known as syndrome X, insulin resistance syndrome, reproductive hormone abnormalities, sexual and reproductive dysfunction, such as impaired fertility, infertility, hypogonadism in males and hirsutism in females, fetal defects associated with maternal obesity, gastrointestinal motility disorders, intestinal motility dyskinesias, obesity-related gastro-esophageal reflux, hypothalmic diseases, hypophysis diseases, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), breathlessness, cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, kidney cancer, increased anesthetic risk, reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy; diseases or disorders where abnormal oscillatory activity occurs in the brain, including depression, migraine, neuropathic pain, Parkinson's disease, psychosis and schizophrenia, as well as diseases or disorders where there is abnormal coupling of activity, particularly through the thalamus; enhancing cognitive function, including cognitive dysfunctions that comprise deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders; treating or controlling Guillain-Barre syndrome; treating or controlling Klein Levin syndrome; treating or controlling psychosis; treating or controlling dysthymic, mood, psychotic and anxiety disorders; treating complications due to anesthesia; enhancing memory; increasing memory retention; increasing immune response; increasing immune function; hot flashes; night sweats; extending life span; schizophrenia; muscle-related disorders that are controlled by the excitation/relaxation rhythms imposed by the neural system such as cardiac rhythm and other disorders of the cardiovascular system; conditions related to proliferation of cells such as vasodilation or vasorestriction and blood pressure; cancer; cardiac arrhythmia; hypertension; congestive heart failure; conditions of the genital/urinary system; disorders of sexual function and fertility; adequacy of renal function; responsivity to anesthetics; mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder, mood disorders due to a general medical condition, and substance-induced mood disorders; affective neurosis; depressive neurosis; anxiety neurosis; anxiety disorders including acute stress disorder, agoraphobia, generalized 25608 anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition; acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington's Chorea; Huntington's disease and Tourette syndrome; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia; hypophysis tumor/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric diskinesia; gastric ulcers; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic- adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; amyotrophic lateral sclerosis; multiple sclerosis; ocular damage; retinopathy; cognitive disorders; idiopathic and drug-induced Parkinson's disease; muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, seizure disorders, absence seisures, complex partial and generalized seizures; Lennox-Gastaut syndrome; cognitive disorders including dementia (associated with Alzheimer’s disease, ischemia, trauma, vascular problems or stroke, HIV disease, Parkinson’s disease, Huntington’s disease, Pick’s disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse); delirium, amnestic disorders or age related cognitive decline; schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced psychotic disorder; dissociative disorders including multiple personality syndromes and psychogenic amnesias; substance-related disorders, substance use, substance abuse, substance seeking, substance reinstatement, all types of psychological and physical addictions and addictive behaviors, reward-related behaviors (including substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder; tolerance, addictive feeding, addictive feeding behaviors, binge/purge feeding behaviors, dependence, withdrawal or relapse from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, morphine, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); appetite, taste, 25608 eating or drinking disorders; movement disorders, including akinesias and akinetic-rigid syndromes (including Parkinson’s disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism-ALS dementia complex and basal ganglia calcification), chronic fatigue syndrome, fatigue, including Parkinson's fatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorder or a circadian rhythm disorder, medication-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Gilles de la Tourette’s syndrome, epilepsy, and dyskinesias [including tremor (such as rest tremor, essential tremor, postural tremor and intention tremor), chorea (such as Sydenham’s chorea, Huntington’s disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including generalised myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), restless leg syndrome and dystonia (including generalised dystonia such as iodiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer’s cramp and hemiplegic dystonia); neurodegenerative disorders including nosological entities such as disinhibition-dementia- parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy; seizure disorders; attention deficit/hyperactivity disorder (ADHD); conduct disorder; migraine (including migraine headache); headache; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection e.g., HIV, post-chemotherapy pain; post-stroke pain; post- operative pain; neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers; Kallman's syndrome (anosmia); asthma; cancer; conditions associated with visceral pain such as irritable bowel syndrome, and angina; eating disorders; urinary incontinence; substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.); psychosis; schizophrenia; anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder); mood disorders (including depression, mania, bipolar disorders); trigeminal neuralgia; hearing loss; tinnitus; neuronal damage including ocular damage; retinopathy; macular degeneration of the eye; emesis; brain edema; pain, including acute and chronic pain states, severe pain, 25608 intractable pain, inflammatory pain, neuropathic pain, post-traumatic pain, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine headache and other diseases related to general orexin system dysfunction. The subject compounds could further be of potential use in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to subjects (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from subject to subject depending upon the nature and severity of disease, the subject's weight, special diets then being followed by a subject, concurrent medication, and other factors which those skilled in the art will recognize. Generally, dosage levels of between 0.0001 to 100 mg/kg. of body weight daily are administered to the subject, e.g., humans, adolescent humans and elderly humans, to obtain effective agonism of orexin receptors. The dosage range will generally be about 0.5 mg to 10.0 g. per subject per day which may be administered in single or multiple doses. In one embodiment, the dosage range will be about 0.5 mg to 500 mg per subject per day; in another embodiment about 0.5 mg to 200 mg per subject per day; and in yet another embodiment about 5 mg to 50 mg per subject per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day. The compounds may be administered once or multiple times during the day. The compounds may be administered upon awakening or 25608 otherwise in the morning, or during waking hours. For example, the compounds may be administered about 1 hour after awakening, about 30 minutes after awakening or immediately after awakening. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is contemplated. However, the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, such as about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s). The compounds of the present invention may be administered in combination with compounds which are known in the art to be useful for treating or controlling narcolepsy, 25608 including e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, gamma- hydroxybutyric acid, sodium oxybate, or other oxybate salts, modafinil, armodafinil, caffeine, and salts thereof, and combinations thereof, and the like, The compounds of the present invention may be administered in combination with compounds which are known in the art to be useful for preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, orexin antagonists, other orexin agonists, prokineticin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone, NGD-2-73, nisobamate, nitrazepam, nortriptyline, ornortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and salts thereof, and combinations thereof, and the like, or the compound of the present invention may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation. In another embodiment, the subject compound may be employed in combination with other compounds which are known in the art, either administered separately or in the same 25608 pharmaceutical compositions, including, but are not limited to: insulin sensitizers including (i) PPARγ antagonists such as glitazones (e.g. ciglitazone; darglitazone; englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone; troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY-300512, and the like); (iii) biguanides such as metformin and phenformin; (b) insulin or insulin mimetics, such as biota, LP-100, novarapid, insulin detemir, insulin lispro, insulin glargine, insulin zinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7) (insulintropin); and GLP-1 (7-36)-NH2); (c) sulfonylureas, such as acetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide; glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such as acarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose; pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14, and the like; (e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, and other statins), (ii) bile acid absorbers/sequestrants, such as cholestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran; Colestid®; LoCholest®, and the like, (ii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iii) proliferator-activater receptor α agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (iv) inhibitors of cholesterol absorption such as stanol esters, beta-sitosterol, sterol glycosides such as tiqueside; and azetidinones such as ezetimibe, and the like, and (acyl CoA:cholesterol acyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide, (v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii) thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; and other fibric acid derivatives, such as Atromid®, Lopid® and Tricor®, and the like, and PPARα agonists as described in WO 97/36579; (g) PPARδ agonists, such as those disclosed in WO 97/28149; (h) PPAR α^δ^agonists, such as muraglitazar, and the compounds disclosed in US 6,414,002; (i) anti-obesity agents, such as (1) growth hormone secretagogues, growth hormone secretagogue receptor agonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429, and L-163,255, and such as those disclosed in U.S. Patent Nos.5,536,716, and 6,358,951, U.S. Patent Application Nos.2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO 02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3) cannabinoid receptor ligands, such as cannabinoid CB1 receptor antagonists or inverse agonists, such as rimonabant, taranabant, AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319 (Solvay), 25608 BAY 65-2520 (Bayer) and those disclosed in U.S. Patent Nos.5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765, WO 98/43636, WO 98/43635, WO 01/09120, WO 98/31227, WO 98/41519, WO 98/37061, WO 00/10967, WO 00/10968, WO97/29079, WO99/02499, WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, WO 02/076949, WO 03/007887, WO 04/048317, and WO 05/000809; (4) anti-obesity serotonergic agents, such as fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5) β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL- 35135A, CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) pancreatic lipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267, lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferyl phosphate, and those disclosed in PCT Application No. WO 01/77094; (7) neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304, LY- 357897, CP-671906, GI-264879A, and those disclosed in U.S. Patent No.6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8) neuropeptide Y5 antagonists, such as GW- 569180A, GW-594884A, GW-587081X, GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, and those disclosed in U.S. Patent Nos.6,057,335; 6,043,246; 6,140,354; 6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332; 6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and 6,723,847, European Patent Nos. EP-01010691, and EP- 01044970; and PCT International Patent Publication Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO 98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO 99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO 02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO 04/002986; and WO 04/031175; (9) melanin-concentrating hormone (MCH) receptor antagonists, such as those disclosed in WO 01/21577 and WO 01/21169; (10) melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such as T-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO 01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO 03/004027; (11) melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists; (12) orexin 25608 receptor antagonists, such as SB-334867-A, and those disclosed in patent publications herein; (13) serotonin reuptake inhibitors such as fluoxetine, paroxetine, and sertraline; (14) melanocortin agonists, such as Melanotan II; (15) Mc4r (melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14 (Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C) agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and those disclosed in U.S. Patent No.3,914,250, and PCT Application Nos. WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19) CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and those discribed in U.S. Patent No.5,739,106; (21) GLP-1 agonists; (22) corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3) modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists, such as hioperamide, 3- (1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), and O-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25) β-hydroxy steroid dehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase) inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram, and cilomilast; (27) phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine) transport inhibitors, such as GW 320659, despiramine, talsupram, and nomifensine; (29) ghrelin receptor antagonists, such as those disclosed in PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (31) leptin derivatives; (32) BRS3 (bombesin receptor subtype 3) agonists such as [D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and [D-Phe6,Phe13]Bn(6- 13)propylamide, and those compounds disclosed in Pept. Sci.2002 Aug; 8(8): 461-75); (33) CNTF (Ciliary neurotrophic factors), such as GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTF derivatives, such as axokine (Regeneron); (35) monoamine reuptake inhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1), 2, or 3 activators, such as phytanic acid, 4-[(E)-2-(5,6,7,8-tetrahydro- 5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoic acid (TTNPB), retinoic acid; (37) thyroid hormone β agonists, such as KB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1) inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; (41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoid antagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44) dipeptidyl peptidase IV (DP- 25608 IV) inhibitors, such as isoleucine thiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, sitagliptin; and the compounds disclosed in US 6,699,871, WO 03/004498; WO 03/004496; EP 1 258476; WO 02/083128; WO 02/062764; WO 03/000250; WO 03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; and WO 03/000181; (46) dicarboxylate transporter inhibitors; (47) glucose transporter inhibitors; (48) phosphate transporter inhibitors; (49) Metformin (Glucophage®); (50) Topiramate (Topimax®); (50) peptide YY, PYY 3-36, peptide YY analogs, derivatives, and fragments such as BIM-43073D, BIM-43004C (Olitvak, D.A. et al., Dig. Dis. Sci.44(3):643-48 (1999)); (51) Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, and cyclo-(28/32)-Ac-[Lys28-Glu32]- (25-36)-pNPY; (52) Neuropeptide Y4 (NPY4) agonists such as pancreatic peptide (PP), and other Y4 agonists such as 1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib, valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522, ABT963, CS502 and GW406381; (55) Neuropeptide Y1 (NPY1) antagonists such as BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56) Opioid antagonists such as nalmefene (Revex ®), 3-methoxynaltrexone, naloxone, naltrexone; (57) 11β HSD-1 (11-beta hydroxy steroid dehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and those disclosed in WO 01/90091, WO 01/90090, WO 01/90092, US 6,730,690 and US 2004-0133011; (58) aminorex; (59) amphechloral; (60) amphetamine; (61) benzphetamine; (62) chlorphentermine; (63) clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67) cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine, (70) N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73) fenproporex; (74) fludorex; (75) fluminorex; (76) furfurylmethylamphetamine; (77) levamfetamine; (78) levophacetoperane; (79) mefenorex; (80) metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83) pentorex; (84) phendimetrazine; (85) phenmetrazine; (86) picilorex; (87) phytopharm 57; and (88) zonisamide., (89) neuromedin U and analogs or derivatives thereof, (90) oxyntomodulin and analogs or derivatives thereof, and (91) Neurokinin-1 receptor antagonists (NK-1 antagonists) such as the compounds disclosed in: U.S. Patent Nos.5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, and 5,637,699. In another embodiment, the subject compound may be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine 25608 oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof. In another embodiment, the subject compound may be employed in combination with anti-Alzheimer's agents; beta-secretase inhibitors, such as verubecestat; gamma-secretase inhibitors; growth hormone secretagogues; recombinant growth hormone; HMG-CoA reductase inhibitors; NSAID's including ibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonists or CB-1 receptor inverse agonists; antibiotics such as doxycycline and rifampin; N- methyl-D-aspartate (NMDA) receptor antagonists, such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H3 antagonists; AMPA agonists; PDE IV inhibitors; GABAA inverse agonists; or neuronal nicotinic agonists. In another embodiment, the subject compound may be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, 25608 nefazodone, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, or the subject compound may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation. In another embodiment, the subject compound may be employed in combination with acetophenazine, alentemol, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene or trifluoperazine. In another embodiment, the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. In another embodiment, the subject compound may be employed in combination with a nicotine agonist or a nicotine receptor partial agonist such as varenicline, opioid antagonists (e.g., naltrexone (including naltrexone depot), antabuse, and nalmefene), dopaminergic agents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidate hydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g., Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g., Adderall®)) and anti-obesity agents, such as apo- B/MTP inhibitors, 11Beta-hydroxy steroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors, peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, β3 adrenergic receptor agonists, dopamine receptor agonists, melanocyte-stimulating hormone receptor analogs, 5-HT2c receptor agonists, melanin 25608 concentrating hormone receptor antagonists, leptin, leptin analogs, leptin receptor agonists, galanin receptor antagonists, lipase inhibitors, bombesin receptor agonists, neuropeptide-Y receptor antagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor antagonists, orexin receptor antagonists, such as suvorexant, other orexin agonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors, human agouti-related protein antagonists, ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, and neuromedin U receptor agonists, and pharmaceutically acceptable salts thereof. In another embodiment, the subject compound may be employed in combination with an agent such as aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; selective serotonin reuptake inhibitor (SSRI); halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof. In another embodiment, the subject compound may be employed in combination with an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the subject compound may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine. The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm- blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention may be effective for use in humans. The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Oily suspensions may be formulated by suspending the active ingredient in a suitable oil. Oil-in-water emulsions may also be employed. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Pharmaceutical compositions of the present compounds may be in the form of a sterile injectable aqueous or oleagenous suspension. The compounds of the present invention may also be administered in the form of suppositories for rectal administration. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed. The compounds of the present invention may also be formulated for administered by inhalation. The compounds of the present invention may also be administered by a transdermal patch by methods known in the art. Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein. The following abbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl; ACN: acetonitrile; DAST: Diethylaminosulfur trifluoride; DCM (CH2Cl2): dichloromethane; DIPEA: N,N-diisopropylethylamine; DMA: N,N-dimethylacetamide; DMAP: 4-dimethylaminopyridine; DMF: N,N-dimethylformamide; DMSO: dimethylsulfoxide; DPPF: 1,1′- Bis(diphenylphosphino)ferrocene; DTBM-SEGPHOS: 5,5′-Bis[di(3,5-di-tert-butyl-4- methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole, [(4R)-(4,4′-bi-1,3-benzodioxole)-5,5′- diyl]bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine]; EA: Ethyl acetate; EDC: N-(3- Dimethylaminopropyl)-N’-ethylcarbodiimide; Et3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; Et3N: Triethylamine; h: hour(s); HABT: 1-Hydroxy-7-azabenzotriazole; HATU: (1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCl: hydrogen chloride; HOBT: hydroxybenzotriazole hydrate; HPLC: high performance liquid chromatography; [IR(DTBBPY)(PPY)2]PF6: [4,4′-Bis(1,1- dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[2-(2-pyridinyl-N)phenyl-C]iridium(III) hexafluorophosphate; LCMS: Liquid chromatography–mass spectrometry; LDA: Lithium diisopropylamide; LRMS: Low resolution Mass Spectrometer; MeOH: methanol; MgSO4: 25608 magnesium sulfate; Ms: methanesulfonyl; MsCl: methanesulfonyl chloride; MTBE: Methyl tertiary-butyl ether; NaHMDS: Sodium bis(trimethylsilyl)amide; [Ni(dtbbpy)(H2O)4]Cl2: Nickel(2+), tetraaqua[4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-κN1,κN1′]-, chloride (1:2); Pd(OAc)2: Palladium(II) acetate; PE: Petroleum ether; PSI: Pressurized sample infusion; R- DTBM-SEGPHOS: (R)-(−)-5,5′-Bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi- 1,3-benzodioxole, [(4R)-(4,4′-bi-1,3-benzodioxole)-5,5′-diyl]bis[bis(3,5-di-tert-butyl-4- methoxyphenyl)phosphine]; S-DTBM-SEGPHOS: (S)-(+)-5,5′-Bis[di(3,5-di-tert-butyl-4- methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole;SOCl2: thionyl chloride; SFC: supercritical fluid chromatography; TBAF: Tetra-n-butylammonium fluoride; TBDMS-Cl: Tert- butyldimethylsilyl chloride; TEA: triethylamine; THF: tetrahydrofuran; TFA: trifluoracetic acid; TLC: Thin-layer chromatography; TMS-CF3: Trifluoromethyltrimethylsilane. The compounds of the present invention can be prepared in a variety of fashions. In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way. EXAMPLES EXAMPLE 1
25608 N N H a b N c O O d
Figure imgf000060_0001
carboxamide (1-1) Step 1: Preparation of methyl 6-methylpyrazine-2-carboxylate (1b) To 2-chloro-6- methylpyrazine (1a, 50.0 g, 388.9 mmol) in MeOH (750 mL) was added triethylamine (81.2 mL, 583 mmol), DPPF (6.50 g, 11.7 mmol), and Pd(OAc)2 (2.60 g, 11.7 mmol). The reaction vessel was charged with carbon monoxide and heated to 80°C for 16 hrs at 50PSI CO. The reactions were combined and the mixture was filtered through celite and concentrated. The crude material was taken up in ethyl acetate and filtered again. Flash column purification using a 0-25% Ethyl acetate/Petroleum ether gradient gave methyl 6-methylpyrazine-2-carboxylate (1b). Step 2: Preparation of cis-methyl 6-methylpiperazine-2-carboxylate (1c) To methyl 6- methylpyrazine-2-carboxylate (1b, 50.0 g, 328 mmol) and PtO2 (5.0 g, 22 mmol) in MeOH (500 mL) was added 4M HCl in methanol (205 mL). The reaction vessel was charged with hydrogen and heated to 50°C for 16 hrs at 50PSI hydrogen. The reactions were combined and the mixture was filtered through celite and concentrated. The crude material was used directly in the next step - cis-methyl 6-methylpiperazine-2-carboxylate (1c). Step 3: Preparation of cis-1-(tert-butyl) 3-methyl 5-methylpiperazine-1,3-dicarboxylate (1d) To a solution of cis-methyl 6-methylpiperazine-2-carboxylate (1c, 160 g, 692 mmol) in MeOH/H2O (0.8/0.8 L) was added tert-butoxycarbonyl tert-butyl carbonate (151.1 g, 692 mmol) and triethylamine (96.4 mL, 692 mmol) and the resulting mixture was stirred 16hrs at room temperature. The reactions were combined and concentrated. The crude material was purified by flash column purification using a 0-50% Ethyl acetate/Petroleum ether gradient to give cis-1- (tert-butyl) 3-methyl 5-methylpiperazine-1,3-dicarboxylate (1d). Step 4: Preparation of cis-1-(tert-butyl) 3-methyl 4-isobutyryl-5-methylpiperazine-1,3- dicarboxylate (1e) To a stirred solution of cis-1-(tert-butyl) 3-methyl 5-methylpiperazine-1,3- dicarboxylate (1d, 3.0 g, 11.61 mmol) in DCM (33.2 mL) was added triethylamine (3.24 mL, 23.2 mmol) and isobutyryl chloride (1.34 mL, 12.78 mmol). The resulting solution was stirred at room temperature for 30min, washed with 1N HCl solution, dried over sodium sulfate and concentrated to give crude cis-1-(tert-butyl) 3-methyl 4-isobutyryl-5-methylpiperazine-1,3- dicarboxylate (1e). LRMS (ES) (M+H)+: observed = 329.3, calculated = 328.4. Step 5: Preparation of cis-4-(tert-butoxycarbonyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (1f) A stirred solution of cis-1-(tert-butyl) 3-methyl 4-isobutyryl-5-methylpiperazine-1,3- dicarboxylate (1e, 3.81 g,11.61 mmol) in THF (39 mL) was chilled in an ice bath to 0°C. To this was added potassium trimethylsilanolate (3.64 g, 25.5 mmol) and the resulting solution was stirred at 0°C for two hours. The reaction was quenched using 1N HCl solution and extracted several times with ethyl acetate. The organic layers were combined and dried over sodium sulfate and concentrated to give cis-4-(tert-butoxycarbonyl)-1-isobutyryl-6-methylpiperazine-2- carboxylic acid (1f) Step 6: Preparation of cis-tert-butyl 3-((4-(furan-2-yl)benzyl)carbamoyl)-4-isobutyryl-5- methylpiperazine-1-carboxylate (1g) To a stirred solution of cis-4-(tert-butoxycarbonyl)-1- isobutyryl-6-methylpiperazine-2-carboxylic acid (1f, 1.0 g, 3.18 mmol) and (4-(furan-2- yl)phenyl)methanamine (0.72 g, 4.14 mmol) in DCM (9.0 mL) was added HABT (0.48 g, 3.50 mmol) and EDC (0.73 g, 3.82 mmol). The resulting mixture was stirred 1 hour, then washed with 1N HCl solution and concentrated. Flash column purification using a 0-50% ethyl acetate /hexane gradient gave cis-tert-butyl 3-((4-(furan-2-yl)benzyl)carbamoyl)-4-isobutyryl-5- methylpiperazine-1-carboxylate (1g). Step 7: Preparation of cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (1h) To a stirred solution of cis-tert-butyl 3-((4-(furan-2-yl)benzyl)carbamoyl)-4- isobutyryl-5-methylpiperazine-1-carboxylate (1g, 1.49 g, 3.18 mmol) in Ethyl acetate (15.0 mL) was chilled in an ice bath to 0°C and saturated with HCl gas. The resulting mixture was stirred for 2 hours and concentrated to give cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) as an HCl salt. LRMS (ES) (M+H)+: observed = 370.3, calculated = 369.4. Step 8: Preparation of cis-4-benzyl-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (1-1) To a stirred solution of cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h, 0.035 g, 0.086 mmol) in DCM (0.5 mL) was added benzaldehyde (0.011 g, 0.10 mmol) and sodium triacetoxyborohydride (0.037 g, 0.17 mmol). The resulting mixture was stirred at room temperature for 30 minutes and concentrated. The crude material was purified by reverse phase purification to give cis-4-benzyl-N-(4-(furan-2- yl)benzyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (1-1). LRMS (ES) (M+H)+: observed = 460.4, calculated = 459.6. The following compounds were prepared in an analogous manner to example 1-1. Table 1 Example Structure Name Calculated Observed M M
Figure imgf000062_0001
25608 1-4 4-[(2,6- 495.574 496.1 difluorophenyl)methyl]
Figure imgf000063_0001
25608 1-8 N-{[4-(furan-2- 544.7 545.1 yl)phenyl]methyl}-6-
Figure imgf000064_0001
25608 1-12 N-{[4-(furan-2- 553.667 554.5 yl)phenyl]methyl}-6-
Figure imgf000065_0001
25608 1-16 O O N-{[4-(furan-2- 533.674 534.5 yl)phenyl]methyl}-4-
Figure imgf000066_0001
25608 1-20 N-{[4-(furan-2- 461.569 462 yl)phenyl]methyl}-6-
Figure imgf000067_0001
25608 1-24 4-{[2- 525.601 526.1 (difluoromethoxy)phen
Figure imgf000068_0001
25608 1-28 4-[(3- 484.603 485.1 cyanophenyl)methyl]-
Figure imgf000069_0001
25608 1-32 4-[(2,3- 495.574 496.1 difluorophenyl)methyl]
Figure imgf000070_0001
25608 1-36 N-{[4-(furan-2- 526.644 527.5 yl)phenyl]methyl}-6-
Figure imgf000071_0001
25608 1-40 N-{[4-(furan-2- 543.591 544 yl)phenyl]methyl}-6-
Figure imgf000072_0001
25608 1-44 4-[(2- 499.659 500.1 cyclopropylphenyl)met
Figure imgf000073_0001
25608 1-48 N-{[4-(furan-2- 480.634 481 yl)phenyl]methyl}-6-
Figure imgf000074_0001
25608 1-52 N-{[4-(furan-2- 525.656 526.5 yl)phenyl]methyl}-6-
Figure imgf000075_0001
25608 1-56 N-{[4-(furan-2- 464.569 465 yl)phenyl]methyl}-6-
Figure imgf000076_0001
25608 1-60 4-({2-[2- 546.716 547.6 (dimethylamino)ethoxy
Figure imgf000077_0001
25608 1-64 4-[(2- 487.648 488.1 ethylphenyl)methyl]-N-
Figure imgf000078_0001
25608 1-68 4-[(5-cyano-2- 502.594 503.1 fluorophenyl)methyl]-
Figure imgf000079_0001
25608 1-72 N-{[4-(furan-2- 463.585 464 yl)phenyl]methyl}-6-
Figure imgf000080_0001
25608 1-76 N-{[4-(furan-2- 463.585 464.1 yl)phenyl]methyl}-6-
Figure imgf000081_0001
25608 1-80 N-{[4-(furan-2- 489.62 490.1 yl)phenyl]methyl}-4-
Figure imgf000082_0002
EXAMPLE 2 Preparation of cis-N-(4-
Figure imgf000082_0001
(quinolin-8- ylmethyl)piperazine-2-carboxamide (2-1) Step 1: To a stirred solution of cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (1h, 0.02 g, 0.049 mmol) in DMF (0.5 mL) was added 8-(bromomethyl)quinoline (0.014 g, 0.10 mmol), Potassium iodide (0.008 g, 0.049 mmol), and triethylamine (0.021 mL, 0.15 mmol). The resulting mixture was stirred at room temperature overnight. The crude material 25608 was purified by reverse phase purification to give cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methyl-4-(quinolin-8-ylmethyl)piperazine-2-carboxamide (2-1, 0.0045 g, 18%). LRMS (ES) (M+H)+: observed = 511.1, calculated = 510.6. The following compounds were prepared in an analogous manner to example 2-1. Ex No Structure Name Calc’d Observed Mass Mass
Figure imgf000083_0001
25608 2-5 N-{[4-(furan-2- 466.607 467.1 yl)phenyl]methyl}-6-
Figure imgf000084_0001
25608 2-9 4-[(2- 494.039 494.1 chlorophenyl)methyl]-N-
Figure imgf000085_0001
EXAMPLE 3
25608
Figure imgf000086_0001
6- methylpiperazine-2-carboxamide (3) Step 1: Preparation of 2-fluoro-6-phenoxybenzaldehyde (3b) To a stirred solution of 2,6- difluorobenzaldehyde (3a, 0.200 g, 1.407 mmol) and phenol (0.146 g, 1.548 mmol) in DMF (5 mL), K2CO3 (0.39 g, 2.81 mmol) was added and the mixture was stirred at 15 °C for 12 h. The reaction mixture was brought to room temperature and partitioned between H2O and CH2Cl2. The organic layer was dried over sodium sulfate, concentrated and purified by prep-TLC (PE: EtOAc = 10:1) to provide 2-fluoro-6-phenoxybenzaldehyde (3b, 0.100 g, 31%). Step 2: Preparation of cis-4-(2-fluoro-6-phenoxybenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl- 6-methylpiperazine-2-carboxamide (3) To the mixture of cis-N-(4-(furan-2-yl)benzyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (1h, 0.020 g, 0.054 mmol) in MeOH (10 mL) was added AcOH (3.10 µL, 0.054 mmol), the mixture was stirred for 5 min. Then 2-fluoro-6- phenoxybenzaldehyde (3b, 0.012 g, 0.054 mmol) was added. The mixture was stirred at 20 °C for 20 min, then NaBH3CN (0.0102 g, 0.162 mmol) was added to the mixture. After stirring for 30 min the mixture was concentrated and the crude product was purified by prep-HPLC (water (10mM NH4HCO3)-ACN) to give cis-4-(2-fluoro-6-phenoxybenzyl)-N-(4-(furan-2-yl)benzyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (3, 0.00976 g, 31%). LRMS (ES) (M+H)+: observed = 570.3, calculated = 569.7. 25608 EXAMPLE 4 Preparation
Figure imgf000087_0001
6- methylpiperazine-2-carboxamide (4) Step 1: Preparation of 2-(benzyloxy)-6-fluorobenzaldehyde (4b) To a stirred solution of 2,6- difluorobenzaldehyde (3a, 0.200 g, 1.407 mmol) and phenylmethanol (0.167 g, 1.548 mmol) in DMA (5 mL) was added Cs2CO3 (0.917 g, 2.81 mmol) and the mixture was stirred at 80 °C for 2 hours. The reaction mixture was brought to room temperature and partitioned between H2O (10 mL) and CH2Cl2 (10 mL). The organic layer was dried over sodium sulfate, concentrated and purified by silica gel chromatography to provide 2-(benzyloxy)-6-fluorobenzaldehyde (4b). Step 2: In an analogous manner to example 3, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-(benzyloxy)-6-fluorobenzaldehyde (4b) were used to prepare cis-4-(2-(benzyloxy)-6-fluorobenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (4) LRMS (ES) (M+H)+: observed = 584.3, calculated = 583.7. EXAMPLE 5
25608
Figure imgf000088_0001
6- methylpiperazine-2-carboxamide (5) Step 1: Preparation of 2-ethoxy-6-fluorobenzaldehyde (5b) To a mixture of 2,6- difluorobenzaldehyde (3a, 0.200 g, 1.407 mmol) and NaOH (0.113 g, 2.81 mmol) was added EtOH (10 mL), and the solution was stirred at 15 °C for 12 hours. The mixture was partitioned between H2O and CH2Cl2, dried over sodium sulfate, concentrated and purified by prep-TLC (PE: EtOAc = 10:1) to provide 2-ethoxy-6-fluorobenzaldehyde (5b) Step 2: In an analogous manner to example 3, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-ethoxy-6-fluorobenzaldehyde (5b) were used to prepare cis-4-(2-ethoxy-6-fluorobenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (5) LRMS (ES) (M+H)+: observed = 522.3, calculated = 521.6.
