EP1370546A2 - Novel amines as histamine-3 receptor ligands and their therapeutic applications - Google Patents

Novel amines as histamine-3 receptor ligands and their therapeutic applications

Info

Publication number
EP1370546A2
EP1370546A2 EP02715079A EP02715079A EP1370546A2 EP 1370546 A2 EP1370546 A2 EP 1370546A2 EP 02715079 A EP02715079 A EP 02715079A EP 02715079 A EP02715079 A EP 02715079A EP 1370546 A2 EP1370546 A2 EP 1370546A2
Authority
EP
European Patent Office
Prior art keywords
pyrrolidinyl
methyl
ethyl
benzofuran
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02715079A
Other languages
German (de)
French (fr)
Inventor
Marlon D. Cowart
Youssef L. Bennani
Ramin Faghih
Gregory A. Gfesser
Lawrence A. Black
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Inc
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/810,648 external-priority patent/US20020177589A1/en
Priority claimed from US10/044,495 external-priority patent/US20020183309A1/en
Priority claimed from US10/081,207 external-priority patent/US6969730B2/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to EP10180385A priority Critical patent/EP2258694A1/en
Publication of EP1370546A2 publication Critical patent/EP1370546A2/en
Withdrawn legal-status Critical Current

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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D491/10—Spiro-condensed systems

Definitions

  • TECHNICAL FIELD This invention relates to compounds useful for treating diseases or conditions caused by or exacerbated by histamine-3 receptor activity, pharmaceutical compositions containing such compounds and methods of treatment using such compounds.
  • Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) which are commonly treated with antagonists of histamine or "antihistamines.” It has also been established that histamine receptors exist in at least two distinct types, referred to as Hi and H 2 receptors.
  • H 3 receptor A third histamine receptor (H 3 receptor) is believed to play a role in neurotransmission in the central nervous system, where the H 3 receptor is thought to be disposed presynaptically on histaminergic nerve endings (Nature, 302, 832-837 (1983)).
  • the existence of the H 3 receptor has been confirmed by the development of selective H 3 receptor agonists and antagonists (Nature, 327, 117-123 (1987)) and has subsequently been shown to regulate the release of other neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs, cardiovascular system and gastrointestinal tract.
  • a number of diseases or conditions may be treated with histamine-3 receptor ligands wherein the H 3 ligand may be an antagonist, agonist or partial agonist.
  • diseases or conditions include cardiovascular disorders such as acute myocardial infarction; memory processes, dementia and cognition disorders such as Alzheimer's disease and attention-deficit hyperactivity disorder; neurological disorders such as Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions; cancer such as cutaneous carcinoma, medullary thyroid carcinoma and melanoma; allergic rhinitis; respiratory disorders such as asthma; sleep disorders such as narcolepsy; vestibular dysfunction such as Meniere's disease; gastrointestinal disorders, inflammation, migraine, motion sickness, obesity, pain, and septic shock.
  • A is selected from carbonyl or a covalent bond
  • D is selected from O or S
  • L is selected from lower alkylene, fluoroalkylene, or hydroxyalkylene
  • Ri and R 2 are each independently selected from hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, alkenyl, or alkynyl; or
  • R 3 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NRAR B , (NR A R B )alkyl, (NR A R B )carbonyl, or (NR A R B )sulfonyl;
  • R-j, R 5 , Re and R are each independently selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )sulfonyl, -L 2 R 20 , or -R 2 oL 3 R 22 ;
  • R 2 o is selected from aryl, heterocycle, or cycloalkyl;
  • R ⁇ is selected from hydrogen or alkyl
  • R 2 2 is selected from aryl, heterocycle, or cycloalkyl
  • R A and R B are each independently selected from hydrogen, alkyl, alkylcarbonyl or formyl; provided that at least one of R 4 , R 5 , Rg, or R 7 is aryl, heterocycle, cycloalkyl, -L 2 R 2 o or -R2oL 3 R 22 .
  • the compounds can be incorporated into pharmaceutical compositions and can be useful in methods for treating or preventing disorders related to histamine-3 receptor modulation.
  • the compounds, compositions comprising the compounds, and methods for treating or preventing disorders by administering the compounds are further described herein.