25608 EXAMPLE 6
Figure imgf000089_0001
6- methylpiperazine-2-carboxamide (6) Step 1: In an analogous manner to example 5b, difluorobenzaldehyde and sodium hydroxide were used to prepare 2-fluoro-6-hydroxybenzaldehyde (6b). Step 2: In an analogous manner to example 3, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-fluoro-6-hydroxybenzaldehyde (6b) were used to prepare cis-4-(2-fluoro-6-hydroxybenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (6) LRMS (ES) (M+H)+: observed = 494.2, calculated = 493.6. EXAMPLE 7
Figure imgf000089_0002
- yloxy)benzyl)piperazine-2-carboxamide (7) 25608 Step 1: Preparation of ethyl 2-(pyridin-4-yloxy)benzoate (7b) To a solution of pyridin-4-ol (0.50 g, 5.26 mmol) in DMF (10 mL) were added K2CO3 (1.45 g, 10.52 mmol) and ethyl 2- fluorobenzoate (0.884 g, 5.26 mmol). The mixture was stirred at 125 °C for 12 hours under N2. The reaction mixture was brought to room temperature and partitioned between H2O (10 mL) and CH2Cl2 (2 times 10 mL), the organic layer was dried by sodium sulfate, concentrated and purified by prep-TLC (DCM:MeOH=10:1) to provide ethyl 2-(pyridin-4-yloxy)benzoate (7b). Step 2: Preparation of (2-(pyridin-4-yloxy)phenyl)methanol (7c) The mixture of NaBH4 (0.233 g, 6.17 mmol), calcium chloride (0.684 g, 6.17 mmol) in THF (5 mL) was stirred at 15 °C for 1 hour under N2, then ethyl 2-(pyridin-4-yloxy)benzoate (7b, 0.10 g, 0.411 mmol) was added to the mixture and then was stirred at 15 °C for 16 hours under N2. The mixture was poured into water (10 mL), extracted with DCM, the organic layer were dried over sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The crude product was purified by prep-TLC (DCM:MeOH=10:1) to give (2-(pyridin-4-yloxy)phenyl)methanol (7c). Step 3: Preparation of 2-(pyridin-4-yloxy)benzaldehyde (7d) DMSO (0.042 mL, 0.596 mmol) in DCM (5 mL) was added to oxalyl chloride (0.026 mL, 0.298 mmol) in DCM (5 mL) at -78 °C. Then the mixture was stirred at -78 °C for 30 min. (2-(pyridin-4-yloxy)phenyl)methanol (7c, 0.030 g, 0.149 mmol) was added to the mixture at -78 °C and stirred at -78 °C for 30 minutes. Triethylamine (0.166 mL, 1.193 mmol) was added to the mixture and the mixture was stirred at - 78 °C for 30 minutes and then 0 °C for 30 minutes. The reaction mixture was poured into water (10 mL) and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 2-(pyridin-4-yloxy)benzaldehyde (7d). Step 4: In an analogous manner to example 3, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-(pyridin-4-yloxy)benzaldehyde (7d) were used to prepare cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(pyridin-4- yloxy)benzyl)piperazine-2-carboxamide (7).
25608 EXAMPLE 8
Figure imgf000091_0001
yloxy)benzyl)piperazine-2-carboxamide (8) Step 1: To a preparation of pyridin-3-ylmethyl acetate (8b) pyridin-3-ylmethanol (0.50 g, 4.58 mmol) in DCM (20 mL) was added pyridine (7.41 mL, 92 mmol) and Ac2O (0.865 mL, 9.16 mmol) at 20 °C for 16 hours. The mixture was concentrated to dryness, and the residue was dissolved in 20 mL of water and extracted DCM. The organic layer was dried by sodium sulfate, filtrated and concentrated to give pyridin-3-ylmethyl acetate (8b). Step 2: Preparation of 2-(pyridin-3-ylmethyl)benzaldehyde (8c) (2-formylphenyl)boronic acid (0.20 g, 1.334 mmol), pyridin-3-ylmethyl acetate (8b, 0.202 g, 1.334 mmol), Pd(OAc) 2 (0.006 g, 0.027 mmol) and Ru-phos (0.025 mg, 0.053 mmol) in 2-Propanol (5 mL) and water (0.5 mL) were stirred for 5 min at N2 atmosphere. K2CO3 (0.461 g, 3.33 mmol) was added under N2 atmosphere and stirred for 5 minutes. The suspention was heated to 80 °C for 24 hours. Then the mixture was filtrated and the filtration was concentrated in vacuo, the crude product was purified by prep-TLC (PE: EtOAc = 2:1) to give 2-(pyridin-3-ylmethyl)benzaldehyde (8c). Step 3: In an analogous manner to example 3, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-(pyridin-3-ylmethyl)benzaldehyde (8c) were used to prepare cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(pyridin-4- yloxy)benzyl)piperazine-2-carboxamide (8). LRMS (ES) (M+H)+: observed = 551.1, calculated = 550.7. 25608 EXAMPLE 9 Preparation
Figure imgf000092_0001
ylmethyl)benzyl)piperazine-2-carboxamide (9) Step 1: Preparation of 2-(2-bromophenyl)acetamide (9b) To a solution of 2-(2- bromophenyl)acetic acid (10.0 g, 46.5 mmol) and DMF (0.576 mL, 7.44 mmol) in toluene (100 mL), sulfurous dichloride (5.81 g, 48.8 mmol) was added. The mixture was heated at 80 °C for 1 hour, then cooled down to 0 °C, 25% Ammmonia (in water) (141 mL, 1628 mmol) was added. The reaction mixture was continued to stir for 30 min, then the precipitate was collected. The precipitate washed with water (50 mL) and pentane (80 mL). The precipitate was dried in a vacuum oven at 50°C to give 2-(2-bromophenyl)acetamide (9b). Step 2: Preparation of 2-(2-bromobenzyl)oxazole (9c) A mixture of 2-(2-bromophenyl)acetamide (9b, 9.6 g, 44.8 mmol) and 1,3-dioxol-2-one (4.63 g, 53.8 mmol) in polyphosphoric acid (40 mL) was stirred at 170 °C for 3 h. The reaction mixture was added to water (100 mL) and extracted with EtOAc (50 mL x 3). The organic layers were washed with brine (20 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, eluent of [0~8]% ethyl acetate/ Petroleum ether gradient @ 40 mL/min) to give 2-(2-bromobenzyl)oxazole (9). LRMS (ES) (M+H)+: observed = 237.9, calculated = 238.0. Step 3: Preparation of 2-(2-vinylbenzyl)oxazole (9d) 25608 To a solution of 2-(2-bromobenzyl)oxazole (9c, 1.0 g, 4.20 mmol), potassium trifluoro(vinyl)borate (1.125 g, 8.40 mmol) and K2CO3 (1.741 g, 12.60 mmol) in Dioxane (15 mL) and H2O (5 mL) were added PdCl2(dppf) (0.307 g, 0.420 mmol) under N2 protection. The mixture was stirred at 100 °C for 3 hours. The reaction mixture was poured into water (30 mL), and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of [5~10]% ethyl acetate/ Petroleum ether gradient @ 40 mL/min) to give 2-(2-vinylbenzyl)oxazole (9d). LRMS (ES) (M+H)+: observed = 186.1, calculated = 185.2. Step 4: Preparation of 2-(oxazol-2-ylmethyl)benzaldehyde (9e) To a solution of 2-(2- vinylbenzyl)oxazole (9d, 0.20 g, 1.08 mmol) in Dioxane (4 mL) was added NaIO4 (0.924 g, 4.32 mmol) in Water (4 mL) and OsO4 (0.0028 g, 10.80 µmol) in turn. The reaction mixture was stirred at 16 °C for 15 minutes. To the mixture was added water (10 mL), which was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with aq.sat.Na2S2O3 (5 mL), dried over Na2SO4, filtered and concentrated to give crude product 2-(oxazol-2- ylmethyl)benzaldehyde (9e). Step 5: In an analogous manner to example 3, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-(oxazol-2-ylmethyl)benzaldehyde (9e) were used to prepare cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(oxazol-2- ylmethyl)benzyl)piperazine-2-carboxamide (9). LRMS (ES) (M+H)+: observed = 541.3, calculated = 540.6. EXAMPLE 10
25608 Preparation of cis-4-(2-((4H-1,2,4-triazol-4-yl)methyl)benzyl)-N-(4-(furan-2-yl)benzyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (10) Step 1: Preparation of 2-((4H-1,2,4-triazol-4-yl)methyl)benzaldehyde (10b) To a solution of (2- ((4H-1,2,4-triazol-4-yl)methyl)phenyl)methanol HCl (10a, 0.30 g, 1.33 mmol) and Hunig’s base (1.74 mL, 9.97 mmol) in DCM (6 mL) and DMSO (1 mL) was added a solution of sulfur trioxide pyridine complex (2.12 g, 13.29 mmol) in DMSO (5 mL) slowly at room temperature. The reaction mixture was stirred for 2 hours at room temperature, diluted with DCM and washed with sat. sodium bicarbonate solution. The organic layer was concentrated and purified by reverse phase purification to give 2-((4H-1,2,4-triazol-4-yl)methyl)benzaldehyde (10b). LRMS (ES) (M+H)+: observed = 188.1, calculated = 187.2. Step 2: In an analogous manner to example 1-1, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-((4H-1,2,4-triazol-4-yl)methyl)benzaldehyde (10b) were used to prepare cis-4-(2-((4H-1,2,4-triazol-4-yl)methyl)benzyl)-N-(4-(furan-2-yl)benzyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (10). LRMS (ES) (M+H)+: observed = 541.5, calculated = 540.6. EXAMPLE 11 Preparation of
Figure imgf000094_0001
2H-pyran-4- yl)benzyl)piperazine-2-carboxamide (11) Step 1: Preparation of 2-(tetrahydro-2H-pyran-4-yl)benzaldehyde (11b) In a clear vial were added 2-(2-bromophenyl)-1,3-dioxolane (11a, 0.162 g, 0.982 mmol), [Ni(dtbbpy)(H2O)4]Cl2 (0.0128 g, 0.033 mmol), 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (0.010 g, 0.013 mmol), 25608 tris(trimethylsilyl)silane (0.20 mL, 0.66 mmol), 2,6-lutidine (0.15 mL, 1.31 mmol) and Dimethoxyethane (6.5 mL) under nitrogen. The resulting mixture was stirred overnight under Kessell lamps with fan cooling. The mixture was then concentrated and taken up in acetonitrile (2 mL) and 1M HCl solution (2 mL). This mixture was allowed to stir at room temperature overnight, extracted with ethyl acetate and the organic phase concentrated. Reverse phase purification provided 2-(tetrahydro-2H-pyran-4-yl)benzaldehyde (11b). Step 2: In an analogous manner to example 1-1, cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (1h) and 2-(tetrahydro-2H-pyran-4-yl)benzaldehyde (11b) were used to prepare cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(tetrahydro-2H-pyran-4- yl)benzyl)piperazine-2-carboxamide (11). LRMS (ES) (M+H)+: observed = 544.6, calculated = 543.7. EXAMPLE 12
Figure imgf000095_0001
yl)benzyl)piperazine-2-carboxamide (12) Step 1: Preparation of 1-(tert-butyl) 3-methyl 4-benzyl-5-methylpiperazine-1,3-dicarboxylate (12a) To a stirred solution of cis-1-(tert-butyl) 3-methyl 5-methylpiperazine-1,3-dicarboxylate (1d, 60.0 g, 232.0 mmol) in DMF (420 mL) was added potassium carbonate (80.3 g, 581.0 25608 mmol) and benzyl bromide (55.2 mL, 464.0 mmol) and resulting mixture was stirred at room temperature for 16 hours. This reaction was run 4 times and combined. The mixture was poured into water and extracted several times with MTBE. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate = 100/1, 5/1). TLC (Petroleum ether / Ethyl acetate = 5:1 to give 1-(tert-butyl) 3-methyl 4-benzyl-5-methylpiperazine-1,3-dicarboxylate (12a). Step 2: Preparation of 1-(tert-butyl) 3-methyl (3R,5R)-4-benzyl-5-methylpiperazine-1,3- dicarboxylate (12b) Compound 1-(tert-butyl) 3-methyl 4-benzyl-5-methylpiperazine-1,3- dicarboxylate (12a) was seperated by SFC using a Thar 200 preparative SFC (SFC-7) with a ChiralPak IC, 300×50 mm I.D., 10 µm. column using a 15% IPA/CO2 gradient with a flow rate of 180 mL/min. The sample was dissolved in 3.5 L of MeOH with 4 mL per injection to give 1- (tert-butyl) 3-methyl (3R,5R)-4-benzyl-5-methylpiperazine-1,3-dicarboxylate (12b) Step 3: Preparation of 1-(tert-butyl) 3-methyl (3R,5R)-5-methylpiperazine-1,3-dicarboxylate (12c) To a stirred solution of 1-(tert-butyl) 3-methyl (3R,5R)-4-benzyl-5-methylpiperazine-1,3- dicarboxylate (12b, 20.0 g, 57.4 mmol) in MeOH (140 mL) was added Pd/C 10% (4.0 g, 57.4 mmol). The reaction was stirred under hydrogen for 5 hours, filtered through celite and concentrated to give 1-(tert-butyl) 3-methyl (3R,5R)-5-methylpiperazine-1,3-dicarboxylate (12c). Step 4: In an analogous manner to example 1e, 1-(tert-butyl) 3-methyl (3R,5R)-5- methylpiperazine-1,3-dicarboxylate (12c) and isobutyryl chloride were used to prepare 1-(tert- butyl) 3-methyl (3R,5R)-4-isobutyryl-5-methylpiperazine-1,3-dicarboxylate (12d). LRMS (ES) (M+H)+: observed = 329.3, calculated = 328.4. Step 5: In an analogous manner to example 1f, 1-(tert-butyl) 3-methyl (3R,5R)-4-isobutyryl-5- methylpiperazine-1,3-dicarboxylate (12d) and potassium trimethylsilanolate were used to prepare (2R,6R)-4-(tert-butoxycarbonyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (12e). LRMS (ES) (M+H)+: observed = 315.3, calculated = 314.4. Step 6: Preparation of tert-butyl (3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazine-1-carboxylate To a stirred solution of (2R,6R)-4-(tert- butoxycarbonyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (12e, 0.15 g, 0.47 mmol) and (4-(pyrimidin-2-yl)phenyl)methanamine, HCl (0.125 g, 0.56 mmol) in DMF (1.34 mL) was added HATU (0.197 g, 0.52 mmol) and triethylamine (0.196 mL, 1.41 mmol). The resulting mixture was stirred at room temperature for 1 hour. The solution was poured into sat. sodium bicarbonate solution and extracted several times with ethyl aceate. The combined organic layers 25608 were concentrated and flash column purification using a 0-100% ethyl acetate/ hexane gradient gave tert-butyl (3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazine-1-carboxylate (12f). Step 7: Preparation of (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (12g) To a stirred solution of tert-butyl (3R,5R)-4-isobutyryl-3-methyl-5-((4- (pyrimidin-2-yl)benzyl)carbamoyl)piperazine-1-carboxylate (12f, 0.47 mmol) in EtOAc (3 mL) chilled to 0°C in an ice bath was added HCl gas until saturated. The resulting solution was stirred at 0°C for 30 minutes and concentrated to give (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin- 2-yl)benzyl)piperazine-2-carboxamide (12g) Step 8: In an analogous manner to example 2-1, (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin- 2-yl)benzyl)piperazine-2-carboxamide (12g) and 2-(bromomethyl)-1,3-difluorobenzene were used to prepare (2R,6R)-4-(2,6-difluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (12). LRMS (ES) (M+H)+: observed = 508.3, calculated = 507.6. EXAMPLE 13 O Preparation of
Figure imgf000097_0001
6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (13-1) Step 1: Preparation of 2-fluoro-6-(2-methoxyphenoxy)benzaldehyde (13a) To a stirred solution of 2,6-difluorobenzaldehyde (3a, 0.200 g, 1.407 mmol) and 2-methoxyphenol (0.175 g, 1.407 mmol) in DMA (4.7 mL) was added K2CO3 (0.58 g, 4.22 mmol) and the mixture was stirred at 120 °C for 20 minutes. The reaction mixture was brought to room temperature and partitioned between 1N HCl and Ethyl acetate. The organic layer was concentrated and flash column 25608 purification using a 0-10% ethyl acetate/ hexane gradient gave 2-fluoro-6-(2- methoxyphenoxy)benzaldehyde (13a). LRMS (ES) (M+H)+: observed = 247.1, calculated = 246.2. Step 2: In an analogous manner to example 1-1, (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin- 2-yl)benzyl)piperazine-2-carboxamide (12g) and 2-fluoro-6-(2-methoxyphenoxy)benzaldehyde (13a) were used to prepare (2R,6R)-4-(2-fluoro-6-(2-methoxyphenoxy)benzyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (13-1). LRMS (ES) (M+H)+: observed = 612.4, calculated = 611.7. The following compounds were prepared in an analogous manner to example 13-1. Example Structure Name Calculated Observed Mass Mass
Figure imgf000098_0001
25608 13-4 (2R,6R)-4-{[2-(2- 609.75 610.5 ethylphenoxy)-6-
Figure imgf000099_0001
25608 13-8 (2R,6R)-4-({2-[(2,6- 610.738 611.5 dimethylpyridin-3-yl)oxy]-6-
Figure imgf000100_0001
25608 yl)phenyl]methyl}piperazine- 2-carboxamide
Figure imgf000101_0001
25608 13-15 (2R,6R)-4-({2-[(6- 610.738 611.5 ethylpyridin-3-yl)oxy]-6-
Figure imgf000102_0001
25608 13-18 (2R,6R)-4-{[2-fluoro-6-(2- 625.75 626.4 methoxy-6-
Figure imgf000103_0001
25608 13-22 (2R,6R)-4-({2-fluoro-6-[(4- 612.71 613.5 methoxypyridin-3-
Figure imgf000104_0001
25608 13-26 (2R,6R)-4-({2-fluoro-6-[(2- 600.674 601.5 fluoropyridin-3-
Figure imgf000105_0001
25608 13-30 (2R,6R)-4-({2-fluoro-6-[(2- 612.71 613.5 methoxypyridin-4-
Figure imgf000106_0001
25608 13-34 (2R,6R)-4-({2-fluoro-6-[(5- 596.711 597.5 methylpyridin-3-
Figure imgf000107_0001
EXAMPLE 14
25608 Preparation of
Figure imgf000108_0001
6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (14) Step 1: In an analogous manner to example 13a, 3-fluoropicolinaldehyde (14a) and 2- methoxyphenol were used to prepare 3-(2-methoxyphenoxy)picolinaldehyde (14b). LRMS (ES) (M+H)+: observed = 230.1, calculated = 229.2. Step 2: In an analogous manner to example 1-1, (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin- 2-yl)benzyl)piperazine-2-carboxamide (12g) and 3-(2-methoxyphenoxy)picolinaldehyde (14b) were used to prepare (2R,6R)-1-isobutyryl-4-((3-(2-methoxyphenoxy)pyridin-2-yl)methyl)-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (14). LRMS (ES) (M+H)+: observed = 595.5, calculated = 594.7. EXAMPLE 15
25608 Preparation of (2R,6R)-1-isobutyryl-6-methyl-4-(2-phenoxybenzyl)-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (15) Step 1: In an analogous manner to example 1-1, (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin- 2-yl)benzyl)piperazine-2-carboxamide (12g) and 2-phenoxybenzaldehyde (15a) were used to prepare (2R,6R)-1-isobutyryl-6-methyl-4-(2-phenoxybenzyl)-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (15). LRMS (ES) (M+H)+: observed = 564.4, calculated = 563.7. EXAMPLE 16
Figure imgf000109_0001
6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (16-1) Step 1: In an analogous manner to example 12g, (2R,6R)-4-(tert-butoxycarbonyl)-1-isobutyryl-6- methylpiperazine-2-carboxylic acid (12e) and HCl were used to prepare (2R,6R)-1-isobutyryl-6- methylpiperazine-2-carboxylic acid (16a). LRMS (ES) (M+H)+: observed = 215.4, calculated = 214.2. Step 2: Preparation of 1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropan-1-ol (16c) To a stirred solution of 2-bromo-3-fluoro-4-methylpyridine (16b, 1.00 g, 5.26 mmol) in THF (13.2 mL) chilled in an ice bath to 0°C under nitrogen was added a 1.3M isopropyl magnesium chloride lithium chloride solution (4.05 mL, 5.26 mmol) dropwise over 5 minutes. The resulting solution 25608 was allowed to warm to room temperature and stirred 3.5 hours. The reacton was rechilled to 0°C and a solution of 3 methoxypropanal (0.47 g, 5.26 mmol) dissolved in THF (1mL) was added dropwise. The resulting mixture was allowed to stir at room temperature overnight, quenched with sat. ammonium chloride solution and extracted several times with ethyl acetate. The organic layers were combined, concentrated, and flash column purification using a 0-50% ethyl acetate/ hexane gradient gave 1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropan-1-ol (16c). LRMS (ES) (M+H)+: observed = 200.1, calculated = 199.2. Step 3: Preparation of 2-(1-chloro-3-methoxypropyl)-3-fluoro-4-methylpyridine (16d) To a vial containing 1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropan-1-ol (16c, 0.444 g, 0.223 mmol) was added thionyl chloride (1.0 mL, 13.70 mmol) dropwise. The resulting solution was heated to 80°C for 1 hour. The mixture was allowed to cool to room temperature and concentrated. The concentrate was taken up in ethyl ether and concentrated to dryness several times. The crude material 2-(1-chloro-3-methoxypropyl)-3-fluoro-4-methylpyridine (16d). Step 4: Preparation of (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1- isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) To a vial containing 2-(1-chloro-3- methoxypropyl)-3-fluoro-4-methylpyridine (16d, 0.223mmol), potassium iodide (0.36 g, 2.20 mmol), potassium carbonate (0.91 g, 6.58 mmol), and (2R,6R)-1-isobutyryl-6-methylpiperazine- 2-carboxylic acid (16a, 0.55 g, 2.20 mmol) was added acetonitrile (3.65 mL). The resulting mixture was stirred at 80°C overnight. The mixture was filtered through celite and concentrated. The crude material was purified by reverse phase purification to give (2R,6R)-4-((R)-1-(3-fluoro- 4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e). LRMS (ES) (M+H)+: observed = 396.3, calculated = 395.5. Step 5: Preparation of (2R,6R)-4-(1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (16-1) To a stirred solution of (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6- methylpiperazine-2-carboxylic acid (16e, 0.010 g, 0.02 mmol) and (4-(pyrimidin-2- yl)phenyl)methanamine (0.006 g, 0.02 mmol) in DMF (0.07 mL) was added HATU (0.008 g, 0.022 mmol) followed by triethylamine (0.008 mL, 0.06 mmol). The resulting solution was stirred 1 hour and purified by reverse phase purification to give (2R,6R)-4-(1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (16-1). LRMS (ES) (M+H)+: observed = 585.5, calculated = 562.7. 25608 The following compounds were prepared in an analogous manner to example 16-1. Example Structure Name Calculated Observed Mass Mass
Figure imgf000111_0001
25608 16-5 (2R,6R)-4-[(1R)-1-(3- 551.67 552.4 fluoro-4-methylpyridin-
Figure imgf000112_0001
25608 methyl-1-(2- methylpropanoyl)pipera
Figure imgf000113_0001
The following compounds were prepared in an analogous manner to example 16-1 using the appropriately substituted bromopyridine. Example Structure Name Calculated Observed
Figure imgf000113_0002
25608 16-11 (2R,6R)-4-[(1R)-1-(3- 562.693 563.6 fluoro-6-methylpyridin-2-
Figure imgf000114_0001
EXAMPLE 17
25608
Figure imgf000115_0001
fluoro-4- methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (17) Step 1: Preparation of tert-butyl (4-(5-chloro-6-methoxypyridin-2-yl)benzyl)carbamate (17b) To a vial containing (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (17a, 0.20 g, 0.80 mmol), 6-bromo-3-chloro-2-methoxypyridine (0.266 g, 1.195 mmol), Potassium phosphate (0.254 g, 1.195 mmol), and Tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.08 mmol) under nitrogen was added Dioxane (2 mL) and water (2 mL) and the resulting mixture was heated overnight at 80°C. The mixture was allowed to cool to room temperature and concentrated. The crude material was partitioned between water and ethyl acetate. The organic phase was concentrated and flash column purification using a 0-30% ethyl acetate/ hexane gradient gave tert-butyl (4-(5-chloro-6-methoxypyridin-2-yl)benzyl)carbamate (17b). LRMS (ES) (M+H)+: observed = 349.2, calculated = 348.8. Step 2: In an analogous manner to example 12g, tert-butyl (4-(5-chloro-6-methoxypyridin-2- yl)benzyl)carbamate (17b) and HCl were used to prepare (4-(5-chloro-6-methoxypyridin-2- yl)phenyl)methanamine (17c, 98%). LRMS (ES) (M+H)+: observed = 249.1, calculated = 248.7. Step 3: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(5-chloro- 6-methoxypyridin-2-yl)phenyl)methanamine (17c) were used to prepare (2R,6R)-N-(4-(5-chloro- 6-methoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (17). LRMS (ES) (M+H)+: observed = 627.4, calculated = 626.2. 25608 EXAMPLE 18 O O F O
Figure imgf000116_0001
1-(3-fluoro- 4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (18) Step 1: Preparation of tert-butyl (4-(5-cyclopropyl-6-methoxypyridin-2-yl)benzyl)carbamate (18a) To a vial containing tert-butyl (4-(5-chloro-6-methoxypyridin-2-yl)benzyl)carbamate (17b, 0.06 g, 0.172 mmol), cyclopropyl boronic acid (0.022 g, 0.258 mmol), Potassium carbonate (0.036 g, 0.258 mmol), and Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.014 g, 0.017 mmol) under nitrogen was added Dioxane (0.43 mL) and water (0.43 mL) and the resulting mixture was heated overnight at 90°C. The mixture was allowed to cool to room temperature and concentrated. The crude material was partitioned between water and ethyl acetate. The organic phase was concentrated and flash column purification using a 0-20% ethyl acetate/ hexane gradient gave tert-butyl (4-(5- cyclopropyl-6-methoxypyridin-2-yl)benzyl)carbamate (18a). LRMS (ES) (M+H)+: observed = 355.3, calculated = 354.5. Step 2: In an analogous manner to example 12g, tert-butyl (4-(5-cyclopropyl-6-methoxypyridin- 2-yl)benzyl)carbamate (18a) and HCl were used to prepare (4-(5-cyclopropyl-6-methoxypyridin- 2-yl)phenyl)methanamine (18b). LRMS (ES) (M+H)+: observed = 255.1, calculated = 254.3. Step 3: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(5- cyclopropyl-6-methoxypyridin-2-yl)phenyl)methanamine (18b) were used to prepare (2R,6R)-N- 25608 (4-(5-cyclopropyl-6-methoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (18). LRMS (ES) (M+H)+: observed = 632.4, calculated = 631.8. EXAMPLE 19
Figure imgf000117_0001
-1-isobutyryl- N-(4-(6-methoxy-5-methylpyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (19) Step 1: In an analogous manner to example 18a, tert-butyl (4-(5-chloro-6-methoxypyridin-2- yl)benzyl)carbamate (17b) and Trimethylboroxine were used to prepare tert-butyl (4-(6-methoxy- 5-methylpyridin-2-yl)benzyl)carbamate (19a). LRMS (ES) (M+H)+: observed = 329.2, calculated = 328.4. Step 2: In an analogous manner to example 12g, tert-butyl (4-(6-methoxy-5-methylpyridin-2- yl)benzyl)carbamate (19a) and HCl were used to prepare (4-(6-methoxy-5-methylpyridin-2- yl)phenyl)methanamine (19b). LRMS (ES) (M+H)+: observed = 229.1, calculated = 228.3. Step 3: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(6- methoxy-5-methylpyridin-2-yl)phenyl)methanamine (19b) were used to prepare (2R,6R)-4-((R)- 1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(6-methoxy-5- methylpyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (19). LRMS (ES) (M+H)+: observed = 606.5, calculated = 605.8. 25608 EXAMPLE 20
Figure imgf000118_0001
-N-(4-(5- fluoro-6-methoxypyridin-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (20-1) Step 1: Preparation of tert-butyl (4-(5-fluoro-6-methoxypyridin-2-yl)benzyl)carbamate (20a) To a vial containing (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (17a, 0.15 g, 0.60 mmol), 6-bromo-3-fluoro-2-methoxypyridine (0.185 g, 0.90 mmol), Potassium phosphate (0.19 g, 0.90 mmol), and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.049 g, 0.06 mmol) under nitrogen was added Dioxane (1.5 mL) and water (1.5 mL) and the resulting mixture was heated 3 hours at 90°C. The mixture was allowed to cool and partitioned between water and ethyl acetate. The organic phase was concentrated and flash column purification using a 0-20% ethyl acetate/ hexane gradient gave tert-butyl (4-(5-fluoro-6- methoxypyridin-2-yl)benzyl)carbamate (20a). LRMS (ES) (M+H)+: observed = 333.2, calculated = 332.4. Step 2: In an analogous manner to example 12g, tert-butyl (4-(5-fluoro-6-methoxypyridin-2- yl)benzyl)carbamate (20a) and HCl were used to prepare (4-(5-fluoro-6-methoxypyridin-2- yl)phenyl)methanamine (20b). LRMS (ES) (M+H)+: observed = 233.1, calculated = 232.3. Step 3: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(5-fluoro- 6-methoxypyridin-2-yl)phenyl)methanamine (20b) were used to prepare (2R,6R)-4-((R)-1-(3- fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-N-(4-(5-fluoro-6-methoxypyridin-2-yl)benzyl)- 25608 1-isobutyryl-6-methylpiperazine-2-carboxamide (20-1). LRMS (ES) (M+H)+: observed = 610.4, calculated = 609.7. The following compounds were prepared in an analogous manner to example 20-1 using the appropriate aryl halide. Example Structure Name Calculated Observed Mass Mass
Figure imgf000119_0001
25608 20-5 (2R,6R)-4-[(1R)-1-(3- 659.731 660.4 fluoro-4-methylpyridin-2-
Figure imgf000120_0001
25608 20-8 (2R,6R)-N-({4-[6- 611.714 612.4 (difluoromethyl)pyridin-2-
Figure imgf000121_0001
25608 20-11 (2R,6R)-4-[(1R)-1-(3- 617.792 618.4 fluoro-4-methylpyridin-2-
Figure imgf000122_0001
25608 20-14 (2R,6R)-4-[(1R)-1-(3- 614.77 615.4 fluoro-4-methylpyridin-2-
Figure imgf000123_0001
25608 20-17 (2R,6R)-N-{[4-(3-fluoro- 609.723 610.4 6-methoxypyridin-2-
Figure imgf000124_0002
EXAMPLE 21 F O Preparation of
Figure imgf000124_0001
-1-isobutyryl- 6-methyl-N-(4-(pyridin-2-yl)benzyl)piperazine-2-carboxamide (21) Step 1: In an analogous manner to example 12g, tert-butyl (4-(pyridin-2-yl)benzyl)carbamate (21a) and HCl were used to prepare (4-(pyridin-2-yl)phenyl)methanamine (21b, used directly). Step 2: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(pyridin- 2-yl)phenyl)methanamine (21b) were used to prepare (2R,6R)-4-((R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyridin-2- yl)benzyl)piperazine-2-carboxamide (21). LRMS (ES) (M+H)+: observed = 562.4, calculated = 561.7. 25608 EXAMPLE 22
Figure imgf000125_0001
4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (22) Step 1: Preparation of tert-butyl (4-(4-chloro-6-methoxypyridin-2-yl)benzyl)carbamate (22b) To a vial containing (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (17a, 0.20 g, 0.80 mmol), 6-bromo-4-chloro-2-methoxypyridine (0.23 g, 1.04 mmol), Potassium phosphate (0.25 g, 1.20 mmol), and Tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.08 mmol) under nitrogen was added Dioxane (2 mL) and water (2 mL) and the resulting mixture was heated 2 hours at 90°C. The mixture was allowed to cool to room temperature and concentrated. The crude material was partitioned between water and ethyl acetate. The organic phase was concentrated and flash column purification using a 0-20% ethyl acetate/ hexane gradient gave tert-butyl (4-(4- chloro-6-methoxypyridin-2-yl)benzyl)carbamate (22b). LRMS (ES) (M+H)+: observed = 349.2, calculated = 348.8. Step 2: In an analogous manner to example 18a, tert-butyl (4-(4-chloro-6-methoxypyridin-2- yl)benzyl)carbamate (22b) and cyclopropyl boronic acid were used to prepare tert-butyl (4-(4- cyclopropyl-6-methoxypyridin-2-yl)benzyl)carbamate (22c). LRMS (ES) (M+H)+: observed = 355.2, calculated = 354.5. Step 3: In an analogous manner to example 12g, tert-butyl (4-(4-cyclopropyl-6-methoxypyridin- 2-yl)benzyl)carbamate (22c) and HCl were used to prepare (4-(4-cyclopropyl-6-methoxypyridin- 2-yl)phenyl)methanamine (22d). LRMS (ES) (M+H)+: observed = 255.1, calculated = 254.3. 25608 Step 4: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(4- cyclopropyl-6-methoxypyridin-2-yl)phenyl)methanamine (22d) were used to prepare (2R,6R)-N- (4-(4-cyclopropyl-6-methoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (22). LRMS (ES) (M+H)+: observed = 632.5, calculated = 631.8. EXAMPLE 23
Figure imgf000126_0001
N-((2'- fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (23) Step 1: Preparation of tert-butyl ((2'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)carbamate (23a) To a vial containing (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (17a, 0.20 g, 0.80 mmol), 2-chloro-1-fluoro-4-methoxybenzene (0.19 g, 1.20 mmol), Potassium phosphate (0.25 g, 1.20 mmol), Pd(OAc)2 (0.018 g, 0.08 mmol) and 2-Dicyclohexylphosphino- 2′,6′-dimethoxybiphenyl (0.065 g, 0.16 mmol) under nitrogen was added Dioxane (2 mL) and water (2 mL) and the resulting mixture was heated overnight at 90°C. The mixture was allowed to cool to room temperature and partitioned between water and ethyl acetate. Both phases were filtered through celite and the organic phase was concentrated and flash column purification 25608 using a 0-100% ethyl acetate/ hexane gradient gave tert-butyl ((2'-fluoro-5'-methoxy-[1,1'- biphenyl]-4-yl)methyl)carbamate (23a). Step 2: In an analogous manner to example 12g, tert-butyl ((2'-fluoro-5'-methoxy-[1,1'-biphenyl]- 4-yl)methyl)carbamate (23a) and HCl were used to prepare (2'-fluoro-5'-methoxy-[1,1'- biphenyl]-4-yl)methanamine (23b). LRMS (ES) (M+H)+: observed = 232.1, calculated = 231.3. Step 3: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (2'-fluoro-5'- methoxy-[1,1'-biphenyl]-4-yl)methanamine (23b) were used to prepare (2R,6R)-4-((R)-1-(3- fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-N-((2'-fluoro-5'-methoxy-[1,1'-biphenyl]-4- yl)methyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (23). LRMS (ES) (M+H)+: observed = 609.4, calculated = 608.7. EXAMPLE 24
Figure imgf000127_0001
4- methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (24) Step 1: Preparation of tert-butyl (4-(6-cyclopropoxypyridin-2-yl)benzyl)carbamate (24a) To a vial containing (4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (17a, 0.15 g, 0.60 mmol), 2-bromo-6-cyclopropoxypyridine (0.166 g, 0.78 mmol), Potassium phosphate (0.19 g, 0.90 mmol), and Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′- amino-1,1′-biphenyl)]palladium(II) (0.047 g, 0.06 mmol) under nitrogen was added Dioxane (1.5 mL) and water (1.5 mL) and the resulting mixture was heated overnight at 90°C. The mixture 25608 was allowed to cool and partitioned between water and ethyl acetate. The organic phase was concentrated and flash column purification using a 0-20% ethyl acetate/ hexane gradient gave tert-butyl (4-(6-cyclopropoxypyridin-2-yl)benzyl)carbamate (24a). LRMS (ES) (M+H)+: observed = 341.1, calculated = 340.4. Step 2: In an analogous manner to example 12g, tert-butyl (4-(6-cyclopropoxypyridin-2- yl)benzyl)carbamate (24a) and HCl were used to prepare (4-(6-cyclopropoxypyridin-2- yl)phenyl)methanamine (24b). LRMS (ES) (M+H)+: observed = 241.1, calculated = 240.3. Step 3: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(6- cyclopropoxypyridin-2-yl)phenyl)methanamine (24b) were used to prepare (2R,6R)-N-(4-(6- cyclopropoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)- 1-isobutyryl-6-methylpiperazine-2-carboxamide (24). LRMS (ES) (M+H)+: observed = 618.4, calculated = 617.8. EXAMPLE 25
Figure imgf000128_0001
1-isobutyryl- N-(4-(6-methoxypyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (25) Step 1: In an analogous manner to example 24a, (4-(((tert- butoxycarbonyl)amino)methyl)phenyl)boronic acid (17a) and 2-bromo-6-methoxypyridine were used to prepare tert-butyl (4-(6-methoxypyridin-2-yl)benzyl)carbamate (25a, 26%). LRMS (ES) (M+H)+: observed = 315.1, calculated = 314.4. 25608 Step 2: In an analogous manner to example 12g, tert-butyl (4-(6-methoxypyridin-2- yl)benzyl)carbamate (25a) and HCl were used to prepare (4-(6-methoxypyridin-2- yl)phenyl)methanamine (25b). LRMS (ES) (M+H)+: observed = 215.0, calculated = 214.2. Step 3: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(6- methoxypyridin-2-yl)phenyl)methanamine (25b) were used to prepare (2R,6R)-4-((R)-1-(3- fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(6-methoxypyridin-2- yl)benzyl)-6-methylpiperazine-2-carboxamide (25). LRMS (ES) (M+H)+: observed = 592.4, calculated = 591.7. EXAMPLE 26
Figure imgf000129_0001
1-isobutyryl- N-(4-(3-methoxypyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (26) Step 1: In an analogous manner to example 24a, (4-(((tert- butoxycarbonyl)amino)methyl)phenyl)boronic acid (17a) and 2-bromo-3-methoxypyridine were used to prepare tert-butyl (4-(3-methoxypyridin-2-yl)benzyl)carbamate (26a). Step 2: In an analogous manner to example 12g, tert-butyl (4-(3-methoxypyridin-2- yl)benzyl)carbamate (26a) and HCl were used to prepare (4-(3-methoxypyridin-2- yl)phenyl)methanamine (26b). LRMS (ES) (M+H)+: observed = 215.1, calculated = 214.2. Step 3: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(3- methoxypyridin-2-yl)phenyl)methanamine (26b) were used to prepare (2R,6R)-4-((R)-1-(3- 25608 fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(3-methoxypyridin-2- yl)benzyl)-6-methylpiperazine-2-carboxamide (26). LRMS (ES) (M+H)+: observed = 592.5, calculated = 591.7. EXAMPLE 27
Figure imgf000130_0001
-6- methylpiperazine-2-carboxamide (27) Step 1: In an analogous manner to example 1f, cis-1-(tert-butyl) 3-methyl 5-methylpiperazine- 1,3-dicarboxylate (1d) and potassium trimethylsilanolate were used to prepare 4-(tert- butoxycarbonyl)-6-methylpiperazine-2-carboxylic acid (27a, Quant.). LRMS (ES) (M+H)+: observed = 245.1, calculated = 244.3. Step 2: Preparation of tert-butyl 3-((4-(furan-2-yl)benzyl)carbamoyl)-5-methylpiperazine-1- carboxylate (27b) To a stirred solution of 4-(tert-butoxycarbonyl)-6-methylpiperazine-2- carboxylic acid (27a, 0.47 g, 1.93 mmol) and (4-(furan-2-yl)phenyl)methanamine (0.40 g, 2.32 mmol) in DCM (8.7 mL) and DMSO (0.96 mL) was added HATU (0.88 g, 2.32 mmol) and N- methyl morpholine (0.85 mL, 7.74 mmol). The resulting mixture was stirred overnight, then concentrated. Flash column purification using a 0-100% (3:1ethyl acetate/ethanol) /hexane 25608 gradient gave tert-butyl 3-((4-(furan-2-yl)benzyl)carbamoyl)-5-methylpiperazine-1-carboxylate (27b, 66%). LRMS (ES) (M+H)+: observed = 400.3, calculated = 399.5. Step 3: In an analogous manner to example 1h, tert-butyl 3-((4-(furan-2-yl)benzyl)carbamoyl)-5- methylpiperazine-1-carboxylate (27b) and HCl in DCM were used to prepare N-(4-(furan-2- yl)benzyl)-6-methylpiperazine-2-carboxamide (27c, Quant.). LRMS (ES) (M+H)+: observed = 300.2, calculated = 299.3. Step 3: In an analogous manner to example 2-1 N-(4-(furan-2-yl)benzyl)-6-methylpiperazine-2- carboxamide (27c) and 2-(bromomethyl)-1,3-difluorobenzene were used to prepare 4-(2,6- difluorobenzyl)-N-(4-(furan-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (27d, 63%). LRMS (ES) (M+H)+: observed = 426.2, calculated = 425.4. Step 4: In an analogous manner to example 1e, 4-(2,6-difluorobenzyl)-N-(4-(furan-2-yl)benzyl)- 6-methylpiperazine-2-carboxamide (27d) and cyclopropanecarbonyl chloride in DCM were used to prepare 1-(cyclopropanecarbonyl)-4-(2,6-difluorobenzyl)-N-(4-(furan-2-yl)benzyl)-6- methylpiperazine-2-carboxamide (27). LRMS (ES) (M+H)+: observed = 494.5, calculated = 493.5. EXAMPLE 28
Figure imgf000131_0001
1-isobutyryl- 6-methyl-N-(4-(prop-1-yn-1-yl)benzyl)piperazine-2-carboxamide (28) Step 1: Preparation of tert-butyl (4-(prop-1-yn-1-yl)benzyl)carbamate (28b) To a vial containing tert-butyl (4-bromobenzyl)carbamate (28a, 0.30 g, 1.05 mmol) and 25608 Tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) under nitrogen was added Dioxane (3.5 mL) and tributyl(prop-1-yn-1-yl)stannane (0.48 ml, 1.57 mmol) and the resulting solution was microwave irradiated at 120°C for 1 hour. The mixture was allowed to cool and partitioned between ethyl acetate and a sat. ammonium chloride solution. The organic phase was concentrated and flash column purification using a 0-20% ethyl acetate/ hexane gradient gave tert-butyl (4-(prop-1-yn-1-yl)benzyl)carbamate (28b). Step 2: In an analogous manner to example 12g, tert-butyl (4-(prop-1-yn-1-yl)benzyl)carbamate (28b) and HCl were used to prepare (4-(prop-1-yn-1-yl)phenyl)methanamine (28c). Step 3: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(prop-1- yn-1-yl)phenyl)methanamine (28c) were used to prepare (2R,6R)-4-((R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(prop-1-yn-1- yl)benzyl)piperazine-2-carboxamide (28). LRMS (ES) (M+H)+: observed = 523.0, calculated = 522.6. EXAMPLE 29
Figure imgf000132_0001
2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (29) Step 1: In an analogous manner to example 28b, tert-butyl (4-bromobenzyl)carbamate (28a) and tributyl(cyclopropylethynyl)stannane were used to prepare tert-butyl (4- (cyclopropylethynyl)benzyl)carbamate (29a). 25608 Step 2: In an analogous manner to example 12g tert-butyl (4- (cyclopropylethynyl)benzyl)carbamate (29a) and HCl were used to prepare (4- (cyclopropylethynyl)phenyl)methanamine (29b). LRMS (ES) (M+H)+: observed = 172.1, calculated = 171.2. Step 3: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4- (cyclopropylethynyl)phenyl)methanamine (29b) were used to prepare (2R,6R)-N-(4- (cyclopropylethynyl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (29). LRMS (ES) (M+H)+: observed = 549.5, calculated = 548.7. EXAMPLE 30
Figure imgf000133_0001
1-isobutyryl- 6-methyl-N-(4-(3,3,3-trifluoroprop-1-yn-1-yl)benzyl)piperazine-2-carboxamide (30) Step 1: In an analogous manner to example 28b, tert-butyl (4-bromobenzyl)carbamate (28a) and tributyl(3,3,3-trifluoroprop-1-yn-1-yl)stannane were used to prepare tert-butyl (4-(3,3,3- trifluoroprop-1-yn-1-yl)benzyl)carbamate (30a). Step 2: In an analogous manner to example 12g tert-butyl (4-(3,3,3-trifluoroprop-1-yn-1- yl)benzyl)carbamate (30a) and HCl were used to prepare (4-(3,3,3-trifluoroprop-1-yn-1- yl)phenyl)methanamine (30b). LRMS (ES) (M+H)+: observed = 200.1, calculated = 199.2. 25608 Step 3: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(3,3,3- trifluoroprop-1-yn-1-yl)phenyl)methanamine (30b) were used to prepare (2R,6R)-4-((R)-1-(3- fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(3,3,3-trifluoroprop- 1-yn-1-yl)benzyl)piperazine-2-carboxamide (30). LRMS (ES) (M+H)+: observed = 577.4, calculated = 576.6. EXAMPLE 31 O O F O
Figure imgf000134_0001
2-yl)-3- methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (31) Step 1: Preparation of tert-butyl (4-(1-hydroxybut-2-yn-1-yl)benzyl)carbamate (31b) To a stirred solution of tert-butyl (4-formylbenzyl)carbamate (31a, 0.20 g, 0.85 mmol) in THF (10 mL) was added 1-propynylmagnesium bromide 0.5M (3.57 mL, 1.79 mmol) dropwise. The resulting solution was stirred 30 minutes and quenched with sat. ammonium choride solution. The mixture was extracted several times with ethyl acetate and the combined organic layers were concentrated. Flash column purification using a 0-30% ethyl acetate/ hexane gradient gave tert- butyl (4-(1-hydroxybut-2-yn-1-yl)benzyl)carbamate (31b). LRMS (ES) (M+H)+: observed = 276.1, calculated = 275.3. Step 2: Preparation of (4-(but-2-yn-1-yl)phenyl)methanamine (31c) To a stirred solution of tert- butyl (4-(1-hydroxybut-2-yn-1-yl)benzyl)carbamate (31b, 0.106 g, 0.385 mmol) in DCM (4.4 mL) was added triethylsilane (0.12 mL, 0.77 mmol). Trifluoroacetic acid (0.27 ml, 3.46 mmol) was then added dropwise. The resulting mixture was stirred at room temperature for 3 hours, poured into sat. sodium bicarbonate solution and extracted several times with dichloromethane. 25608 The combined organic phases were concentrated to give (4-(but-2-yn-1-yl)phenyl)methanamine (31c) LRMS (ES) (M+H)+: observed = 160.1, calculated = 159.2. Step 3: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(but-2-yn- 1-yl)phenyl)methanamine (31c) were used to prepare (2R,6R)-N-(4-(but-2-yn-1-yl)benzyl)-4- ((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (31). LRMS (ES) (M+H)+: observed = 537.5, calculated = 536.7. EXAMPLE 32