  • the present invention discloses compounds and compositions thereof which are useful for selectively modulating the effects of the histamine-3 receptors in a mammal.
  • the compounds of the invention can be used for treating and preventing disorders modulated by the histamine-3 receptor.
  • the disorders are those that are ameliorated by selectively modulating the histamine-3 receptors in a mammal.
  • One method of the invention provides for treating a disorder selected from acute myocardial infarction, asthma, bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric disorders, cutaneous carcinoma, drug abuse, depression, gastrointestinal disorders, inflammation, jet lag, medullary thyroid carcinoma, melanoma, allergic rhinitis, Meniere's disease, migraine, mood and attention alteration, motion sickness, neurogenic inflammation, obsessive compulsive disorder, pain, Parkinson's disease, schizophrenia, seizures, septic shock, Tourette's syndrome, vertigo, or wakefulness.
  • the method can be particularly useful for treating Alzheimer's disease, attention-deficit hyperactivity disorder, epilepsy, narcolepsy, and cognitive and memory-related disorders, for example, mild cognitive impairment, deficits of memory, and deficits of learning and dementia.
  • alkenyl refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkenylene means a divalent group derived from a straight or branched chain hydrocarbon of from 2 to 10 carbon atoms containing at least one double bond.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl and methoxymethyl.
  • alkoxycarbonyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.
  • alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • alkylcarbonyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-l-oxopropyl, 1 -oxobutyl and 1-oxopentyl.
  • alkylcarbonyloxy refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy and tert-butylcarbonyloxy.
  • alkylene means a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms.
  • Representative examples of alkylene include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH(CH 3 )CH 2 -.
  • alkylsulfinyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein.
  • Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl and ethylsulfinyl.
  • alkylsulfonyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkylsulfonyl include, but are not limited to, ethylsulfonyl, isopropylsulfonyl and methylsulfonyl.
  • alkylthio refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sufur atom, as defined herein.
  • Representative examples of alkylthio include, but are not limited to, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl and hexylsulfanyl.
  • aryl refers to a monocyclic-ring system, or a bicyclic- or a tricyclic- fused ring system wherein one or more of the fused rings are aromatic.
  • Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • the aryl groups of this invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, oximyl, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, and (NR A R B )sulfonyl.
  • arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3- phenylpropyl, and 2-naphth-2-ylethyl.
  • arylcarbonyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • arylcarbonyl include, but are not limited to, benzoyl, phenylacetyl, 3-chlorophenylacetyl, 3-methoxyphenylacetyl, 4-fiuoro-3-methylphenylacetyl, 3-phenylpropionyl, and 2-naphthylacetyl.
  • carbonyl refers to a -C(O)- group.
  • carboxyalkyl refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2- carboxyethyl, and 3-carboxypropyl.
  • cyano refers to a -CN group.
  • cyanoalkyl refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl and 3-cyanopropyl.
  • cycloalkyl refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons.
  • examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl .
  • cycloalkylalkyl refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl.
  • fluoroalkylene means an alkylene, as defined herein, containing 1 or fluorine atoms.
  • Representative examples of fluoroalkylene include, but are not limited to, -CH 2 CH(F)-, -CH 2 C(F) 2 -, -CH 2 C(F) 2 CH 2 -, and -CH 2 CH 2 C(F) 2 -.
  • halo or halogen, refers to -CI, -Br, -I or -F.
  • haloalkoxy refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2- fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • haloalkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, fluoromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • heterocycle refers to a monocyclic or bicyclic ring system.
  • Monocyclic ring systems are exemplified by any 3- or 4-membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5-, 6-, or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur.
  • the 5-membered ring has from 0-2 double bonds and the 6- and 7-membered rings have from 0-3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl,
  • example of monocyclic ring systems can include, but are not limited to, 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2 -methyl- 1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyr
  • Bicyclic ring systems are exemplified by any of the above monocyclic heterocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic heterocyclic ring system.
  • bicyclic ring systems include but are not limited to, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, indazolyl, indolyl, indolinyl, indolizinyl, naphthyridinyl, 3H-imidazo[4,5-c]pyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, isoquinolinyl, phthalazinyl, pyranopyridyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolin
  • heterocycles of this invention are substituted with 0, 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, arylalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, haloalkylcarbonyl, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl and (NR A R B )sulfonyl.
  • heterocyclealkyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocyclealkyl include, but are not limited to, pyridin-3- ylmethyl and 2-pyrimidin-2-ylpropyl.
  • heterocyclecarbonyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of heterocyclecarbonyl include, but are not limited to, lH-imidazol- 1 -ylcarbonyl, 4-mo ⁇ holinylcarbonyl, 1-piperidinylcarbonyl and cyclopentylaminocarbonyl.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to one or two hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypro ⁇ yl and 2-ethyl-4- hydroxyheptyl.
  • hydroxyalkylene means an alkylene, as defined herein, containing 1 or hydroxy groups.
  • Representative examples of hydroxyalkylene include, but are not limited to, -CH 2 CH(OH)-, -CH 2 CH(OH)CH 2 -, -CH 2 CH 2 CH(OH)-, and -CH 2 CH(OH)CH(OH)-.
  • lower alkylene is a subset of alkylene as defined herein and means a straight or branched chain hydrocarbon group containing from 1 to 6 carbon atoms.
  • Representative examples of lower alkylene are -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, and -CH 2 CH 2 CH 2 CH .
  • mercapto refers to a -SH group.
  • nitro refers to a -NO 2 group.
  • -NR A R B refers to two groups, R A and R B , which are appended to the parent molecular moiety through a nitrogen atom.
  • R A and R B are each independently selected from hydrogen, alkoxy, alkyl, alkylcarbonyl, and formyl.
  • Representative examples of -NR A R B include, but are not limited to, acetylamino, amino, formylamino, dimethylamino, and methylamino.
  • (NR A R B )alkyl refers to a -NR A R ⁇ group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of (NR A R ⁇ )alkyl include, but are not limited to, (amino)methyl, (dimethylamino)methyl and (ethylamino)methyl.
  • (NR A R B )carbonyl refers to a -NR A R B group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (NR A RB)carbonyl include, but are not limited to, aminocarbonyl, dimethylaminocarbonyl and ethylaminocarbonyl.
  • (NR A RB)sulfonyl refers to an amino group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of aminosulfonyl include, but are not limited to, aminosulfonyl, dimethylaminosulfonyl and ethylaminosulfonyl.
  • oximyl refers to a group wherein R 99 and Rioo are independently selected from hydrogen and alkyl.
  • oxy refers to a -O- moiety.
  • sulfinyl refers to a -S(O)- group.
  • sulfonyl refers to a -SO2- group.
  • Compounds of the present invention include at least those compounds of formula (I) wherein one substituent represented by R , R 5 , R 6 or R 7 are selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )sulfonyl, -L 2 R 2 o, or -R20L3R22.
  • R , R 5 , R 6 or R 7 are selected from hydrogen, alk
  • R4, R5, Re and R 7 is selected from hydrogen or alkyl.
  • Particular groups for the substituents represented by R ⁇ R 5 , Re and R can be selected from hydrogen, alkyl, heterocycle, -L 2 R 2 o, and -R20L3R22.
  • Compounds of the present invention also can have the formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached form heterocycle; R 3 , R , R 5 , and R are hydrogen; and R$ is L 2 R20.
  • Heterocycles formed by R ⁇ and R 2 can include, but are not limited to, azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl. (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl.
  • Particular examples of heterocycles for compounds of the invention are, for example, 1-azepanyl, (3S)-3-
  • the (2R)-2-methyl-l -pyrrolidinyl group may be preferred.
  • Groups for R 6 can include, but are not limited to, a group represented by the formula L 2 R 20 , alkylcarbonyl, heterocycle, or a group represented by R 2 oL 3 R 22 .
  • R ⁇ is L2R20
  • R 2 0 include, but are not limited to, phenyl that is substituted with 0, 1, 2 or 3 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NR A R B )carbonyl, or NR A R ⁇ .
  • substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NR A R B )carbonyl, or NR A R ⁇ .
  • Heterocycle groups suitable for R ⁇ are, for example, furyl, imidazolyl, isothiazolyl, isothiazolinyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, quinolinyl, quino
  • the heterocycle group for R 6 is substituted with 0, 1 , 2 or 3 substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, arylalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, haloalkylcarbonyl, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NR A R B , (NR A R ⁇ )alkyl, (NR A R B )carbonyl and (NR A R B )sulfonyl; wherein R A and R B are as defined in formula (I).