Figure imgf000135_0001
6-methyl-N-(4-(4-methyl-2H-1,2,3-triazol-2-yl)benzyl)piperazine-2-carboxamide (32) Step 1: Preparation of 2-(2-(4-bromophenyl)hydrazono)propanal oxime (32b) To a solution of (4- bromophenyl)hydrazine (32a, 16.0 g, 71.6 mmol) in anhydrous EtOH (200 mL) was added (E)-2- oxopropanal oxime (6.23 g, 71.6 mmol). The resulting mixture was stirred at 12 °C under N2 protection for 15 hours. The reaction was poured into water (500 mL), extracted with EtOAc 25608 (200 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, eluent of 13% EtOAc gradient) to give 2-(2-(4-bromophenyl)hydrazono)propanal oxime (32b). LRMS (ES) (M+H)+: observed = 257.9, calculated = 256.1. Step 2: Preparation of 2-(4-bromophenyl)-4-methyl-2H-1,2,3-triazole 1-oxide (32c) To a solution of 2-(2-(4-bromophenyl)hydrazono)propanal oxime (32b, 4.80 g, 18.74 mmol) in Pyridine (200 mL) was added a solution of CuSO4 (5.98 g, 37.5 mmol) in Water (50 mL). The resulting mixture was stirred at 120 °C under N2 protection for 1.5 hours. The mixture reaction was poured into ice- water (500 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give 2-(4-bromophenyl)-4-methyl-2H-1,2,3-triazole 1- oxide (32c). LRMS (ES) (M+H)+: observed = 254.3, calculated = 254.1. Step 3: Preparation of 2-(4-bromophenyl)-4-methyl-2H-1,2,3-triazole (32d) A solution of 2-(4- bromophenyl)-4-methyl-2H-1,2,3-triazole 1-oxide (32c, 3.10 g, 12.20 mmol) in triethyl phosphite (12 mL, 12.20 mmol) was stirred at 160 °C under N2 protection for 5 hours. The reaction mixture was poured into ice-water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 7% EtOAc gradient) to give 2-(4-bromophenyl)-4-methyl-2H-1,2,3-triazole (32d). Step 4: Preparation of 4-(4-methyl-2H-1,2,3-triazol-2-yl)benzonitrile (32e) To a solution of 2-(4- bromophenyl)-4-methyl-2H-1,2,3-triazole (32d, 1.40 g, 5.88 mmol) and zinc cyanide (1.38 g, 11.76 mmol) in DMF (20 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.68 g, 0.59 mmol). The resulting mixture was stirred at 140 °C under MW for 30 minutes. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and the filtrate was concentrated. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 11% EtOAc gradient) to give 4-(4-methyl-2H-1,2,3- triazol-2-yl)benzonitrile (32e). Step 5: Preparation of (4-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanamine (32f) To a solution of 4-(4-methyl-2H-1,2,3-triazol-2-yl)benzonitrile (32e, 0.85 g, 4.61 mmol) in MeOH (20 mL) was added ammonium hydroxide (1 mL, 4.61 mmol) and nickel (0.135 g, 2.31 mmol) at 12 °C. The mixture was stirred at 30 °C under H2 (excess) (30 psi) for 6 hours. The reaction mixture was filtration and concentration to give (4-(4-methyl-2H-1,2,3-triazol-2- yl)phenyl)methanamine (32f). LRMS (ES) (M+H)+: observed = 189.5, calculated = 188.2. 25608 Step 6: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(4-methyl- 2H-1,2,3-triazol-2-yl)phenyl)methanamine (32f) were used to prepare (2R,6R)-4-((R)-1-(3- fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(4-methyl-2H-1,2,3- triazol-2-yl)benzyl)piperazine-2-carboxamide (32). LRMS (ES) (M+H)+: observed = 566.4, calculated = 565.7. EXAMPLE 33
Figure imgf000137_0001
methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (33) Step 1: Preparation of 3-(2-(4-bromophenyl)hydrazono)butan-2-one (33a) A solution of (4- bromophenyl)hydrazine (32a, 10.86 g, 58.1 mmol) and biacetyl (50.0 g, 581 mmol) in EtOH (500 mL), the mixture was stirred at 15 °C for 4 hours. The mixture was concentrated to give the crude product. After the crude product was stirred in 30 mL of Petroleum ether: EtOAc (1:1) for 25608 10 minutes, the mixture was filtered to give 3-(2-(4-bromophenyl)hydrazono)butan-2-one (33a). LRMS (ES) (M+H)+: observed = 255.0, calculated = 255.1. Step 2: Preparation of 3-(2-(4-bromophenyl)hydrazono)butan-2-one oxime (33b) To a solution of 3-(2-(4-bromophenyl)hydrazono)butan-2-one (33a, 8.0 g, 31.4 mmol) in EtOH (80 mL) was added Hydroxylamine hydrochloride (2.18 g, 31.4 mmol), the mixture was stirred at 60 °C for 2 hours. The mixture was concentrated under reduced pressure to afford 3-(2-(4- bromophenyl)hydrazono)butan-2-one oxime (33b). LRMS (ES) (M+H)+: observed = 271.9, calculated = 270.1. Step 3: In an analogous manner to example 32c, 3-(2-(4-bromophenyl)hydrazono)butan-2-one oxime (33b) was used to prepare 2-(4-bromophenyl)-4,5-dimethyl-2H-1,2,3-triazole 1-oxide (33c). LRMS (ES) (M+H)+: observed = 269.5, calculated = 268.1. Step 4: In an analogous manner to example 32d, 2-(4-bromophenyl)-4,5-dimethyl-2H-1,2,3- triazole 1-oxide (33c) and triethyl phosphite were used to prepare 2-(4-bromophenyl)-4,5- dimethyl-2H-1,2,3-triazole (33d). LRMS (ES) (M+H)+: observed = 253.5, calculated = 252.1. Step 5: In an analogous manner to example 32e, 2-(4-bromophenyl)-4,5-dimethyl-2H-1,2,3- triazole (33d) and zinc cyanide were used to prepare 4-(4,5-dimethyl-2H-1,2,3-triazol-2- yl)benzonitrile (33e, 38%). Step 6: In an analogous manner to example 32f, 4-(4,5-dimethyl-2H-1,2,3-triazol-2- yl)benzonitrile (33e) was used to prepare (4-(4,5-dimethyl-2H-1,2,3-triazol-2- yl)phenyl)methanamine (33f). LRMS (ES) (M+H)+: observed = 186.0(M+1-17), calculated = 202.3. Step 7: In an analogous manner to example 16-1, (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (16e) and (4-(4,5- dimethyl-2H-1,2,3-triazol-2-yl)phenyl)methanamine (33f) were used to prepare (2R,6R)-N-(4- (4,5-dimethyl-2H-1,2,3-triazol-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (33). LRMS (ES) (M+H)+: observed = 580.4, calculated = 579.7.
25608 EXAMPLE 34
Figure imgf000139_0001
-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (34) Step 1: Preparation of 2-bromo-3,5-difluoro-4-methylpyridine (34b) To a stirred solution of 2- bromo-3,5-difluoropyridine (34a, 0.50 g, 2.58 mmol) in THF (10 mL) chilled to -78°C was added LDA (2M, 1.4 mL, 2.84 mmol). The resulting solution was stirred 40 minutes. To this was added methyl iodide (0.16 mL, 2.58 mmol) dropwise at -78°C. The mixure was allowed to warm to room temperature, quenched with a sat. sodium bicarbonate solution and extracted several times with ethyl acetate. The combined organic layers were concentrated and flash column purification using a 0-10% ethyl acetate/ hexane gradient gave 2-bromo-3,5-difluoro-4- methylpyridine (34b). LRMS (ES) (M+H)+: observed = 209.9, calculated = 208.0. Step 2-5: In an analogous manner to example 16-1, 2-bromo-3,5-difluoro-4-methylpyridine (34b) was used to prepare (2R,6R)-4-((R)-1-(3,5-difluoro-4-methylpyridin-2-yl)-3- methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (34) LRMS (ES) (M+H)+: observed = 581.4, calculated = 580.7. 25608 EXAMPLE 35
Figure imgf000140_0001
-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (35-1) Step 1: In an analogous manner to example 34b, 2-bromo-3-fluoro-6-methylpyridine (35a) and methyl iodide was used to prepare 2-bromo-3-fluoro-4,6-dimethylpyridine (35b) LRMS (ES) (M+H)+: observed = 205.9, calculated = 204.0. Step 2: Preparation of 1-(3-fluoro-4,6-dimethylpyridin-2-yl)-3-methoxypropan-1-ol (35c) To a stirred solution of 2-bromo-3-fluoro-4,6-dimethylpyridine (35b, 0.28 g, 1.37 mmol) in DCM (3.4 mL) chilled to -78°C was added n-butyl lithium (2.5M, 0.55 mL, 1.37 mmol). The resulting solution was stirred 15 minutes. To this was added 3-methoxypropanal (0.12 g, 1.37 mmol) dropwise at -78°C. The mixure was stirred at -78°C for 30min, quenched with a sat. ammonium chloride solution and extracted several times with DCM. The combined organic layers were concentrated and flash column purification using a 0-30% ethyl acetate/ hexane gradient gave 1- (3-fluoro-4,6-dimethylpyridin-2-yl)-3-methoxypropan-1-ol (35c). LRMS (ES) (M+H)+: observed = 214.0, calculated = 213.3. 25608 Steps 3-5: In an analogous manner to example 16-1, 1-(3-fluoro-4,6-dimethylpyridin-2-yl)-3- methoxypropan-1-ol (35c) was used to prepare (2R,6R)-4-((R)-1-(3-fluoro-4,6-dimethylpyridin- 2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (35-1) LRMS (ES) (M+H)+: observed = 577.3, calculated = 576.7. The following compounds were prepared in an analogous manner to example 35-1 using the appropriately substituted aryl halide. Example Structure Name Calculate Observed Mass d Mass (M+H)
Figure imgf000141_0001
25608 35-4 (2R,6R)-4-[(1R)-1-(5- 549.654 550.4 fluoropyrimidin-2-yl)-3-
Figure imgf000142_0001
EXAMPLE 36
25608 Preparation of (2R,6R)-1-isobutyryl-4-((R)-3-methoxy-1-(2,4,6-trifluorophenyl)propyl)-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (36) Step 1: Preparation of 3-methoxy-1-(2,4,6-trifluorophenyl)propan-1-ol (36b) To a stirred solution of 1,3,5-trifluorobenzene (36a, 1.0 g, 7.57 mmol) in THF (21.6 mL) chilled to -78°C was added n-butyl lithium (2.5M, 3.18 mL, 7.95 mmol). The resulting solution was stirred 1 hour. To this was added 3-methoxypropanal (0.67 g, 7.57 mmol) dissolved in THF (2mL) dropwise at -78°C. The mixure was allowed to warm to room temperature, quenched with a sat. ammonium chloride solution and extracted several times with ethyl acetate. The combined organic layers were concentrated and flash column purification using a 0-30% ethyl acetate/ hexane gradient gave 3- methoxy-1-(2,4,6-trifluorophenyl)propan-1-ol (36b, 55%). Step 2: Preparation of 2-(1-bromo-3-methoxypropyl)-1,3,5-trifluorobenzene (36c) To a stirred solution of 3-methoxy-1-(2,4,6-trifluorophenyl)propan-1-ol (36b, 0.92 g, 4.18 mmol) in ethyl ether (1 mL) was added pyridine (0.135 mL, 1.67 mmol). The resulting mixture was chilled to 0°C in an ice bath and treated with PBr3 (0.59 mL, 6.27 mmol) dissolved in ethyl ether (1 mL) dropwise. The mixture was allowed to stir at room temperature for 1 hour then chilled in an ice bath and quenched with ice. The mixture was extracted with ether and the combined organic phases were dried over sodium sulfite and concentrated to give 2-(1-bromo-3-methoxypropyl)- 1,3,5-trifluorobenzene (36c, used crude) Steps 3-4: In an analogous manner to example 16-1, 2-(1-bromo-3-methoxypropyl)-1,3,5- trifluorobenzene (36c) was used to prepare (2R,6R)-1-isobutyryl-4-((R)-3-methoxy-1-(2,4,6- trifluorophenyl)propyl)-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (36) LRMS (ES) (M+H)+: observed = 584.5, calculated = 583.6. EXAMPLE 37
25608
Figure imgf000144_0001
6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (37) Step 1: Preparation of 1-(3,5-difluoropyridin-4-yl)-3-methoxypropan-1-ol (37b) To a stirred solution of 3,5-difluoropyridine (37a, 0.5 mL, 5.47 mmol) in THF (15.6 mL) chilled to -78°C was added LDA (2.0M, 3.01 mL, 6.02 mmol). The resulting solution was stirred 1 hour. To this was added 3-methoxypropanal (0.67 g, 7.57 mmol) dissolved in THF (2mL) dropwise at -78°C. The mixure was allowed to warm to room temperature, stirred 1 hr, quenched with a sat. ammonium chloride solution and extracted several times with ethyl acetate. The combined organic layers were concentrated and flash column purification using a 0-50% ethyl acetate/ hexane gradient gave 1-(3,5-difluoropyridin-4-yl)-3-methoxypropan-1-ol (37b, 66%). LRMS (ES) (M+H)+: observed = 204.1, calculated = 203.2. Steps 2-4: In an analogous manner to example 16-1, 1-(3,5-difluoropyridin-4-yl)-3- methoxypropan-1-ol (37b) was used to prepare (2R,6R)-4-((R)-1-(3,5-difluoropyridin-4-yl)-3- methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (37) LRMS (ES) (M+H)+: observed = 567.0, calculated = 566.6. 25608 EXAMPLE 38 F F F
Figure imgf000145_0001
isobutyryl- 6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (38) Step 1: Preparaton of 1-(4-ethyl-3-fluoropyridin-2-yl)-3-methoxypropan-1-ol (38b) To a stirred solution of N,N-dimethylethanolamine (0.20 mL, 2.00 mmol) in Hexane (6.25 mL) chilled to 0°C was added n-butyl lithium (2.5M, 1.60 mL, 4.00 mmol). The resulting mixture was stirred for 20 minutes, then 4-ethyl-3-fluoropyridine (38a, 0.125 g, 1.00 mmol) in Hexane (1.2 mL) and the resulting solution was stirred 1 hour. The reaction was chilled to -78°C, and 3- methoxypropanal (0.22 g, 2.50 mmol) dissolved in THF (2mL) dropwise at -78°C. The mixure was allowed to warm to room temperature, quenched with a sat. sodium bicarbonate solution and extracted several times with ethyl acetate. The combined organic layers were concentrated and flash column purification using a 0-50% ethyl acetate/ hexane gradient gave 1-(4-ethyl-3- fluoropyridin-2-yl)-3-methoxypropan-1-ol (38b, 50%). LRMS (ES) (M+H)+: observed = 214.1, calculated = 213.3. Steps 2-4: In an analogous manner to example 16-1, 1-(4-ethyl-3-fluoropyridin-2-yl)-3- methoxypropan-1-ol (38b) was used to prepare (2R,6R)-4-((R)-1-(4-ethyl-3-fluoropyridin-2-yl)- 25608 3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (38) LRMS (ES) (M+H)+: observed = 577.3, calculated = 576.7. EXAMPLE 39
Figure imgf000146_0001
6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (39) Step 1: Preparation of 1-(6-chloro-3-fluoropyridin-2-yl)-3-methoxypropan-1-one (39b) To a stirred solution of 1-(6-chloro-3-fluoropyridin-2-yl)ethan-1-one (39a, 0.47 g, 2.71 mmol) in DCM (6.7 mL) chilled to 0°C in an ice bath was added Hunig’s base (0.57 mL, 3.25 mmol). To this solution was added Trimethylsilyl trifluoromethanesulfonate (0.69 mL, 3.79 mmol) dropwise and the resulting solution was stirred 15 minutes at 0°C, then dimethoxylmethane (0.264 mL, 2.98 mmol) was added and the mixture was allowed to warm to room temperature for 3 hours. The reaction was partitioned between water and dichloromethane. The organic phase was concentrated and extracted several times with ethyl acetate. The combined organic layers were concentrated and flash column purification using a 0-20% ethyl acetate/ hexane gradient gave 1- (6-chloro-3-fluoropyridin-2-yl)-3-methoxypropan-1-one (39b, 80%). LRMS (ES) (M+H)+: observed = 218.0, calculated = 217.6. Step 2: Preparation of 1-(6-chloro-3-fluoropyridin-2-yl)-3-methoxypropan-1-ol (39c) To a stirred solution of 1-(6-chloro-3-fluoropyridin-2-yl)-3-methoxypropan-1-one (39b, 0.47 g, 2.16 mmol) 25608 in THF (4 ml) and MeOH (0.5 mL) chilled to 0°C, was added sodium borohydride (0.08 g, 2.16 mmol) and the resulting mixture was stirred for 1 hour. Brine was added to the solution and the mixture was extracted with ethyl acetate. The organic phase was concentrated and flash column purification using a 0-30% ethyl acetate/ hexane gradient gave 1-(6-chloro-3-fluoropyridin-2-yl)- 3-methoxypropan-1-ol (39c, 93%). LRMS (ES) (M+H)+: observed = 220.0, calculated = 219.6. Steps 3-5: In an analogous manner to example 16-1, 1-(6-chloro-3-fluoropyridin-2-yl)-3- methoxypropan-1-ol (39c) was used to prepare (2R,6R)-4-((R)-1-(6-chloro-3-fluoropyridin-2-yl)- 3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (39) LRMS (ES) (M+H)+: observed = 583.3, calculated = 583.1. EXAMPLE 40
Figure imgf000147_0001
6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (40) Step 1: Preparation of 1-(3-fluoro-5-methylpyridin-2-yl)ethan-1-one (40b) To a stirred solution of 2-chloro-3-fluoro-5-methylpyridine (40a, 0.50 g, 3.43 mmol) and Tetrakis(triphenylphosphine)palladium(0) (0.40 g, 0.34 mmol) under nitrogen was added Dioxane (8.5 mL) and tributyl(1-ethoxyvinyl)tin (1.39 mL, 4.12 mmol). The resulting solution was heated via microwave irradiation to 140°C for 1 hour. The mixture was allowed to cool to 25608 room temperature and 1N HCl (7 mL) was added. The mixture was stirred overnight at room temperature, quenched with sat. sodium bicarbonate solution and extracted several times with ethyl acetate. The combined organic layers were filtered through celite and concentrated. Flash column purification using a 0-20% ethyl acetate/ hexane gradient gave 1-(3-fluoro-5- methylpyridin-2-yl)ethan-1-one (40b, used directly). LRMS (ES) (M+H)+: observed = 154.0, calculated = 153.1. Steps 2-6: In an analogous manner to example 39, 1-(3-fluoro-5-methylpyridin-2-yl)ethan-1-one (40b) was used to prepare (2R,6R)-4-((R)-1-(3-fluoro-5-methylpyridin-2-yl)-3-methoxypropyl)- 1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (40) LRMS (ES) (M+H)+: observed = 563.4, calculated = 562.7. EXAMPLE 41
Figure imgf000148_0001
-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (41) 25608 Step 1: In an analogous manner to example 28b, 1-(6-chloro-3-fluoropyridin-2-yl)-3- methoxypropan-1-ol (39c) and tributyl(prop-1-yn-1-yl)stannane were used to prepare 1-(3- fluoro-6-(prop-1-yn-1-yl)pyridin-2-yl)-3-methoxypropan-1-ol (41a, used directly). LRMS (ES) (M+H)+: observed = 224.1, calculated = 223.2. Steps 2-4: In an analogous manner to example 16-1, 1-(3-fluoro-6-(prop-1-yn-1-yl)pyridin-2-yl)- 3-methoxypropan-1-ol (41a) was used to prepare (2R,6R)-4-((R)-1-(3-fluoro-6-(prop-1-yn-1- yl)pyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (41) LRMS (ES) (M+H)+: observed = 587.4, calculated = 586.7. EXAMPLE 42
Figure imgf000149_0001
isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (42) Step 1: In an analogous manner to example 18a, 1-(6-chloro-3-fluoropyridin-2-yl)-3- methoxypropan-1-ol (39c) and cyclopropyl boronic acid were used to prepare 1-(6-cyclopropyl- 3-fluoropyridin-2-yl)-3-methoxypropan-1-ol (42a, 43%). LRMS (ES) (M+H)+: observed = 226.1, calculated = 225.3. 25608 Steps 2-4: In an analogous manner to example 16-1, 1-(6-cyclopropyl-3-fluoropyridin-2-yl)-3- methoxypropan-1-ol (42a) was used to prepare (2R,6R)-4-((R)-1-(6-cyclopropyl-3-fluoropyridin- 2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (42) LRMS (ES) (M+H)+: observed = 589.4, calculated = 588.7. EXAMPLE 43
Figure imgf000150_0001
isobutyryl- 6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (43) Steps 1-4: In an analogous manner to example 42, 1-(6-chloro-3-fluoropyridin-2-yl)-3- methoxypropan-1-ol (39c) and potassium ethyltrifluoroborate was used to prepare (2R,6R)-4- ((R)-1-(6-ethyl-3-fluoropyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin- 2-yl)benzyl)piperazine-2-carboxamide (43) LRMS (ES) (M+H)+: observed = 577.4, calculated = 576.7. EXAMPLE 44
25608
Figure imgf000151_0001
-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (44) Step 1: Step 1: In an analogous manner to example 34b, 2-chloro-3-fluoro-5-methylpyridine (40a) and methyl iodide was used to prepare 2-chloro-3-fluoro-4,5-dimethylpyridine (44a) LRMS (ES) (M+H)+: observed = 160.0, calculated = 159.6. Steps 2-7: In an analogous manner to example 40, 2-chloro-3-fluoro-4,5-dimethylpyridine (44a) was used to prepare (2R,6R)-4-((R)-1-(3-fluoro-4,5-dimethylpyridin-2-yl)-3-methoxypropyl)-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (44) LRMS (ES) (M+H)+: observed = 577.5, calculated = 576.7. EXAMPLE 45
25608
Figure imgf000152_0001
isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (45) Step 1: In an analogous manner to example 37b, 4-chloro-3-fluoropyridine (45a) and 3- methoxypropanal was used to prepare 1-(4-chloro-3-fluoropyridin-2-yl)-3-methoxypropan-1-ol (45b, 32%) LRMS (ES) (M+H)+: observed = 220.0, calculated = 219.6. Step 2: In an analogous manner to example 18a, 1-(4-chloro-3-fluoropyridin-2-yl)-3- methoxypropan-1-ol (45b) and cyclopropyl boronic acid were used to prepare 1-(4-cyclopropyl- 3-fluoropyridin-2-yl)-3-methoxypropan-1-ol (45c, 26%). LRMS (ES) (M+H)+: observed = 226.1, calculated = 225.3. Step 3-5: In an analogous manner to example 16-1, 1-(4-cyclopropyl-3-fluoropyridin-2-yl)-3- methoxypropan-1-ol (45c) was used to prepare (2R,6R)-4-((R)-1-(4-cyclopropyl-3-fluoropyridin- 2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (45) LRMS (ES) (M+H)+: observed = 589.3, calculated = 588.7. 25608 EXAMPLE 46
Figure imgf000153_0001
-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (46) Step 1: In an analogous manner to example 28b, 1-(4-chloro-3-fluoropyridin-2-yl)-3- methoxypropan-1-ol (45b) and tributyl(prop-1-yn-1-yl)stannane were used to prepare 1-(3- fluoro-4-(prop-1-yn-1-yl)pyridin-2-yl)-3-methoxypropan-1-ol (46a, 85%). LRMS (ES) (M+H)+: observed = 224.1, calculated = 223.2. Steps 2-4: In an analogous manner to example 16-1, 1-(3-fluoro-4-(prop-1-yn-1-yl)pyridin-2-yl)- 3-methoxypropan-1-ol (46a) was used to prepare (2R,6R)-4-((R)-1-(3-fluoro-4-(prop-1-yn-1- yl)pyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (46) LRMS (ES) (M+H)+: observed = 587.3, calculated = 586.7. 25608 EXAMPLE 47
Figure imgf000154_0001
-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (47) Step 1: In an analogous manner to example 37b, 2-chloro-5-fluoropyridine (47a) and 3- methoxypropanal was used to prepare 1-(2-chloro-5-fluoropyridin-4-yl)-3-methoxypropan-1-ol (47b, 54%) LRMS (ES) (M+H)+: observed = 220.0, calculated = 219.6. Step 2: In an analogous manner to example 28b, 1-(2-chloro-5-fluoropyridin-4-yl)-3- methoxypropan-1-ol (47b) and tributyl(prop-1-yn-1-yl)stannane were used to prepare 1-(5- fluoro-2-(prop-1-yn-1-yl)pyridin-4-yl)-3-methoxypropan-1-ol (47c, 91%). LRMS (ES) (M+H)+: observed = 224.1, calculated = 223.2. Steps 2-4: In an analogous manner to example 16-1, 1-(5-fluoro-2-(prop-1-yn-1-yl)pyridin-4-yl)- 3-methoxypropan-1-ol (47c) was used to prepare (2R,6R)-4-((R)-1-(5-fluoro-2-(prop-1-yn-1- yl)pyridin-4-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (47) LRMS (ES) (M+H)+: observed = 587.3, calculated = 586.7. 25608 EXAMPLE 48
Figure imgf000155_0001
isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (48) Step 1: In an analogous manner to example 37b, 4-bromo-3,5-difluoropyridine (48a) and 3- methoxypropanal was used to prepare 1-(2-bromo-3,5-difluoropyridin-4-yl)-3-methoxypropan-1- ol (48b, 55%) LRMS (ES) (M+H)+: observed = 282.0, calculated = 282.0. Step 2: In an analogous manner to example 20a, 1-(2-bromo-3,5-difluoropyridin-4-yl)-3- methoxypropan-1-ol (48b) and methylboronic acid was used to prepare 1-(3,5-difluoro-2- methylpyridin-4-yl)-3-methoxypropan-1-ol (48c, 56%) LRMS (ES) (M+H)+: observed = 218.1, calculated = 217.2. Steps 3-5: In an analogous manner to example 16-1, 1-(3,5-difluoro-2-methylpyridin-4-yl)-3- methoxypropan-1-ol (48c) was used to prepare (2R,6R)-4-((R)-1-(3,5-difluoro-2-methylpyridin- 4-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (48) LRMS (ES) (M+H)+: observed = 581.3, calculated = 580.7. 25608 EXAMPLE 49 Preparation
Figure imgf000156_0001
N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (49) Step 1: To a solution of 2,2,6,6-tetramethylpiperidine (6.35 g, 45.0 mmol) in THF (150 mL) was added butyllithium (17.98 mL, 45.0 mmol) at -78 °C under N2. The mixture was stirred at 0 °C for 30 mins. then the mixture was added pyrazine (49a, 3.0 g, 37.5 mmol) in THF (50 mL) at - 78 °C and stirred the mixture was stirred at -78 °C for 20 minutes. Then to the mixture was added 3-methoxypropanal (6.60 g, 74.9 mmol) at -78 °C and stirred at -78 °C for 2 hours. The mixture was quenched with water (10 mL), which was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the crude, which was purified by Pre-TLC (SiO2, EtOAc 100%) to give 3-methoxy-1-(pyrazin-2-yl)propan-1-ol (49b, 0.57 g, 8.7%) Steps 2-4: In an analogous manner to example 16-1, 3-methoxy-1-(pyrazin-2-yl)propan-1-ol (49b) was used to prepare (2R,6R)-1-isobutyryl-4-((R)-3-methoxy-1-(pyrazin-2-yl)propyl)-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (49) LRMS (ES) (M+H)+: observed = 532.3, calculated = 531.7. 25608 EXAMPLE 50
Figure imgf000157_0001
isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (50) Step 1: Preparation of 2-(3-methoxyprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50b) A mixture of K2CO3 (0.39 g, 2.85 mmol), CuFe2O4 (0.68 g, 2.85 mmol), 3-methoxyprop-1- yne (50a, 2.0 g, 28.5 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.97 g, 31.4 mmol) in MeOH (20 mL) was stirred at 50 °C for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The mixture was quenched with water and extracted with EtOAc (3 x 30 mL). Filtered and concentrated in vacuo to give crude 2-(3-methoxyprop-1-en-1- yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50b, 6.0 g, 85%). LRMS (ES) (M+H)+: observed = 199.1, calculated = 198.0. Step 2: Preparation of 2-chloro-5-fluoro-4-(3-methoxyprop-1-en-1-yl)pyrimidine (50c) To a solution of 2,4-dichloro-5-fluoropyrimidine (2.0 g, 11.98 mmol) in Dioxane (50 mL) and Water (10 mL) were added 2-(3-methoxyprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50b, 2.97 g, 11.98 mmol), K2CO3 (3.31 g, 23.96 mmol) and PdCl2(dppf) (0.175 g, 0.240 mmol). The resulting mixture was stirred at 90 °C under N2 protection for 15 hours. The reaction mixture was concentrated, 100 mL H2O was added and extracted with EtOAc (50 mL×3). The organic layer dried over Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel 25608 chromatography (ISCO®; 120 g Biotage® Silica Flash Column, Eluent of 0-18% EtOAc/PE gradient) to give 2-chloro-5-fluoro-4-(3-methoxyprop-1-en-1-yl)pyrimidine (50c, 2.3 g, 85%). Step 3: Preparation of 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methoxypropan-1-ol (50d) A mixture of 2-chloro-5-fluoro-4-(3-methoxyprop-1-en-1-yl)pyrimidine (50c, 2.3 g, 11.35 mmol), cobalt(ii) acetylacetonate hydrate (0.312 g, 1.135 mmol) and phenylsilane (2.457 g, 22.70 mmol) in THF (20 mL) was stirred at 25 °C under N2 protection for 15 hours. The reaction was filtered and concentrated. The crude product was purified by column chormatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 50% EtOAc/ Petroleum ether gradient) to give 1-(2- chloro-5-fluoropyrimidin-4-yl)-3-methoxypropan-1-ol (50d, 1.7 g, 61%). LRMS (ES) (M+H)+: observed = 221.0, calculated = 220.6. Step 4: Preparation of 1-(5-fluoro-2-methylpyrimidin-4-yl)-3-methoxypropan-1-ol (50e) Na2CO3 (0.60 g, 5.67 mmol) and 1-(2-chloro-5-fluoropyrimidin-4-yl)-3-methoxypropan-1-ol (50d, 0.50 g, 2.27 mmol) were combined in a flask, 4-Dioxane (4 mL) / Water (1 mL).2,4,6-trimethyl- 1,3,5,2,4,6-trioxatriborinane (341 mg, 2.72 mmol) and PdCl2(dppf) (166 mg, 0.227 mmol) were added at 25 °C. Then the mixture was stired at 90 °C under N2 . for 12 hours. The reaction was quenched with water and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (2 x 10 mL), dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give crude product. The crude material was dissolved in EtOAc (10 mL) and aqueous HCl solution (1 M, 40 mL). The water was basified to pH= 7 with 1M aq. Na2CO3 and extracted with DCM: MeOH=10:1(3 x 10 mL), dried (Na2SO4). Filtered and the filtrate was concentrated in vacuo. The crude product was purified by prep-TLC (Petroleum ether: EtOAc= 2:1) to give 1-(5-fluoro-2-methylpyrimidin-4-yl)-3-methoxypropan-1-ol (50e, 98%) LRMS (ES) (M+H)+: observed = 201.0, calculated = 200.2. Steps 5-7: In an analogous manner to example 16-1, 1-(5-fluoro-2-methylpyrimidin-4-yl)-3- methoxypropan-1-ol (50e) was used to prepare (2R,6R)-4-((R)-1-(5-fluoro-2-methylpyrimidin-4- yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (50) LRMS (ES) (M+H)+: observed = 564.3, calculated = 563.7.
25608 EXAMPLE 51
Figure imgf000159_0001
2- yl)benzyl)piperazine-2-carboxamide (51) Step 1: Preparation of 3-methoxy-1-phenylpropan-1-one (51b) To a stirred solution of 3-chloro- 1-phenylpropan-1-one (51a, 0.30 g, 1.78 mmol) in Methanol (6 mL) was added sodium iodide (0.267 g, 1.78 mmol) and the resulting mixture was heated overnight at 60°C. The mixture was allowed to cool to room temperature, filtered through celite and concentrated. Flash column purification using a 0-20% ethyl acetate/ hexane gradient gave 3-methoxy-1-phenylpropan-1-one (51b, 0.247 g, 85%). Step 2: Preparation of (2R,6R)-1-isobutyryl-4-(3-methoxy-1-phenylpropyl)-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (51) To a stirred solution of (2R,6R)-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (12g, 0.024 g, 0.063 mmol) and 3-methoxy-1-phenylpropan-1-one (51b, 0.041 g, 0.252 mmol) in dichloroethane (0.42 mL) was added solid supported sodium cyanoborohydride 2.51 mmol/g (0.08 g) and acetic acid (0.022 mL). The resulting mixture was heated via microwave irradiation to 100°C for 2 hours. The mixture was filtered through celite and concentrated. The crude material was purified by reverse phase purification to give (2R,6R)-1-isobutyryl-4-(3-methoxy-1-phenylpropyl)-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (51, 0.007 g, 17%). LRMS (ES) (M+H)+: observed = 530.4, calculated = 529.7. 25608 EXAMPLE 52
Figure imgf000160_0001
2- yl)benzyl)piperazine-2-carboxamide (52) Steps 1-2: In an analogous manner to example 51, 3-chloro-1-phenylpropan-1-one (51a) and ethanol were used to prepare (2R,6R)-4-(3-ethoxy-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (52) LRMS (ES) (M+H)+: observed = 544.4, calculated = 543.7. EXAMPLE 53
25608 Preparation of (2R,6R)-1-isobutyryl-4-((S)-(1-(methoxymethyl)cyclobutyl)(phenyl)methyl)-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (53) Step 1: Preparation of (1-(methoxymethyl)cyclobutyl)(phenyl)methanol (53b) To a stirred solution of 1-(methoxymethyl)cyclobutanecarbaldehyde (53a, 0.40 g, 3.12 mmol) in THF (10 mL) chilled in an ice bath under N2 was added phenyl magnesium bromide solution (1M, 4.68 mL, 4.68 mmol) and the resulting mixture was at 0°C for 90 minutes. The mixture was poured into saturated ammonium chloride solution and extracted several times with ethyl acetate. The combined organic layers were concentrated. Flash column purification using a 0-10% ethyl acetate/ hexane gradient gave (1-(methoxymethyl)cyclobutyl)(phenyl)methanol (53b, 0.547 g, 85%). Step 2: Preparation of (bromo(1-(methoxymethyl)cyclobutyl)methyl)benzene (53c) To a stirred solution of (1-(methoxymethyl)cyclobutyl)(phenyl)methanol (53b, 0.540 g, 2.62 mmol) in ethyl ether (4 mL) was added pyridine (0.085 mL, 1.05 mmol) and the resulting mixture was chilled in an ice bath. To this was added PBr3 (0.37 mL, 3.93 mmol) dissolved in ethyl ether (3mL) dropwise over 5 minutes. The resulting solution was stirred 30 minutes and allowed to warm to room temperature. The mixture was chilled to 0°C and quenched with ice. The mixture was extracted with ethyl ether, dried over sodium sulfate and concentrated to give (bromo(1- (methoxymethyl)cyclobutyl)methyl)benzene (53c, 0.568 g, 81%) Steps 3-4: In an analogous manner to example 16-1, (bromo(1-(methoxymethyl) cyclobutyl)methyl)benzene (53c) was used to prepare (2R,6R)-1-isobutyryl-4-((S)-(1- (methoxymethyl)cyclobutyl)(phenyl)methyl)-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine- 2-carboxamide (53) LRMS (ES) (M+H)+: observed = 570.5, calculated = 569.7. EXAMPLE 54
25608 a b c O O
Figure imgf000162_0001
6-methyl-N- (4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (54) Step 1: Preparation of 3-methoxy-1-phenylpropan-1-one (54b) To a stirred solution of propiophenone (54a, 0.66 g, 4.93 mmol) in methanol (3 mL) was added potassium carbonate (0.068 g, 0.493 mmol) and formaldehyde (0.367 mL, 4.93 mmol) and the resulting mixture was stirred 10 days at room temperature. The mixture was concentrated and flash column purification using a 0-10% ethyl acetate/ hexane gradient gave 3-methoxy-1-phenylpropan-1-one (54b, 0.624 g, 71%). Step 2: Preparation of 3-methoxy-2-methyl-1-phenylpropan-1-ol (54c) To a stirred solution of 3- methoxy-1-phenylpropan-1-one (54b, 0.818 g, 4.59 mmol) in THF (15 mL) and Methanol (1 mL) chilled in an ice bath was added sodium borohydride (0.174 g, 4.59 mmol) and the mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate and washed with brine. The organic phase was concentrated and flash column purification using a 0-30% ethyl acetate/ hexane gradient gave 3-methoxy-2-methyl-1-phenylpropan-1-ol (54c, 0.627 g, 76%). Step 3: In an analogous manner to example 53c, 3-methoxy-2-methyl-1-phenylpropan-1-ol (54c) was used to prepare (1-bromo-3-methoxy-2-methylpropyl)benzene (54d). 25608 Steps 4-5: In an analogous manner to example 16-1, (1-bromo-3-methoxy-2- methylpropyl)benzene (54d) was used to prepare (2R,6R)-1-isobutyryl-4-((1R)-3-methoxy-2- methyl-1-phenylpropyl)-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (54) LRMS (ES) (M+H)+: observed = 544.5, calculated = 543.7. EXAMPLE 55
Figure imgf000163_0001
6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (55) Steps 1-4: In an analogous manner to example 36, 1,3-difluorobenzene (55a) was used to prepare (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (55) LRMS (ES) (M+H)+: observed = 566.4, calculated = 565.6. EXAMPLE 56 25608
Figure imgf000164_0001
6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (56) Steps 1-4: In an analogous manner to example 36, 1,3-difluorobenzene (55a) and 3- (methylthio)propanal was used to prepare (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3- (methylthio)propyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (56) LRMS (ES) (M+H)+: observed = 582.4, calculated = 581.7. EXAMPLE 57
25608 Preparation of (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-3-(methylsulfinyl)propyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (57) Step 1: To a stirred solution of (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-(methylthio)propyl)-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (56, 0.025g, 0.036 mmol) in dichloromethane (0.30 mL) was added mCPBA (0.009 g, 0.036 mmol) and the resulting solution was stirred 20 min and concentrated. The crude material was purified by reverse phase purification to give (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-3- (methylsulfinyl)propyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (57, 0.014 g, 55%). LRMS (ES) (M+H)+: observed = 598.4, calculated = 597.7. EXAMPLE 58 Preparation of
Figure imgf000165_0001
propyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (58) Step 1: To a stirred solution of (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-(methylthio)propyl)-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (56, 0.020 g, 0.036 mmol) in dichloromethane (0.30 mL) was added mCPBA (0.014 g, 0.057 mmol) and the resulting solution was stirred 20 min and concentrated. The crude material was purified by reverse phase purification to give (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3- (methylsulfonyl)propyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (58, 0.010 g, 48%). LRMS (ES) (M+H)+: observed = 614.5, calculated = 613.7. 25608 EXAMPLE 59
Figure imgf000166_0001
4-yl)methyl)-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (59) Steps 1-4: In an analogous manner to example 36, 1,3-difluorobenzene (55a) and tetrahydro-2H- pyran-4-carbaldehyde was used to prepare (2R,6R)-4-((R)-(2,6-difluorophenyl)(tetrahydro-2H- pyran-4-yl)methyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (59) LRMS (ES) (M+H)+: observed = 592.5, calculated = 591.7. EXAMPLE 60
25608
Figure imgf000167_0001
6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (60) Step 1: Preparation of N-methoxy-N-methyl-1,4-dioxane-2-carboxamide (60b) To a stirred solution of 1,4-dioxane-2-carboxylic acid (60a, 3.0 g, 22.71 mmol), N,O-dimethylhydroxylamine HCl (2.66 g, 27.2 mmol) and DMAP (0.277 g, 2.27 mmol) in Dichloromethane (65 mL) was added EDC (5.22 g, 27.2 mmol) and triethylamine (3.8 mL, 27.2 mmol). The resulting solution was stirred 4 hours, quenched with 1N HCl solution and extracted with dichloromethane, and ethyl acetate. The combined organic layers were concentrated. Flash column purification using a 0-100% ethyl acetate/ hexane gradient gave N-methoxy-N-methyl-1,4-dioxane-2-carboxamide (60b, 2.95 g, 74%). LRMS (ES) (M+H)+: observed = 175.1, calculated = 176.1. Step 2: In an analogous manner to example 36, 1,3-difluorobenzene (55a) and N-methoxy-N- methyl-1,4-dioxane-2-carboxamide (60b) were used to prepare (2,6-difluorophenyl)(tetrahydro- 2H-pyran-4-yl)methanone (60c) LRMS (ES) (M+H)+: observed = 229.1, calculated = 228.1. Step 3: In an analogous manner to example 54c, (2,6-difluorophenyl)(tetrahydro-2H-pyran-4- yl)methanone (60c) and sodium borohydride were used to prepare (2,6-difluorophenyl)(1,4- dioxan-2-yl)methanol (60d) LRMS (ES) (M+H)+: observed = 231.1, calculated = 230.2. Steps 4-6: In an analogous manner to example 36, (2,6-difluorophenyl)(1,4-dioxan-2- yl)methanol (60d) was used to prepare (2R,6R)-4-((1S)-(2,6-difluorophenyl)(1,4-dioxan-2- yl)methyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (60) LRMS (ES) (M+H)+: observed = 594.7, calculated = 593.6. 25608 EXAMPLE 61
Figure imgf000168_0001
N- (4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (61) Step 1: Preparation of -(2,6-difluorophenyl)-4-oxobutanenitrile (61b) To a stirred solution of 1- (2,6-difluorophenyl)ethan-1-one (61a, 0.7 mL, 5.37 mmol) in THF (16.7 ml) chilled in an ice bath to 0°C was added LDA (2.0M, 2.68 mL, 5.37 mmol) dropwise. The resulting solution was stirred for 20 minutes and then bromoacetonitrile (0.41 mL, 5.90 mmol) was added. The reaction was stirred for 90 minutes then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was concentrated and flash column purification using a 0-30% ethyl acetate/ hexane gradient gave 4-(2,6-difluorophenyl)-4-oxobutanenitrile (61b, 0.35 g, 33%). Step 2: In an analogous manner to example 54c, 4-(2,6-difluorophenyl)-4-oxobutanenitrile (61b) and sodium borohydride were used to prepare 4-(2,6-difluorophenyl)-4-hydroxybutanenitrile (61c) LRMS (ES) (M+H)+: observed = 198.0, calculated = 197.1. Steps 3-5: In an analogous manner to example 16-1, 4-(2,6-difluorophenyl)-4- hydroxybutanenitrile (61c) was used to prepare (2R,6R)-4-((R)-3-cyano-1-(2,6- 25608 difluorophenyl)propyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (61) LRMS (ES) (M+H)+: observed = 561.2, calculated = 560.6. EXAMPLE 62 Preparation of
Figure imgf000169_0001
5-((4- (pyrimidin-2-yl)benzyl)carbamoyl)piperazin-1-yl)propanoate (62) Step 1: To a stirred solution of (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (12g, 0.04 g, 0.105 mmol) in DCM (0.24 mL) under nitrogen was added triethylamine (0.03 mL, 0.215 mmol), followed by addition of trimethylsilyl chloride (0.02 mL, 0.156 mmol). The resulting solution was stirred at room temperature for 1 hour 30 minutes and concentrated under nitrogen. The mixture was dissolved in THF (0.24 mL) under nitrogen. To this was added 2,6-difluorobenzaldehyde (0.02 mL, 0.185 mmol) and trimethylsilyl chloride (0.02 mL, 0.156 mmol). The resulting mixture was stirred 30 minutes then concentrated under nitrogen. To the mixture was added THF (0.24 mL) and 1- (tertbutyldimethylsilyloxy)-1-methoxyethene (0.046 mL, 0.21 mmol) under nitrogen. Upon completion of reaction the mixture was concentrated and purified by reverse phase purification to give methyl 3-(2,6-difluorophenyl)-3-((3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazin-1-yl)propanoate (62, 0.012 g, 17%). LRMS (ES) (M+H)+: observed = 580.7, calculated = 579.6. 25608 EXAMPLE 63 F F F O F O F F F
Figure imgf000170_0001
6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (63) Step 1: In an analogous manner to example 13a, 2,6-difluorobenzaldehyde (3a) and 1,1,1- trifluoropropan-2-ol was used to prepare 2-fluoro-6-((1,1,1-trifluoropropan-2- yl)oxy)benzaldehyde (63a, 65%) LRMS (ES) (M+H)+: observed = 237.0, calculated = 236.1. Step 2: In an analogous manner to example 1-1, (2R,6R)-1-isobutyryl-6-methylpiperazine-2- carboxylic acid (16a) and 2-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)benzaldehyde (63a) were used to prepare (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxylic acid (63b, 76%). LRMS (ES) (M+H)+: observed = 435.3, calculated = 434.4. Step 3: In an analogous manner to example 16-1, (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoropropan- 2-yl)oxy)benzyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (63b) and (4-(pyrimidin-2- yl)phenyl)methanamine, HCl were used to prepare (2R,6R)-4-(2-fluoro-6-((1,1,1- trifluoropropan-2-yl)oxy)benzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine- 2-carboxamide (63, 68%). LRMS (ES) (M+H)+: observed = 602.3, calculated = 601.6. 25608 EXAMPLE 64 F F F O F F O F F
Figure imgf000171_0001
6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (64) Steps 1-3: In an analogous manner to example 63, 2,6-difluorobenzaldehyde (3a) and 1- cyclopropyl-2,2,2-trifluoroethan-1-ol were used to prepare (2R,6R)-4-(2-(1-cyclopropyl-2,2,2- trifluoroethoxy)-6-fluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine- 2-carboxamide (64) LRMS (ES) (M+H)+: observed = 628.3, calculated = 627.6. EXAMPLE 65
25608 Preparation of (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoro-3,3-dimethylbutan-2-yl)oxy)benzyl)-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (65) Steps 1-3: In an analogous manner to example 63, 2,6-difluorobenzaldehyde (3a) and 1,1,1- trifluoro-3,3-dimethylbutan-2-ol were used to prepare (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoro- 3,3-dimethylbutan-2-yl)oxy)benzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (65) LRMS (ES) (M+H)+: observed = 644.3, calculated = 643.7. EXAMPLE 66 F F F O F F O F
Figure imgf000172_0001
6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (66) Steps 1-3: In an analogous manner to example 63, 2,6-difluorobenzaldehyde (3a) and 1,1,1- trifluorobutan-2-ol were used to prepare (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluorobutan-2- yl)oxy)benzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (66) LRMS (ES) (M+H)+: observed = 616.3, calculated = 615.6.
25608 EXAMPLE 67 F F F O F F O F F
Figure imgf000173_0001
isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (67) Steps 1-3: In an analogous manner to example 63, 2,6-difluorobenzaldehyde (3a) and 1,1,1- trifluoro-3-methylbutan-2-ol were used to prepare (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoro-3- methylbutan-2-yl)oxy)benzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (67) LRMS (ES) (M+H)+: observed = 630.3, calculated = 629.7. EXAMPLE 68 Preparation
Figure imgf000173_0002
- - 2- yl)benzyl)piperazine-2-carboxamide (68) 25608 Step 1: Preparation of (3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazin-1-yl benzoate (68a). To a stirred solution of (2R,6R)-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide HCl (12g, 1.11 g, 2.66 mmol) in DMF (20.0 mL) under nitrogen was added K2HPO4 (2.32 g, 13.32 mmol), followed by addition of benzoyl peroxide (0.71 g, 2.93 mmol). The resulting solution was stirred at room temperature overnight. Additional K2HPO4 (2.32 g, 13.32 mmol) and benzoyl peroxide (0.71 g, 2.93 mmol) were added and stirred for 3 hours under nitrogen. The mixture was diluted with water and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. Flash column purification using a 0-100% ethyl acetate/ heptane gradient gave (3R,5R)-4-isobutyryl-3-methyl-5-((4- (pyrimidin-2-yl)benzyl)carbamoyl)piperazin-1-yl benzoate (68a, 0.389 g, 29%). LRMS (ES) (M+H)+: observed = 502.3, calculated = 501.5. Step 2: Preparation of (2R,6R)-1-isobutyryl-6-methyl-4-(1-phenylpropyl)-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (68). To a solution of (3R,5R)-4-isobutyryl-3-methyl-5-((4- (pyrimidin-2-yl)benzyl)carbamoyl)piperazin-1-yl benzoate (68a, 0.045 g, 0.090 mmol) dissolved in THF (0.3 mL) under nitrogen was added (E)-prop-1-en-1-ylbenzene (15.0 uL, 0.116 mmol). To this mixture was added a catalyst solution prepared by combining Cu(OAc)2 (1 mg, 5.51 uM), DTBM-SEGPHOS (6.5 mg, 5.51 uM) in THF (0.3 mL) under nitrogen followed by addition of methyldiethoxysilane (29uL, 0.181 mmol). After addition of the catalyst solution, the reaction was heated overnight at 40°C. The reaction was concentrated and flash column purification using a 0-100% ethyl acetate/ heptane gradient gave (2R,6R)-1-isobutyryl-6-methyl-4-(1- phenylpropyl)-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (68, 0.015 g, 33%). LRMS (ES) (M+H)+: observed = 500.3, calculated = 499.6. EXAMPLE 69
25608
Figure imgf000175_0001
(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (69) Step 1: Preparation of tert-butyl(cinnamyloxy)dimethylsilane (69b). To a stirred solution of (E)- 3-phenylprop-2-en-1-ol (69a, 0.25 g, 1.86 mmol) in DCM (10.0 mL) was added imidazole (0.19 g, 2.79 mmol), followed by addition of TBDMS-Cl (0.42 g, 2.79 mmol). The resulting solution was stirred at room temperature overnight. The solution was filtered through celite and concentrated. Flash column purification using a 0-25% ethyl acetate/ heptane gradient gave tert- butyl(cinnamyloxy)dimethylsilane (69b, 0.423 g, 91%). Step 2: In an analogous manner to example 68, (3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin- 2-yl)benzyl)carbamoyl)piperazin-1-yl benzoate (68a), tert-butyl(cinnamyloxy)dimethylsilane (69b) and R-DTBM-SEGPHOS were used to prepare (2R,6R)-4-((R)-3-((tert- butyldimethylsilyl)oxy)-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (69c) LRMS (ES) (M+H)+: observed = 630.4, calculated = 629.9. Step 3: Preparation of (2R,6R)-4-((R)-3-hydroxy-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (69). To a stirred solution of (2R,6R)-4-((R)-3- ((tert-butyldimethylsilyl)oxy)-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (69c, 0.032 g, 0.051 mmol) in THF (0.5 mL) was added TBAF (1M, 0.16 mL, 0.16 mmol) and the resulting mixture was stirred at room temperature for 4 hours and concentrated. Flash column purification using a 0-100% ethyl acetate/ heptane gradient gave (2R,6R)-4-((R)-3-hydroxy-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (69, 0.021 g, 80%). 25608 EXAMPLE 70 Preparation
Figure imgf000176_0001
2-yl)ethyl)- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (70) Step 1: Preparation of (E)-2-styryltetrahydrofuran (70b) To a stirred solution of tetrahydrofuran- 2-carboxylic acid (70a, 0.24 mL, 2.50 mmol) and cesium bicarbonate (0.794 g, 4.09 mmol) in dioxane (4 mL) under nitrogen was added (E)-(2-(phenylsulfon yl)vinyl)benzene (0.20 g, 0.819 mmol) and [IR(DTBBPY)(PPY)2]PF6 (0.004 g, 4.38 uM). The resulting mixture was irradiated with 450nM 100% blue LED in an integrated photoreactor with fan cooling overnight. The crude reaction was diluted with ethyl acetate, filtered through celite and concentrated. Flash column purification using a 0-25% ethyl acetate/ heptane gradient gave (E)-2-styryltetrahydrofuran (70b, 0.021 g, 14%). Step 2: In an analogous manner to example 68, (3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin- 2-yl)benzyl)carbamoyl)piperazin-1-yl benzoate (68a), (E)-2-styryltetrahydrofuran (70b) and R- DTBM-SEGPHOS were used to prepare (2R,6R)-1-isobutyryl-6-methyl-4-((1R)-1-phenyl-2- (tetrahydrofuran-2-yl)ethyl)-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (70) LRMS (ES) (M+H)+: observed = 556.4, calculated = 555.7. EXAMPLE 71 25608
Figure imgf000177_0001
Preparation of (2R,6R)-4-((R)-3-(difluoromethoxy)-1-phenylpropyl)-1-isobutyryl-6-methyl-N- (4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (71) Step 1: Preparation of (E)-(3-(difluoromethoxy)prop-1-en-1-yl)benzene (71a) To a stirred solution of (E)-3-phenylprop-2-en-1-ol (69a, 0.25 g, 1.86 mmol) in DCM (1.2 mL) under nitrogen was added potassium hydrogen flouride (0.58 g, 7.45 mmol) and water (1.2 mL). This mixture was degassed with nitrogen and added to this was (bromodifluoromethyl)trimethylsilane (0.58 mL, 3.74 mmol) dropwise. The resulting mixture was stirred at room temperature overnight, diluted with DCM, filtered through celite and concentrated. Flash column purification using a 100% hexanes gave (E)-(3-(difluoromethoxy)prop-1-en-1-yl)benzene (71a, 0.281 g, 82%). Step 2: In an analogous manner to example 68, (3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin- 2-yl)benzyl)carbamoyl)piperazin-1-yl benzoate (68a), (E)-(3-(difluoromethoxy)prop-1-en-1- yl)benzene (71a) and R-DTBM-SEGPHOS were used to prepare (2R,6R)-4-((R)-3- (difluoromethoxy)-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (71) LRMS (ES) (M+H)+: observed = 566.3, calculated = 565.6. 25608 EXAMPLE 72
Figure imgf000178_0001
-N- (4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (72) Step 1: Preparation of (E)-(3-(trifluoromethoxy)prop-1-en-1-yl)benzene (72a) To a microwave vial containing (E)-3-phenylprop-2-en-1-ol (69a, 0.25 g, 1.86 mmol), silver trifluoromethanesulfonate (0.957 mg, 3.73 mmol), Selectfluor (990 mg, 2.79 mmol), and potassium flouride (325 mg, 5.59mmol) was added ethyl acetate (8 mL) under nitrogen. After one minute was added 2-fluoropyridine (032 mL, 3.73 mmol) and TMS-CF3 (0.55 mL, 3.72 mmol). This mixture was degassed with nitrogen and was stirred at room temperature overnight, diluted with ethyl acetate, filtered through celite and concentrated. Flash column purification using a 100% hexanes gave (E)-(3-(trifluoromethoxy)prop-1-en-1-yl)benzene (72a, 0.211 g, 56%). Step 2: In an analogous manner to example 68, (3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin- 2-yl)benzyl)carbamoyl)piperazin-1-yl benzoate (68a), (E)-(3-(trifluoromethoxy)prop-1-en-1- yl)benzene (72a) and R-DTBM-SEGPHOS were used to prepare (2R,6R)-1-isobutyryl-6-methyl- 4-((R)-1-phenyl-3-(trifluoromethoxy)propyl)-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (72) LRMS (ES) (M+H)+: observed = 584.3, calculated = 583.6. 25608 EXAMPLE 73
Figure imgf000179_0001
trifluoro-1-phenylbutyl)piperazine-2-carboxamide (73) Step 1: Preparation of (E)-(4,4,4-trifluorobut-1-en-1-yl)benzene (73b) To a stirred solution of copper (I) thiophene-2-carboxylate (0.005 g, 0.026 mmol) and potassium flouride (0.223 g, 3.85 mmol) in THF (6 mL) under nitrogen was added cinnamyl bromide (0.19 mL, 1.28 mmol) and TMS-CF3 (0.57 mL, 3.86 mmol). The resulting mixture was heated to 60°C overnight, diluted with ethyl acetate, filtered through celite and concentrated. Flash column purification using a 100% hexanes gave (E)-(4,4,4-trifluorobut-1-en-1-yl)benzene (73b, 0.130 g, 54%). Step 2: In an analogous manner to example 68, (3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin- 2-yl)benzyl)carbamoyl)piperazin-1-yl benzoate (68a), (E)-(4,4,4-trifluorobut-1-en-1-yl)benzene (73b) and R-DTBM-SEGPHOS were used to prepare (2R,6R)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)-4-((R)-4,4,4-trifluoro-1-phenylbutyl)piperazine-2-carboxamide (73) LRMS (ES) (M+H)+: observed = 568.3, calculated = 567.6.
25608 EXAMPLE 74 F F H F N a O b P
Figure imgf000180_0001
isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (74) Step 1: Preparation of diethyl (2,6-difluorobenzyl)phosphonate (74b) 2-(bromomethyl)-1,3- difluorobenzene (74a, 500 mg, 2.415 mmol) and triethyl phosphite (1.3 mL, 7.43 mmol) were combined neat then heated to 130 °C overnight. The mixture was allowed to cool and flash column purification using a 0-50% ethyl acetate/ heptane gradient gave diethyl (2,6- difluorobenzyl)phosphonate (74b, 0.693 g, Quan). Step 2: Preparation of (E)-2-(2,6-difluorostyryl)tetrahydrofuran (74c) A solution of diethyl (2,6- difluorobenzyl)phosphonate (74b, 165 mg, 0.624 mmol) in 4 mL THF was cooled to 0 °C. To this was added 1M NaHMDS (0.625 ml, 0.625 mmol) in THF slowly. After 15 minutes, a solution of tetrahydrofuran-2-carbaldehyde (50 mg, 0.499 mmol) in 1 mL THF was added slowly. After 2 hr the mixture was diluted with saturated aqueous NH4Cl and extracted with EtOAc (3x). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. Flash column purification using a 0-10% EtOAc/heptane gradient gave (E)-2-(2,6- difluorostyryl)tetrahydrofuran. (74c, 0.015 g, 15%). Step 3: In an analogous manner to example 68a, methyl (2R,6R)-1-isobutyryl-6- methylpiperazine-2-carboxylate (16a), and benzoyl peroxide were used to prepare methyl 25608 (2R,6R)-4-(benzoyloxy)-1-isobutyryl-6-methylpiperazine-2-carboxylate (74d) LRMS (ES) (M+H)+: observed = 349.2, calculated = 348.4. Step 4: In an analogous manner to example 68, methyl (2R,6R)-4-(benzoyloxy)-1-isobutyryl-6- methylpiperazine-2-carboxylate (74d), (E)-2-(2,6-difluorostyryl)tetrahydrofuran. (74c) and S- DTBM-SEGPHOS were used to prepare methyl (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-2- (tetrahydrofuran-2-yl)ethyl)-1-isobutyryl-6-methylpiperazine-2-carboxylate (74e) LRMS (ES) (M+H)+: observed = 439.3, calculated = 438.5. Step 5: In an analogous manner to example 1f, methyl (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-2- (tetrahydrofuran-2-yl)ethyl)-1-isobutyryl-6-methylpiperazine-2-carboxylate (74e) and potassium trimethylsilanolate were used to prepare (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-2- (tetrahydrofuran-2-yl)ethyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (74f). LRMS (ES) (M+H)+: observed = 425.3, calculated = 424.5. Step 6: In an analogous manner to example 12f, (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-2- (tetrahydrofuran-2-yl)ethyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (74f) and (4- (pyrimidin-2-yl)phenyl)methanamine were used to prepare (2R,6R)-4-((1R)-1-(2,6- difluorophenyl)-2-(tetrahydrofuran-2-yl)ethyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (74). LRMS (ES) (M+H)+: observed = 592.4, calculated = 591.7. EXAMPLE 75 F F a O Br TMS F F 75a 75b F F F O OH OH OH O N F N F N F N O b O c O d O N N N N O O OH NH O O O O 74d 75c 75d 75 N N 25608 Preparation of (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-hydroxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (75) Step 1: Preparation of (E)-((3-(2,6-difluorophenyl)allyl)oxy)trimethylsilane (75b) To a vial charged with 2-bromo-1,3-difluorobenzene (75a, 250 mg, 1.295 mmol), (E)- trimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane (431 mg, 1.684 mmol), and Pd(Ph3P)4 (150 mg, 0.130 mmol), was added DME (10 ml) and 2M K2CO3 (1.3 ml, 2.60 mmol). The vial was sealed then degassed (3xpump/N2). The gas inlet was removed and the mixture heated to 80 °C overnight. The mixture was allowed to cool, diluted with EtOAc, filtered through a pad of Celite and concentrated. Flash column purification using a 0-25% EtOAc/heptane gradient gave (E)-((3-(2,6-difluorophenyl)allyl)oxy)trimethylsilane (75b, 0.137 g, 44%). Step 2: In an analogous manner to example 68, methyl (2R,6R)-4-(benzoyloxy)-1-isobutyryl-6- methylpiperazine-2-carboxylate (74d), (E)-((3-(2,6-difluorophenyl)allyl)oxy)trimethylsilane (75b) and S-DTBM-SEGPHOS were used to prepare methyl (2R,6R)-4-((R)-1-(2,6- difluorophenyl)-3-hydroxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylate (75c) LRMS (ES) (M+H)+: observed = 399.4, calculated = 398.4. Step 3: In an analogous manner to example 1f, methyl (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3- hydroxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylate (75c) and potassium trimethylsilanolate were used to prepare (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3- hydroxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (75d). LRMS (ES) (M+H)+: observed = 385.3, calculated = 384.4. Step 4: In an analogous manner to example 12f, (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3- hydroxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (75d) and (4-(pyrimidin-2- yl)phenyl)methanamine were used to prepare (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3- hydroxypropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (75). LRMS (ES) (M+H)+: observed = 552.4, calculated = 551.6.
25608 EXAMPLE 76
Figure imgf000183_0001
trifluoro-3-hydroxy-3-methyl-1-phenylbutyl)piperazine-2-carboxamide (76) Step 1: Preparation of (E)-trimethyl((1,1,1-trifluoro-2-methyl-4-phenylbut-3-en-2-yl)oxy)silane (76b) A vial was charged with CsF (12 mg, 0.079 mmol), DME (7 ml), and (E)-4-phenylbut-3- en-2-one (225 mg, 1.539 mmol). The vial was sealed with a septum cap then TMS-CF3 (0.28 ml, 1.894 mmol) was added via syringe at room temperature. After 3 hr the mixture was concentrated. Flash column purification using a 100% hexanes gave (E)-trimethyl((1,1,1- trifluoro-2-methyl-4-phenylbut-3-en-2-yl)oxy)silane (76b, 0.402 g, 91%). Step 2: In an analogous manner to example 68, methyl (2R,6R)-4-(benzoyloxy)-1-isobutyryl-6- methylpiperazine-2-carboxylate (74d), (E)-trimethyl((1,1,1-trifluoro-2-methyl-4-phenylbut-3-en- 2-yl)oxy)silane (76b) and S-DTBM-SEGPHOS were used to prepare methyl (2R,6R)-1- isobutyryl-6-methyl-4-((1R)-4,4,4-trifluoro-3-methyl-1-phenyl-3- ((trimethylsilyl)oxy)butyl)piperazine-2-carboxylate (76c) LRMS (ES) (M+H)+: observed = 517.4, calculated = 516.6. Step 3: In an analogous manner to example 1f, methyl (2R,6R)-1-isobutyryl-6-methyl-4-((1R)- 4,4,4-trifluoro-3-methyl-1-phenyl-3-((trimethylsilyl)oxy)butyl)piperazine-2-carboxylate (76c) 25608 and potassium trimethylsilanolate were used to prepare (2R,6R)-1-isobutyryl-6-methyl-4-((1R)- 4,4,4-trifluoro-3-hydroxy-3-methyl-1-phenylbutyl)piperazine-2-carboxylic acid (76d). LRMS (ES) (M+H)+: observed = 431.3, calculated = 430.4. Step 4: In an analogous manner to example 12f, (2R,6R)-1-isobutyryl-6-methyl-4-((1R)-4,4,4- trifluoro-3-hydroxy-3-methyl-1-phenylbutyl)piperazine-2-carboxylic acid (76d) and (4- (pyrimidin-2-yl)phenyl)methanamine were used to prepare (2R,6R)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)-4-((1R)-4,4,4-trifluoro-3-hydroxy-3-methyl-1-phenylbutyl)piperazine-2- carboxamide (76). LRMS (ES) (M+H)+: observed = 598.4, calculated = 597.6. EXAMPLE 77
Figure imgf000184_0001
N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (77) Step 1: Preparation of (E)-tert-butyl((4-(2,6-difluorophenyl)but-3-en-2-yl)oxy)dimethylsilane (77a) To a vial charged with 2-bromo-1,3-difluorobenzene (75a, 100 mg, 0.518 mmol), (E)-tert- butyldimethyl((4-(tributylstannyl)but-3-en-2-yl)oxy)silane (296 mg, 0.622 mmol), and Pd(Ph3P)4 (60 mg, 0.052 mmol), was added toluene (4 ml). The vial was sealed then degassed (3xpump/N2). The gas inlet was removed and the mixture heated to 100 °C overnight. The mixture was allowed to cool and concentrated. Flash column purification using a 0-10% 25608 EtOAc/heptane gradient gave (E)-tert-butyl((4-(2,6-difluorophenyl)but-3-en-2- yl)oxy)dimethylsilane (77a, 0.086 g, 55%). Step 2: In an analogous manner to example 68, methyl (2R,6R)-4-(benzoyloxy)-1-isobutyryl-6- methylpiperazine-2-carboxylate (74d), (E)-tert-butyl((4-(2,6-difluorophenyl)but-3-en-2- yl)oxy)dimethylsilane (77a) and S-DTBM-SEGPHOS were used to prepare methyl (2R,6R)-4- ((1R)-3-((tert-butyldimethylsilyl)oxy)-1-(2,6-difluorophenyl)butyl)-1-isobutyryl-6- methylpiperazine-2-carboxylate (77b) LRMS (ES) (M+H)+: observed = 527.5, calculated = 526.7. Step 3: In an analogous manner to example 1f, methyl (2R,6R)-4-((1R)-3-((tert- butyldimethylsilyl)oxy)-1-(2,6-difluorophenyl)butyl)-1-isobutyryl-6-methylpiperazine-2- carboxylate (77b) and potassium trimethylsilanolate were used to prepare (2R,6R)-4-((1R)-1- (2,6-difluorophenyl)-3-hydroxybutyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (77c). LRMS (ES) (M+H)+: observed = 399.3, calculated = 398.4. Step 4: In an analogous manner to example 12f, (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-3- hydroxybutyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (77c) and (4-(pyrimidin-2- yl)phenyl)methanamine were used to prepare (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-3- hydroxybutyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (77). LRMS (ES) (M+H)+: observed = 566.4, calculated = 565.6. EXAMPLE 78
25608 Preparation of (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)-4-((1R)-4,4,4- trifluoro-3-hydroxy-1-phenylbutyl)piperazine-2-carboxamide (78) Step 1: Preparation of (E)-trimethyl((1,1,1-trifluoro-4-phenylbut-3-en-2-yl)oxy)silane (78b) A vial was charged with CsF (12 mg, 0.079 mmol), DME (7 ml), and cinnamaldehyde (78a, 0.190 ml, 1.513 mmol). The vial was sealed with a septum cap then TMS-CF3 (0.27 ml, 1.827 mmol) was added vial syringe at room temperature. After 3 hr the mixture was concentrated. Flash column purification using a 100% hexanes gave (E)-trimethyl((1,1,1-trifluoro-4-phenylbut-3-en- 2-yl)oxy)silane (78b, 0.379 g, 91%). Step 2: In an analogous manner to example 68, methyl (2R,6R)-4-(benzoyloxy)-1-isobutyryl-6- methylpiperazine-2-carboxylate (74d), (E)-trimethyl((1,1,1-trifluoro-4-phenylbut-3-en-2- yl)oxy)silane (78b) and S-DTBM-SEGPHOS were used to prepare methyl (2R,6R)-1-isobutyryl- 6-methyl-4-((1R)-4,4,4-trifluoro-1-phenyl-3-((trimethylsilyl)oxy)butyl)piperazine-2-carboxylate (78c) LRMS (ES) (M+H)+: observed = 503.4, calculated = 502.6. Step 3: In an analogous manner to example 1f, methyl (2R,6R)-1-isobutyryl-6-methyl-4-((1R)- 4,4,4-trifluoro-1-phenyl-3-((trimethylsilyl)oxy)butyl)piperazine-2-carboxylate (78c) and potassium trimethylsilanolate were used to prepare (2R,6R)-1-isobutyryl-6-methyl-4-((1R)-4,4,4- trifluoro-3-hydroxy-1-phenylbutyl)piperazine-2-carboxylic acid (78d). LRMS (ES) (M+H)+: observed = 417.3, calculated = 416.4. Step 4: In an analogous manner to example 12f, (2R,6R)-1-isobutyryl-6-methyl-4-((1R)-4,4,4- trifluoro-3-hydroxy-1-phenylbutyl)piperazine-2-carboxylic acid (78d) and (4-(pyrimidin-2- yl)phenyl)methanamine were used to prepare (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)-4-((1R)-4,4,4-trifluoro-3-hydroxy-1-phenylbutyl)piperazine-2-carboxamide (78). LRMS (ES) (M+H)+: observed = 584.4, calculated = 583.6.
25608 EXAMPLE 79
Figure imgf000187_0001
6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (79) Step 1: Preparation of (E)-4-(2,6-difluorophenyl)-2-methylbut-3-en-2-ol (79a) To a vial charged with 2-bromo-1,3-difluorobenzene (75a, 200 mg, 1.036 mmol), (E)-2-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol (275 mg, 1.295 mmol), and PdCl2(dppf) (76 mg, 0.104 mmol), was added DME (10 ml) and 2M K2CO3 (1.04 ml, 2.08 mmol). The vial was sealed then degassed (3xpump/N2). The gas inlet was removed and the mixture heated to 80 °C overnight. The mixture was allowed to cool, diluted with EtOAc, filtered through a pad of Celite and concentrated. Flash column purification using a 0-25% EtOAc/heptane gradient gave (E)-4-(2,6-difluorophenyl)-2-methylbut-3-en-2-ol (79a, 0.156 g, 76%). Step 2: Preparation of (E)-tert-butyl((4-(2,6-difluorophenyl)-2-methylbut-3-en-2- yl)oxy)dimethylsilane (79b) A solution of (E)-4-(2,6-difluorophenyl)-2-methylbut-3-en-2-ol (79a, 156 mg, 0.787 mmol) in DCM (4 mL) was cooled to 0 °C. To this was added 2,6-lutidine (0.37 mL, 3.18 mmol) then tert-butyldimethylsillyl trifluoromethanesulfonate (0.365 mL, 1.588 mmol). Additional 2,6-lutidine and tert-butyldimethylsillyl trifluoromethanesulfonate were added as needed until reaction completion. The mixture was concentrated. Flash column purification 25608 using a 0-10% EtOAc/heptane gradient gave (E)-tert-butyl((4-(2,6-difluorophenyl)-2-methylbut- 3-en-2-yl)oxy)dimethylsilane (79b, 0.122 g, 50%). Step 3: In an analogous manner to example 68, methyl (2R,6R)-4-(benzoyloxy)-1-isobutyryl-6- methylpiperazine-2-carboxylate (74d), (E)-tert-butyl((4-(2,6-difluorophenyl)-2-methylbut-3-en- 2-yl)oxy)dimethylsilane (79b) and S-DTBM-SEGPHOS were used to prepare methyl (2R,6R)-4- ((R)-3-((tert-butyldimethylsilyl)oxy)-1-(2,6-difluorophenyl)-3-methylbutyl)-1-isobutyryl-6- methylpiperazine-2-carboxylate (79c) LRMS (ES) (M+H)+: observed = 541.5, calculated = 540.7. Step 4: In an analogous manner to example 1f, methyl (2R,6R)-4-((R)-3-((tert- butyldimethylsilyl)oxy)-1-(2,6-difluorophenyl)-3-methylbutyl)-1-isobutyryl-6-methylpiperazine- 2-carboxylate (79c) and potassium trimethylsilanolate were used to prepare (2R,6R)-4-((R)-3- ((tert-butyldimethylsilyl)oxy)-1-(2,6-difluorophenyl)-3-methylbutyl)-1-isobutyryl-6- methylpiperazine-2-carboxylic acid (79d). LRMS (ES) (M+H)+: observed = 528.5, calculated = 526.7. Step 5: Preparation of (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-hydroxy-3-methylbutyl)-1- isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (79) To a stirred solution of (2R,6R)-4-((R)-3-((tert-butyldimethylsilyl)oxy)-1-(2,6-difluorophenyl)-3- methylbutyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (79d, 0.032 g, 0.061 mmol) and (4-(pyrimidin-2-yl)phenyl)methanamine, HCl (0.018 g, 0.08 mmol) in DMF (0.5 mL) was added HATU (0.030 g, 0.079 mmol) and triethylamine (0.034 mL, 0.244 mmol). The resulting mixture was stirred at room temperature for 3 hours. To this was added HF-pyridine (0.03 mL, 0.333 mmol) and the mixture was heated to 50C for 30 minutes. The solution was allowed to cool, concentrated, and purified by prep-HPLC to give (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3- hydroxy-3-methylbutyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (79, 0.011 g, 26%). LRMS (ES) (M+H)+: observed = 580.5, calculated = 579.6.
25608 EXAMPLE 80 N-
Figure imgf000189_0001
(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (80) Step 1: Preparation of (S)-2-(2,6-difluorophenyl)-2-((3R,5R)-4-isobutyryl-3-methyl-5-((4- (pyrimidin-2-yl)benzyl)carbamoyl)piperazin-1-yl)acetic acid (80a) (2R,6R)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (12g, 300 mg, 0.786 mmol) dissolved in CH2Cl2 (1.5 ml) was added to a 2 mL microwave vial containing solid (2,6- difluorophenyl)boronic acid (248 mg, 1.573 mmol).2-oxoacetic acid (0.084 ml, 1.573 mmol) was added. The vial was sealed and heated to 120 C for 10 min. LCMS analysis showed formation of the desired product. The reaction was concentrated and purified by prep-HPLC to give (S)-2-(2,6-difluorophenyl)-2-((3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazin-1-yl)acetic acid (80a, 0.012 g, 3%). LRMS (ES) (M+H)+: observed = 552.4, calculated = 551.1. Step 2: Preparation of methyl (S)-2-(2,6-difluorophenyl)-2-((3R,5R)-4-isobutyryl-3-methyl-5- ((4-(pyrimidin-2-yl)benzyl)carbamoyl)piperazin-1-yl)acetate (80b) (S)-2-(2,6-difluorophenyl)-2- ((3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin-2-yl)benzyl)carbamoyl)piperazin-1-yl)acetic acid (80a, 12 mg, 0.022 mmol) was dissolved in DCM (290 µl) and MeOH (145 µl). The solution was cooled to 0 C and (trimethylsilyl)diazomethane (32.6 µl, 0.065 mmol) was added. Reaction was stirred 1 hr and concentrated to give crude methyl (S)-2-(2,6-difluorophenyl)-2-((3R,5R)-4- 25608 isobutyryl-3-methyl-5-((4-(pyrimidin-2-yl)benzyl)carbamoyl)piperazin-1-yl)acetate (80b) LRMS (ES) (M+H)+: observed = 566.5, calculated = 565.6. Step 3: Preparation of (2R,6R)-4-((S)-1-(2,6-difluorophenyl)-2-hydroxyethyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (80) methyl 2-(2,6- difluorophenyl)-2-((3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazin-1-yl)acetate (80b, 12 mg, 0.021 mmol) was dissolved in THF (450 µl) and MeOH (50 µl). Lithium tetrahydroborate (106 µl, 0.212 mmol) was added and the reaction was allowed to stir at rt for 30 min. The reaction was quenched with water (5 mL) and extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were washed with water (5 mL), dried (MgSO4) and concentrated. Purification by prep-HPLC to gave (2R,6R)-4-((S)-1- (2,6-difluorophenyl)-2-hydroxyethyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (80, 0.0075 g, 46%). LRMS (ES) (M+H)+: observed = 538.1, calculated = 537.6. EXAMPLE 81 N
Figure imgf000190_0001
N-(4-(oxazol-2-yl)benzyl)piperazine-2-carboxamide (81) Step 1: In an analogous manner to example 12f, (2R,6R)-4-(tert-butoxycarbonyl)-1-isobutyryl-6- methylpiperazine-2-carboxylic acid (12e) and (4-(oxazol-2-yl)phenyl)methanamine were used to prepare tert-butyl (3R,5R)-4-isobutyryl-3-methyl-5-((4-(oxazol-2- yl)benzyl)carbamoyl)piperazine-1-carboxylate (81a). LRMS (ES) (M+H)+: observed = 471.3, calculated = 470.5. 25608 Step 2: In an analogous manner to example 12g, tert-butyl (3R,5R)-4-isobutyryl-3-methyl-5-((4- (oxazol-2-yl)benzyl)carbamoyl)piperazine-1-carboxylate (81a) and HCl were used to prepare (2R,6R)-1-isobutyryl-6-methyl-N-(4-(oxazol-2-yl)benzyl)piperazine-2-carboxamide (81b). LRMS (ES) (M+H)+: observed = 371.3, calculated = 370.4. Step 3: In an analogous manner to example 13-5, (2R,6R)-1-isobutyryl-6-methyl-N-(4-(oxazol-2- yl)benzyl)piperazine-2-carboxamide (81b) was used to prepare (2R,6R)-4-(2-((2-ethylpyridin-3- yl)oxy)-6-fluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(oxazol-2-yl)benzyl)piperazine-2- carboxamide (81). LRMS (ES) (M+H)+: observed = 600.4, calculated = 599.7. EXAMPLE 82
Figure imgf000191_0001
2- yl)benzyl)piperazine-2-carboxamide (82) Step 1: In an analogous manner to example 12f, 4-(tert-butoxycarbonyl)-6-methylpiperazine-2- carboxylic acid (27a) and (4-(pyrimidin-2-yl)phenyl)methanamine were used to prepare tert- 25608 butyl 3-methyl-5-((4-(pyrimidin-2-yl)benzyl)carbamoyl)piperazine-1-carboxylate (82a). LRMS (ES) (M+H)+: observed = 412.3, calculated = 411.5. Step 2: In an analogous manner to example 1e, tert-butyl 3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazine-1-carboxylate (82a) and acetic anhydride were used to prepare tert-butyl 4-acetyl-3-methyl-5-((4-(pyrimidin-2-yl)benzyl)carbamoyl)piperazine-1-carboxylate (82b). LRMS (ES) (M+H)+: observed = 454.3, calculated = 453.5. Step 3: In an analogous manner to example 1h tert-butyl 4-acetyl-3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazine-1-carboxylate (82b) and HCl were used to prepare 1-acetyl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (82c). LRMS (ES) (M+H)+: observed = 354.3, calculated = 353.4. Step 4: In an analogous manner to example 13-1, 1-acetyl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (82c) was used to prepare 1-acetyl-4-(2-(2-ethylphenoxy)-6- fluorobenzyl)-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (82). LRMS (ES) (M+H)+: observed = 582.4, calculated = 581.6. EXAMPLE 83
Figure imgf000192_0001
N-(4-(pyridin-2-yl)benzyl)piperazine-2-carboxamide (83) Step 1: In an analogous manner to example 12f, (2R,6R)-4-(tert-butoxycarbonyl)-1-isobutyryl-6- methylpiperazine-2-carboxylic acid (12e) and (4-(pyridin-2-yl)phenyl)methanamine were used to 25608 prepare tert-butyl (3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyridin-2-yl)benzyl)carbamoyl) piperazine-1-carboxylate (83a). LRMS (ES) (M+H)+: observed = 481.4, calculated = 480.6. Step 2: In an analogous manner to example 12g, tert-butyl (3R,5R)-4-isobutyryl-3-methyl-5-((4- (pyridin-2-yl)benzyl)carbamoyl)piperazine-1-carboxylate (83a) and HCl were used to prepare (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyridin-2-yl)benzyl)piperazine-2-carboxamide (83b). LRMS (ES) (M+H)+: observed = 381.3, calculated = 380.5. Step 3: In an analogous manner to example 13-5, (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyridin- 2-yl)benzyl)piperazine-2-carboxamide (83b) was used to prepare (2R,6R)-4-(2-((2-ethylpyridin- 3-yl)oxy)-6-fluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(pyridin-2-yl)benzyl)piperazine-2- carboxamide (83). LRMS (ES) (M+H)+: observed = 610.5, calculated = 609.8. EXAMPLE 84 Preparation of
Figure imgf000193_0001
3-yl)oxy)-6- fluorobenzyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (84) Step 1: In an analogous manner to example 13-5, (2R,6R)-1-isobutyryl-6-methylpiperazine-2- carboxylic acid (16a) was used to prepare (2R,6R)-4-(2-((2-ethylpyridin-3-yl)oxy)-6- fluorobenzyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (84a). LRMS (ES) (M+H)+: observed = 444.4, calculated = 443.5. 25608 Step 2: In an analogous manner to example 16-1, (2R,6R)-4-(2-((2-ethylpyridin-3-yl)oxy)-6- fluorobenzyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (84a) and (4-(1,1- difluoroethoxy)phenyl)methanamine was used to prepare (2R,6R)-N-(4-(1,1- difluoroethoxy)benzyl)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (84). LRMS (ES) (M+H)+: observed = 613.5, calculated = 612.7. EXAMPLE 85 Preparation of (2R,6R)-
Figure imgf000194_0001
ethylpyridin-3-yl)oxy)-6- fluorobenzyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (85) In an analogous manner to example 16-1, (2R,6R)-4-(2-((2-ethylpyridin-3-yl)oxy)-6- fluorobenzyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (84a) and (4-(2H-1,2,3-triazol- 2-yl)phenyl)methanamine was used to prepare (2R,6R)-N-(4-(2H-1,2,3-triazol-2-yl)benzyl)-4-(2- ((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (85). LRMS (ES) (M+H)+: observed = 600.5, calculated = 599.7.
25608 EXAMPLE 86 Preparation of (2R,6R)-4-
Figure imgf000195_0001
-1-isobutyryl-N-(4-(6- methoxypyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (86) In an analogous manner to example 16-1, (2R,6R)-4-(2-((2-ethylpyridin-3-yl)oxy)-6- fluorobenzyl)-1-isobutyryl-6-methylpiperazine-2-carboxylic acid (84a) and (4-(6- methoxypyridin-2-yl)phenyl)methanamine was used to prepare (2R,6R)-4-(2-((2-ethylpyridin-3- yl)oxy)-6-fluorobenzyl)-1-isobutyryl-N-(4-(6-methoxypyridin-2-yl)benzyl)-6-methylpiperazine- 2-carboxamide (86). LRMS (ES) (M+H)+: observed = 640.0, calculated = 639.8. The following table shows data for representative compounds of the Examples as orexin receptor agonists as determined by assays described herein. Emax (%) represents precent activity at maximum tested concentration. Example hOX2R_IP IC50 (nM) Emax (%)
Figure imgf000195_0002
25608 1-7 362.2 99.67 1-8 401.4 99.35
Figure imgf000196_0001
25608 1-38 2969 61.9 1-39 3128 51.65
Figure imgf000197_0001
25608 1-69 16340 47.71 1-70 18210 84.3
Figure imgf000198_0001
25608 10 835.2 101.7 11 871.7 102.2
Figure imgf000199_0001
25608 13-29 112.3 98.87 13-30 114.8 100.7
Figure imgf000200_0001
25608 20-6 9.251 101.3 20-7 12.91 100.3
Figure imgf000201_0001
25608 37 464 100.3 38 454.4 100.2
Figure imgf000202_0001
25608 68 6260 93.41 69 26.2 99.42 While th
Figure imgf000203_0001
e invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention.

Claims

25608 WHAT IS CLAIMED IS: 1. A compound of formula I: wherein:
Figure imgf000204_0001
Ring A is selected from aryl and heteroaryl; R is independently selected from H, -C 1-6 alkyl, O-C 1-6 alkyl, CF 3 , CHF 2 , CH 2 F, and C 3-6 cycloalkyl; Ra is selected from -C 1-6 alkyl and -C 3-6 cycloalkyl; R 1 is independently selected from: (1) -(CR2)n-heteroaryl, where the heteroaryl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (2) -(CR2)n-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R4, (3) -(CR2)n- C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (4) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (5) -O(CR2)pR 4 , 25608 (6) -OR, (7) halo, (8) -OCR2C(O)NR2, (9) -OCR2CF3, (10) -O(CR2)tOCR3, (11) -(CR2)nCN (12) -(CR2)nNR2, (13) -O(CR2)tNR2 (14) -C2-C6 alkenyl, where the alkenyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , and (15) -C2-C6 alkynyl, where the alkynyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ; R 2 is selected from: (1) H, (2) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three substituents selected from R 5 , (3) halo, (4) -(CR2)sOR, (5) -(CR2)sCN (6) -(CR2)sS(O)zR, (7) -(CR2)sC(O)OR, (8) aryl, where the aryl is unsubstituted or substituted with one to three substituents selected from R 5 ; and (9) -(CR2)s-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to three substituents selected from R 5 ; R 3 is independently selected from: (1) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , 25608 (2) -C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (3) aryl, where the aryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (4) heteroaryl, where the heteroaryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (5) -(CH2)x-C2-C6 alkenyl, where the alkenyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (6) -(CH2)x-C2-C6 alkynyl, where the alkynyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , and (7) -OCF2CH3; R 4 is independently selected from: (1) hydrogen, (2) -C 1-6 alkyl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (3) aryl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (4) heteroaryl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (5) heterocyclyl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (6) halo, (7) -OR, (8) -CN, (9) -S(O)zR, and (10) -C(O)OR; R 5 is independently selected from: (1) halo, (2) -OR, 25608 (3) -CN, (4) -S(O)zR, (5) -C(O)OR, (6) -CF3, (7) heterocyclyl, and (8) -C 1-6 alkyl; R6 is independently selected from: H, halo, -OR, -NR 2 , -CF 3 , and -C 1-6 alkyl; R7 is independently selected from: halo, -OR, C3-C6 cycloalkyl, -CF3, -CHF2, -CH2F, and -C 1-6 alkyl; m is independently selected from 0, 1, 2, 3 and 4; n is independently selected from 0, 1 and 2; p is independently selected from 0, 1 and 2; s is independently selected from 0, 1, 2 and 3; t is independently selected from 1, 2, 3 and 4; x is independently selected from 0, 1, and 2; and z is independently selected from 0, 1 and 2; or a pharmaceutically acceptable salt thereof. 2. A compound of Claim 1, wherein: Ring A is selected from pyrazinyl, naphthyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, imidazolyl, quinolinyl, pyradazinyl, phenyl and pyridinyl; Ra is -C 1-6 alkyl; R1 is independently selected from: (1) -(CR2)n-heteroaryl, where the heteroaryl is unsubstituted or substituted with one to six substituents independently selected from R 4 , 25608 (2) -(CR2)n-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R4, (3) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (4) -O(CR2)pR 4 , (5) -OR, (6) halo, (7) -OCR2C(O)NR2, (8) -OCR2CF3, (9) -O(CR2)tOCR3, (10) -(CR2)nCN (11) -(CR2)nNR2, and (12) -O(CR2)tNR2; R 2 is selected from: (1) H, (2) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three substituents selected from R 5 , (3) halo, (4) -(CR2)sOR, and (5) -(CR2)sC(O)OR; R 3 is independently selected from: (1) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (2) aryl, where the aryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (3) heteroaryl, where the heteroaryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , and (4) -OCF2CH3; 25608 R 4 is independently selected from: (1) -C 1-6 alkyl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (2) aryl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (3) heteroaryl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (4) heterocyclyl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 (5) halo, and (6) -OR; R 5 is independently selected from: (1) halo, (2) -OR, (3) -CN, (4) -S(O)zR, (5) -C(O)OR, (6) -CF3, (7) heterocyclyl, and (8) -C 1-6 alkyl; R6 is independently selected from: H, halo, -OR, -NR 2 , -CF 3 , and -C 1-6 alkyl; R7 is independently selected from: halo, -OR, C3-C6 cycloalkyl, -CF3, -CHF2, -CH2F, and -C 1-6 alkyl; m is independently selected from 0, 1, 2 and 3; n is independently selected from 0, 1 and 2; p is independently selected from 0, 1 and 2; s is independently selected from 0, 1, 2 and 3; 25608 t is independently selected from 1, 2, 3 and 4; x is independently selected from 0, 1, and 2; and z is independently selected from 0, 1 and 2; or a pharmaceutically acceptable salt thereof. 3. A compound of Claim 1, wherein: Ring A is selected from phenyl and pyridinyl; Ra is -C 1-6 alkyl; R 1 is independently selected from: (1) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (2) -O(CR2)pR 4 , (3) -OR, and (4) Halo; R 2 is selected from: (1) H, (2) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three substituents selected from R 5 , (3) -(CR2)sOR, and (4) -(CR2)sC(O)OR; R 3 is independently selected from: (1) Heteroaryl which is selected from pyrimidinyl, pyridinyl, or oxazolyl, where the heteroaryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , and (2) -OCF2CH3; or a pharmaceutically acceptable salt thereof. 25608 4. A compound of Claim 1, as depicted in Formula IB: wherein:
Figure imgf000211_0001
Ring A is selected from aryl and heteroaryl; R is independently selected from H, -C 1-6 alkyl, -O-C 1-6 alkyl, -CF3, -CHF2, -CH2F, and -C 3-6 cycloalkyl; R 1 is independently selected from: (1) -(CR2)n-heteroaryl, where the heteroaryl is unsubstituted or substituted with one to six substituents independently selected from R4, (2) -(CR2)n-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (3) -(CR2)n- C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (4) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (5) -O(CR2)pR 4 , (6) -OR, (7) halo, (8) -OCR2C(O)NR2, (9) -OCR2CF3, 25608 (10) -O(CR2)tOCR3, (11) -(CR2)nCN (12) -(CR2)nNR2, (13) -O(CR2)tNR2 (14) C2-C6 alkenyl, where the alkenyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , and (15) C2-C6 alkynyl, where the alkynyl is unsubstituted or substituted with one to six substituents independently selected from R 4 ; R 2 is selected from: (1) H, (2) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three substituents selected from R 5 , (3) halo, (4) -(CR2)sOR, (5) -(CR2)sCN (6) -(CR2)sS(O)zR, (7) -(CR2)sC(O)OR, (8) aryl, where the aryl is unsubstituted or substituted with one to three substituents selected from R 5 ; and (9) -(CR2)s-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to three substituents selected from R 5 ; R 3 is independently selected from: (1) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (2) -C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one to four substituents independently selected from R7, (3) aryl, where the aryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , 25608 (4) heteroaryl, where the heteroaryl is unsubstituted or substituted with one to four substituents independently selected from R7, (5) -(CH2)x-C2-C6 alkenyl, where the alkenyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (6) -(CH2)x-C2-C6 alkynyl, where the alkynyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , and (8) -OCF2CH3; R4 is independently selected from: (1) hydrogen, (2) -C 1-6 alkyl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (3) aryl, which is unsubstituted or substituted with one to six substituents independently selected from R6, (4) heteroaryl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (5) heterocyclyl, which is unsubstituted or substituted with one to six substituents independently selected from R 6 , (6) halo, (7) -OR, (8) -CN, (9) -S(O)zR, and (10) -C(O)OR; R 5 is independently selected from: (1) halo, (2) -OR, (3) -CN, (4) -S(O)zR, (5) -C(O)OR, (6) -CF3, (7) heterocyclyl, and 25608 (8) -C 1-6 alkyl; R6 is independently selected from: H, halo, -OR, -NR2, -CF3, and -C 1-6 alkyl; R7 is independently selected from: halo, -OR, C3-C6 cycloalkyl, -CF3, -CHF2, -CH2F, and -C1-6 alkyl; m is independently selected from 0, 1, 2, 3 and 4; n is independently selected from 0, 1 and 2; p is independently selected from 0, 1 and 2; s is independently selected from 0, 1, 2 and 3; t is independently selected from 1, 2, 3 and 4; x is independently selected from 0, 1, and 2; and z is independently selected from 0, 1 and 2; or a pharmaceutically acceptable salt thereof. 5. The compound of any of Claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from: pyrazinyl, naphthyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, imidazolyl, quinolinyl, pyradazinyl, phenyl and pyridinyl. 6. The compound of any of Claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from: (1) -(CR2)n-heteroaryl, where the heteroaryl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (2) -(CR2)n-heterocyclyl, where the heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R4, (3) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to six substituents independently selected from R 4 , (4) -O(CR2)pR 4 , (5) -OR, (6) halo, 25608 (7) -OCR2C(O)NR2, (8) -OCR2CF3, (9) -O(CR2)tOCR3, (10) -(CR2)nCN, (11) -(CR2)nNR2, and (12) -O(CR2)tNR2. 7. The compound of any of Claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from H, -(CR2)sOR, -C1-6alkyl, where the alkyl is unsubstituted or substituted with one to three substituents selected from R5, -(CR2)sC(O)OR, and -CF3. 8. The compound of any of Claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from (1) -C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (2) aryl, where the aryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , (3) heteroaryl, where the heteroaryl is unsubstituted or substituted with one to four substituents independently selected from R 7 , and (4) -OCF2CH3. 9. The compound of any of Claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from -OR, halo, -C 1-6 alkyl, aryl, heteroaryl, and heterocyclyl, where said alkyl, aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with one to six substituents independently selected from R 6 . 10. A compound which is selected from: cis-4-benzyl-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (1-1); (2R,6R)-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(morpholin- 4-yl)phenyl]methyl}piperazine-2-carboxamide (1-2); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(2- phenoxyphenyl)methyl]piperazine-2-carboxamide (1-3); 25608 4-[(2,6-difluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-4); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-({2-[(pyridin-3- yl)oxy]phenyl}methyl)piperazine-2-carboxamide (1-5); 4-{[2-(2-amino-2-oxoethoxy)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-6); 4-{[2-fluoro-6-(morpholin-4-yl)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1- (2-methylpropanoyl)piperazine-2-carboxamide (1-7); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(morpholin-4- yl)phenyl]methyl}piperazine-2-carboxamide (1-8); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-({2-[(1H-pyrazol-1- yl)methyl]phenyl}methyl)piperazine-2-carboxamide (1-9); 4-[(3-fluoropyridin-2-yl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-10); 4-[(2-fluoro-6-methoxyphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-11); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-({2-[(pyrazin-2- yl)oxy]phenyl}methyl)piperazine-2-carboxamide (1-12); 4-[(2-fluoro-5-methylphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-13); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-({2-[(pyridin-2- yl)oxy]phenyl}methyl)piperazine-2-carboxamide (1-14); 4-[(2-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-15); N-{[4-(furan-2-yl)phenyl]methyl}-4-{[2-(2-methoxyethoxy)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-16); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(2,2,2- trifluoroethoxy)phenyl]methyl}piperazine-2-carboxamide (1-17); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-({2-[(oxolan-2- yl)methoxy]phenyl}methyl)piperazine-2-carboxamide (1-18); 4-[(2-chloro-6-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-19); 25608 N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(pyrimidin-2- yl)methyl]piperazine-2-carboxamide (1-20); N-{[4-(furan-2-yl)phenyl]methyl}-4-{[2-(4-hydroxypiperidin-1-yl)phenyl]methyl}-6-methyl-1- (2-methylpropanoyl)piperazine-2-carboxamide (1-21); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(4-methyl-1,3-thiazol-2- yl)methyl]piperazine-2-carboxamide (1-22); N-{[4-(furan-2-yl)phenyl]methyl}-4-[(2-methoxyphenyl)methyl]-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-23); 4-{[2-(difluoromethoxy)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-24); 4-[(2-ethoxyphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-25); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[4-(propan-2-yl)-1,3- thiazol-2-yl]methyl}piperazine-2-carboxamide (1-26); 4-[(2-cyanophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-27); 4-[(3-cyanophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-28); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(pyridin-4- yl)phenyl]methyl}piperazine-2-carboxamide (1-29); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(pyridin-2- yl)methyl]piperazine-2-carboxamide (1-30); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(pyridin-3- yl)methyl]piperazine-2-carboxamide (1-31); 4-[(2,3-difluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-32); 4-[(2-fluoro-3-methoxyphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-33); 4-[(2-fluoro-5-methoxyphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-34); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(3-methylphenyl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-35); 25608 N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(1H-1,2,4-triazol-1- yl)phenyl]methyl}piperazine-2-carboxamide (1-36); N-{[4-(furan-2-yl)phenyl]methyl}-4-[(3-methoxyphenyl)methyl]-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-37); 4-[(3-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-38); 4-[(4-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-39); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2- (trifluoromethoxy)phenyl]methyl}piperazine-2-carboxamide (1-40); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(pyridin-3- yl)phenyl]methyl}piperazine-2-carboxamide (1-41); 4-[(2-fluoro-6-hydroxyphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-42); 4-[(3-chloro-2-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-43); 4-[(2-cyclopropylphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-44); 4-{[2-(cyanomethyl)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-45); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(pyrimidin-5- yl)phenyl]methyl}piperazine-2-carboxamide (1-46); N-{[4-(furan-2-yl)phenyl]methyl}-4-[(2-hydroxyphenyl)methyl]-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-47); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(5-methyl-1,3-thiazol-2- yl)methyl]piperazine-2-carboxamide (1-48); 4-{[3-(dimethylamino)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-49); 4-[(3-fluoropyridin-4-yl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-50); 4-{[2-fluoro-5-(trifluoromethyl)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1- (2-methylpropanoyl)piperazine-2-carboxamide (1-51); 25608 N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(1H-pyrazol-1- yl)phenyl]methyl}piperazine-2-carboxamide (1-52); 4-{[2-(difluoromethyl)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-53); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(piperidin-1- yl)phenyl]methyl}piperazine-2-carboxamide (1-54); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(pyrrolidin-1- yl)phenyl]methyl}piperazine-2-carboxamide (1-55); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(3-methyl-1,2-oxazol-5-yl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-56); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(5-methyl-1H-pyrazol-3- yl)methyl]piperazine-2-carboxamide (1-57); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(2-methylphenyl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-58); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-({2-[(morpholin-4- yl)methyl]phenyl}methyl)piperazine-2-carboxamide (1-59); 4-({2-[2-(dimethylamino)ethoxy]phenyl}methyl)-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1- (2-methylpropanoyl)piperazine-2-carboxamide (1-60); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(2-methyl-1,3-thiazol-5- yl)methyl]piperazine-2-carboxamide (1-61); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2-(1H-1,2,3-triazol-1- yl)phenyl]methyl}piperazine-2-carboxamide (1-62); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-{[2-(4-methylpiperazin-1-yl)phenyl]methyl}-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-63); 4-[(2-ethylphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-64); 4-{[2-fluoro-3-(trifluoromethyl)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1- (2-methylpropanoyl)piperazine-2-carboxamide (1-65); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-{[2- (trifluoromethyl)phenyl]methyl}piperazine-2-carboxamide (1-66); N-{[4-(furan-2-yl)phenyl]methyl}-4-[(3-hydroxypyridin-2-yl)methyl]-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-67); 25608 4-[(5-cyano-2-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-68); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(pyridin-4- yl)methyl]piperazine-2-carboxamide (1-69); 4-{[2-(dimethylamino)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-70); 4-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-71); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(1-methyl-1H-pyrazol-5- yl)methyl]piperazine-2-carboxamide (1-72); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-73); 4-[(4-cyanophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-74); 4-({2-[(dimethylamino)methyl]phenyl}methyl)-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1- (2-methylpropanoyl)piperazine-2-carboxamide (1-75); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(4-methyl-1H-imidazol-2-yl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-76); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(2-methyl-1H-imidazol-4-yl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-77); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(4-methyl-4H-1,2,4- triazol-3-yl)methyl]piperazine-2-carboxamide (1-78); 4-{[4-(dimethylamino)phenyl]methyl}-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-79); N-{[4-(furan-2-yl)phenyl]methyl}-4-[(4-methoxyphenyl)methyl]-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-80); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-4-[(4-methylphenyl)methyl]-1-(2- methylpropanoyl)piperazine-2-carboxamide (1-81); cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(quinolin-8-ylmethyl)piperazine-2- carboxamide (2-1); 4-[(2,6-difluoro-3-methylphenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (2-2); 25608 N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(2,4,6- trifluorophenyl)methyl]piperazine-2-carboxamide (2-3); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(2,3,5,6- tetrafluorophenyl)methyl]piperazine-2-carboxamide (2-4); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(1,3-thiazol-2- yl)methyl]piperazine-2-carboxamide (2-5); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-(pent-2-yn-1- yl)piperazine-2-carboxamide (2-6); 4-(but-2-yn-1-yl)-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)piperazine- 2-carboxamide (2-7); 4-[(2-bromo-6-fluorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (2-8); 4-[(2-chlorophenyl)methyl]-N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)piperazine-2-carboxamide (2-9); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(pyridazin-3- yl)methyl]piperazine-2-carboxamide (2-10); N-{[4-(furan-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-4-[(naphthalen-1- yl)methyl]piperazine-2-carboxamide (2-11); cis-4-(2-fluoro-6-phenoxybenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (3); cis-4-(2-(benzyloxy)-6-fluorobenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine- 2-carboxamide (4); cis-4-(2-ethoxy-6-fluorobenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (5); cis-4-(2-fluoro-6-hydroxybenzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2- carboxamide (6); cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(pyridin-4-yloxy)benzyl)piperazine-2- carboxamide (7); cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(pyridin-4-yloxy)benzyl)piperazine-2- carboxamide (8); cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(oxazol-2-ylmethyl)benzyl)piperazine- 2-carboxamide (9); 25608 cis-4-(2-((4H-1,2,4-triazol-4-yl)methyl)benzyl)-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6- methylpiperazine-2-carboxamide (10); cis-N-(4-(furan-2-yl)benzyl)-1-isobutyryl-6-methyl-4-(2-(tetrahydro-2H-pyran-4- yl)benzyl)piperazine-2-carboxamide (11); (2R,6R)-4-(2,6-difluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine- 2-carboxamide (12); (2R,6R)-4-(2-fluoro-6-(2-methoxyphenoxy)benzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (13-1) (2R,6R)-4-({2-[(2-ethyl-5-methylpyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-2); (2R,6R)-4-({2-[2-(dimethylamino)phenoxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-3); (2R,6R)-4-{[2-(2-ethylphenoxy)-6-fluorophenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-4); (2R,6R)-4-({2-[(2-ethylpyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-5); (2R,6R)-4-({2-fluoro-6-[2-(trifluoromethyl)phenoxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-6); (2R,6R)-4-({2-fluoro-6-[(imidazo[1,2-a]pyridin-8-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-7); (2R,6R)-4-({2-[(2,6-dimethylpyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-8); (2R,6R)-4-{[2-(2,6-dimethylphenoxy)-6-fluorophenyl]methyl}-6-methyl-1-(2-methylpropanoyl)- N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-9); (2R,6R)-4-({2-fluoro-6-[(2-methylpyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-10); (2R,6R)-4-({2-fluoro-6-[(3-methoxy-2-methylpyridin-4-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-11); (2R,6R)-4-{[2-fluoro-6-(2-methylphenoxy)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-12); (2R,6R)-4-({2-fluoro-6-[2-(trifluoromethoxy)phenoxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-13); 25608 (2R,6R)-4-{[2-(2-chlorophenoxy)-6-fluorophenyl]methyl}-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-14); (2R,6R)-4-({2-[(6-ethylpyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-15); (2R,6R)-4-({2-[(2-chloro-6-methylpyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-16); (2R,6R)-4-({2-fluoro-6-[(4-methylpyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-17); (2R,6R)-4-{[2-fluoro-6-(2-methoxy-6-methylphenoxy)phenyl]methyl}-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-18); (2R,6R)-4-({2-[(6-chloropyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-19); (2R,6R)-4-[(2-fluoro-6-phenoxyphenyl)methyl]-6-methyl-1-(2-methylpropanoyl)-N-{[4- (pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-20); (2R,6R)-4-({2-[(2,6-dichloropyridin-3-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-21); (2R,6R)-4-({2-fluoro-6-[(4-methoxypyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-22); (2R,6R)-4-({2-[(2-chloropyrimidin-5-yl)oxy]-6-fluorophenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-23); (2R,6R)-4-({2-fluoro-6-[(6-methylpyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-24); (2R,6R)-4-({2-fluoro-6-[(6-fluoropyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-25); (2R,6R)-4-({2-fluoro-6-[(2-fluoropyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-26); (2R,6R)-4-({2-fluoro-6-[(2-fluoro-6-methylpyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-27); (2R,6R)-4-({2-fluoro-6-[(4-methylpyridin-2-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-28); (2R,6R)-4-({2-fluoro-6-[(5-methoxypyridin-2-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-29); 25608 (2R,6R)-4-({2-fluoro-6-[(2-methoxypyridin-4-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-30); (2R,6R)-4-({2-fluoro-6-[(pyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-31); (2R,6R)-4-({2-fluoro-6-[(6-methylpyridin-2-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-32); (2R,6R)-4-({2-fluoro-6-[(5-methylpyridin-2-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-33); (2R,6R)-4-({2-fluoro-6-[(5-methylpyridin-3-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-34); (2R,6R)-4-({2-fluoro-6-[(2-methoxypyrimidin-5-yl)oxy]phenyl}methyl)-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-35); (2R,6R)-4-({2-fluoro-6-[(pyridin-2-yl)oxy]phenyl}methyl)-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (13-36); (2R,6R)-4-(2-fluoro-6-(2-methoxyphenoxy)benzyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (14); (2R,6R)-1-isobutyryl-6-methyl-4-(2-phenoxybenzyl)-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (15); (2R,6R)-4-(1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (16-1); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(1,3-thiazol-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-2); (2R,6R)-N-{[4-(1,1-difluoroethoxy)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)- 3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (16-3); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(1,3-oxazol-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-4); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(2H-1,2,3-triazol-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-5); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-[(4-propylphenyl)methyl]piperazine-2-carboxamide (16-6); (2R,6R)-N-[(4-cyclopropylphenyl)methyl]-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (16-7); 25608 (2R,6R)-N-[(4-tert-butylphenyl)methyl]-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (16-8); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(propan-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-9); (2R,6R)-N-[(4-ethylphenyl)methyl]-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (16-10); (2R,6R)-4-[(1R)-1-(3-fluoro-6-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-11); (2R,6R)-4-[(1R)-1-(3-fluoropyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)-N- {[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-12); (2R,6R)-4-[(1R)-1-(3,5-difluoropyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (16-13); (2R,6R)-N-(4-(5-chloro-6-methoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (17); (2R,6R)-N-(4-(5-cyclopropyl-6-methoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (18); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(6- methoxy-5-methylpyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (19); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-N-(4-(5-fluoro-6- methoxypyridin-2-yl)benzyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (20-1); (2R,6R)-N-{[4-(4,6-dimethoxypyridin-2-yl)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl) piperazine-2- carboxamide (20-2); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-N-{[4-(6-methoxy-4- methylpyridin-2-yl) phenyl]methyl}-6-methyl-1-(2-methylpropanoyl) piperazine-2-carboxamide (20-3); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-N-{[4-(4- methoxypyrimidin-2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-4); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-N-({4-[6-methoxy-4- (trifluoromethyl)pyridin-2-yl]phenyl}methyl)-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-5); 25608 (2R,6R)-N-{[4-(6-ethoxypyridin-2-yl)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (20-6); (2R,6R)-N-{[4-(3,6-dimethoxypyridin-2-yl)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-7); (2R,6R)-N-({4-[6-(difluoromethyl)pyridin-2-yl]phenyl}methyl)-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-8); (2R,6R)-N-[(2'-fluoro-3'-methoxy[1,1'-biphenyl]-4-yl)methyl]-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-9); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-N-{[4-(5-fluoropyrimidin- 2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (20-10); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(thieno[2,3-b]pyridin-6-yl)phenyl]methyl}piperazine-2-carboxamide (20-11); (2R,6R)-N-({4-[6-(difluoromethoxy)pyridin-2-yl]phenyl}methyl)-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-12); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-N-{[4-(6-methoxypyrazin- 2-yl)phenyl]methyl}-6-methyl-1-(2-methylpropanoyl)piperazine-2-carboxamide (20-13); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-{[4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)phenyl]methyl}piperazine-2- carboxamide (20-14); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2- methylpropanoyl)-N-({4-[6-(trifluoromethoxy)pyridin-2-yl]phenyl}methyl)piperazine-2- carboxamide (20-15); (2R,6R)-4-[(1R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-N-{[4-(1- methyl-6-oxo-1,6-dihydropyridin-2-yl)phenyl]methyl}-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-16); (2R,6R)-N-{[4-(3-fluoro-6-methoxypyridin-2-yl)phenyl]methyl}-4-[(1R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)piperazine-2- carboxamide (20-17); 25608 (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N- (4-(pyridin-2-yl)benzyl)piperazine-2-carboxamide (21); (2R,6R)-N-(4-(4-cyclopropyl-6-methoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4- methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (22); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-N-((2'-fluoro-5'-methoxy- [1,1'-biphenyl]-4-yl)methyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (23); (2R,6R)-N-(4-(6-cyclopropoxypyridin-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (24); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(6- methoxypyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (25); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-N-(4-(3- methoxypyridin-2-yl)benzyl)-6-methylpiperazine-2-carboxamide (26); 1-(cyclopropanecarbonyl)-4-(2,6-difluorobenzyl)-N-(4-(furan-2-yl)benzyl)-6-methylpiperazine- 2-carboxamide (27); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N- (4-(prop-1-yn-1-yl)benzyl)piperazine-2-carboxamide (28); (2R,6R)-N-(4-(cyclopropylethynyl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (29); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N- (4-(3,3,3-trifluoroprop-1-yn-1-yl)benzyl)piperazine-2-carboxamide (30); (2R,6R)-N-(4-(but-2-yn-1-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3- methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (31); (2R,6R)-4-((R)-1-(3-fluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N- (4-(4-methyl-2H-1,2,3-triazol-2-yl)benzyl)piperazine-2-carboxamide (32); (2R,6R)-N-(4-(4,5-dimethyl-2H-1,2,3-triazol-2-yl)benzyl)-4-((R)-1-(3-fluoro-4-methylpyridin-2- yl)-3-methoxypropyl)-1-isobutyryl-6-methylpiperazine-2-carboxamide (33); (2R,6R)-4-((R)-1-(3,5-difluoro-4-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (34); (2R,6R)-4-((R)-1-(3-fluoro-4,6-dimethylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (35-1); (2R,6R)-4-[(1R)-3-methoxy-1-(2,4,6-trifluorophenyl)propyl]-6-methyl-1-(2-methylpropanoyl)- N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (35-2); 25608 (2R,6R)-4-{(1R)-1-[3-fluoro-6-(trifluoromethyl)pyridin-2-yl]-3-methoxypropyl}-6-methyl-1-(2- methylpropanoyl)-N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (35-3); (2R,6R)-4-[(1R)-1-(5-fluoropyrimidin-2-yl)-3-methoxypropyl]-6-methyl-1-(2-methylpropanoyl)- N-{[4-(pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamid (35-4); (2R,6R)-4-[(1R)-3-methoxy-1-(pyrimidin-2-yl)propyl]-6-methyl-1-(2-methylpropanoyl)-N-{[4- (pyrimidin-2-yl)phenyl]methyl}piperazine-2-carboxamide (35-5); (2R,6R)-1-isobutyryl-4-((R)-3-methoxy-1-(2,4,6-trifluorophenyl)propyl)-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (36); (2R,6R)-4-((R)-1-(3,5-difluoropyridin-4-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (37); (2R,6R)-4-((R)-1-(4-ethyl-3-fluoropyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (38); (2R,6R)-4-((R)-1-(6-chloro-3-fluoropyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (39); (2R,6R)-4-((R)-1-(3-fluoro-5-methylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N- (4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (40); (2R,6R)-4-((R)-1-(3-fluoro-6-(prop-1-yn-1-yl)pyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (41); (2R,6R)-4-((R)-1-(6-cyclopropyl-3-fluoropyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (42); (2R,6R)-4-((R)-1-(6-ethyl-3-fluoropyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (43); (2R,6R)-4-((R)-1-(3-fluoro-4,5-dimethylpyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (44); (2R,6R)-4-((R)-1-(4-cyclopropyl-3-fluoropyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (45); (2R,6R)-4-((R)-1-(3-fluoro-4-(prop-1-yn-1-yl)pyridin-2-yl)-3-methoxypropyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (46); (2R,6R)-4-((R)-1-(5-fluoro-2-(prop-1-yn-1-yl)pyridin-4-yl)-3-methoxypropyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (47); (2R,6R)-4-((R)-1-(3,5-difluoro-2-methylpyridin-4-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (48); 25608 (2R,6R)-1-isobutyryl-4-((R)-3-methoxy-1-(pyrazin-2-yl)propyl)-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (49); (2R,6R)-4-((R)-1-(5-fluoro-2-methylpyrimidin-4-yl)-3-methoxypropyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (50); (2R,6R)-1-isobutyryl-4-(3-methoxy-1-phenylpropyl)-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (51); (2R,6R)-4-(3-ethoxy-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (52); (2R,6R)-1-isobutyryl-4-((S)-(1-(methoxymethyl)cyclobutyl)(phenyl)methyl)-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (53); (2R,6R)-1-isobutyryl-4-((1R)-3-methoxy-2-methyl-1-phenylpropyl)-6-methyl-N-(4-(pyrimidin- 2-yl)benzyl)piperazine-2-carboxamide (54); (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-methoxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (55); (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-(methylthio)propyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (56); (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-3-(methylsulfinyl)propyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (57); (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-(methylsulfonyl)propyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (58); (2R,6R)-4-((R)-(2,6-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (59); (2R,6R)-4-((1S)-(2,6-difluorophenyl)(1,4-dioxan-2-yl)methyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (60); (2R,6R)-4-((R)-3-cyano-1-(2,6-difluorophenyl)propyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (61); methyl 3-(2,6-difluorophenyl)-3-((3R,5R)-4-isobutyryl-3-methyl-5-((4-(pyrimidin-2- yl)benzyl)carbamoyl)piperazin-1-yl)propanoate (62); (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoropropan-2-yl)oxy)benzyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (63); (2R,6R)-4-(2-(1-cyclopropyl-2,2,2-trifluoroethoxy)-6-fluorobenzyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (64); 25608 (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoro-3,3-dimethylbutan-2-yl)oxy)benzyl)-1-isobutyryl-6- methyl-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (65); (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluorobutan-2-yl)oxy)benzyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (66); (2R,6R)-4-(2-fluoro-6-((1,1,1-trifluoro-3-methylbutan-2-yl)oxy)benzyl)-1-isobutyryl-6-methyl- N-(4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (67); (2R,6R)-1-isobutyryl-6-methyl-4-(1-phenylpropyl)-N-(4-(pyrimidin-2-yl)benzyl)piperazine-2- carboxamide (68); (2R,6R)-4-((R)-3-hydroxy-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (69); (2R,6R)-1-isobutyryl-6-methyl-4-((1R)-1-phenyl-2-(tetrahydrofuran-2-yl)ethyl)-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (70); (2R,6R)-4-((R)-3-(difluoromethoxy)-1-phenylpropyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (71); (2R,6R)-1-isobutyryl-6-methyl-4-((R)-1-phenyl-3-(trifluoromethoxy)propyl)-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (72); (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)-4-((R)-4,4,4-trifluoro-1- phenylbutyl)piperazine-2-carboxamide (73); (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-2-(tetrahydrofuran-2-yl)ethyl)-1-isobutyryl-6-methyl-N- (4-(pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (74); (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-hydroxypropyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (75); (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)-4-((1R)-4,4,4-trifluoro-3-hydroxy- 3-methyl-1-phenylbutyl)piperazine-2-carboxamide (76); (2R,6R)-4-((1R)-1-(2,6-difluorophenyl)-3-hydroxybutyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (77); (2R,6R)-1-isobutyryl-6-methyl-N-(4-(pyrimidin-2-yl)benzyl)-4-((1R)-4,4,4-trifluoro-3-hydroxy- 1-phenylbutyl)piperazine-2-carboxamide (78); (2R,6R)-4-((R)-1-(2,6-difluorophenyl)-3-hydroxy-3-methylbutyl)-1-isobutyryl-6-methyl-N-(4- (pyrimidin-2-yl)benzyl)piperazine-2-carboxamide (79); (2R,6R)-4-((S)-1-(2,6-difluorophenyl)-2-hydroxyethyl)-1-isobutyryl-6-methyl-N-(4-(pyrimidin- 2-yl)benzyl)piperazine-2-carboxamide (80); 25608 (2R,6R)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(oxazol-2- yl)benzyl)piperazine-2-carboxamide (81); 1-acetyl-4-(2-(2-ethylphenoxy)-6-fluorobenzyl)-6-methyl-N-(4-(pyrimidin-2- yl)benzyl)piperazine-2-carboxamide (82); (2R,6R)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1-isobutyryl-6-methyl-N-(4-(pyridin-2- yl)benzyl)piperazine-2-carboxamide (83); (2R,6R)-N-(4-(1,1-difluoroethoxy)benzyl)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (84); (2R,6R)-N-(4-(2H-1,2,3-triazol-2-yl)benzyl)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1- isobutyryl-6-methylpiperazine-2-carboxamide (85); and (2R,6R)-4-(2-((2-ethylpyridin-3-yl)oxy)-6-fluorobenzyl)-1-isobutyryl-N-(4-(6-methoxypyridin- 2-yl)benzyl)-6-methylpiperazine-2-carboxamide (86); or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition which comprises an inert carrier and a compound of any of Claims 1-10 or a pharmaceutically acceptable salt thereof. 12. A compound of any of Claims 1-10 or a pharmaceutically acceptable salt thereof for use in therapy. 13. A compound of any of Claims 1-10, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a sleep disorder. 14. A method for treating narcolepsy in a mammalian subject which comprises administering to the patient an effective amount of the compound of any of Claims 1-10 or a pharmaceutically acceptable salt thereof. 15. A method for treating hypersomnia in a mammalian subject which comprises administering to the patient an effective amount of the compound of any of Claims 1-10 or a pharmaceutically acceptable salt thereof.
PCT/US2023/079457 2022-11-17 2023-11-13 Orexin receptor agonists WO2024107615A1 (en)

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