  • heterocycles for Rg are l,2,4-oxadiazol-3-yl, 3-pyridinyl, 4-isoxazolyl and lH-imidazol-1-yl, wherein the heterocycle is substituted with 0, 1 or 2 substituents selected from hydrogen, alkyl, haloalkyl, or hydroxyalkyl.
  • Phenyl groups are particularly suitable for an aryl group R 22 .
  • Such phenyl groups is substituted with 0, 1, 2 or 3 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NR A R B )carbonyl, and NR A R B .
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH 2 -; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3 R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl,
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; R t and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R ⁇ R 5 and R are hydrogen; R ⁇ is L-R 2 0. L 2 is selected from alkylene and al
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3 R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R)-3-
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R 3 , R ⁇ R 5 and R 7 are hydrogen; and R 6 is L 2 R 20 ; L 2 is selected from alkylene and alkenylene; and R20 is phenyl substituted with 0, 1 , 2, or 3 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NR A R B )carbonyl, or -NR A R B .
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ ho.inyl; R 3) R- t , R 5 and R are hydrogen; and R ⁇ is alkylcarbonyl.
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3 R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2 -methyl- 1 -pyrrolidinyl; R 3 , R-(, R s and R are hydrogen; and Re is alkylcarbonyl.
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl- 1 -pyrrolidinyl, 2,5-dihydro- 1 H-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R- ⁇ , R 5 and R 7 are hydrogen; and R ⁇ is heterocycle.
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3 R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R 4 , R 5 and R are hydrogen; Re is a heterocycle selected from furyl, imidazolyl, iso
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R 3 , R- t , R 5 and R 7 are hydrogen; and R 6 is a heterocycle selected from l,2,4-oxadiazol-3-yl, 3-pyridinyl, 4-isoxazolyl, or lH-imidazol-1- yl wherein the heterocycle is substituted with 0, 1, or 2 substituents selected from hydrogen, alkyl, haloalkyl, or hydroxyalkyl.
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R 4 , R 5 and R are hydrogen; Re is -R 2 oL 3 R 22 ; R 2 0 is
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R 3 , R-,, R 5 and R 7 are hydrogen; R is -R 2 oL 3 R 22 ; R20 is l,2,4-oxadiazol-3-yl; L 3 is selected from a covalent bond and alkylene; and R 22 is phenyl substituted with 0, 1, 2, or 3 substitutents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NR A R B )carbony
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R-i, R 5 and R are hydrogen; Re is -R2oL 3 R 22 ; R 2 0 is
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l-pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethy -piperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l-pyrrolidinyl; R 3 , R 4 , R 5 and R 7 are hydrogen; Re is -R 2 oL 3 R 22 ; R20 is l,2,4-oxadiazol-3-yl; L 3 is selected from a covalent bond and alkylene; and R 22 is 2- thienyl.
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R 4 , R 5 and R are hydrogen; R is -R20L3R22; R20 is aryl; L
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l -pyrrolidinyl, (3S)-3- hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R , R 5 and R are hydrogen; Re is -R 2 oL 3 R 22 ; R 2 o is
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl,
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R 4 , R 5 and R 7 are hydrogen; Re is -R2oL 3 R 22 ; R 20 is
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2
  • compounds of the present invention have formula (II) (II), or a pharmaceutical acceptable salt, ester, amide, or prodrug thereof, wherein
  • R is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, or (NR A R B )sulfonyl;
  • R 8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl, or (NR A R B )carbonyl;
  • R 9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, or (NR A R B )sulfonyl;
  • X is selected from CH, CRx, or N;
  • Y is selected from CH, CR ⁇ ; or N;
  • Z is selected from CH, CRz, or N;
  • Rx, R Y and Rz groups are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, or (NR A R ⁇ )sulfonyl; and A, D, L, R A) R B , R I , R 2 , R3, R , and R5 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; and D, L, R A , R B , Ri, R 2 , R 3 , Rt, R5, R7, R 8 , R9, X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond, Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R is cyano; and D, L, R A , R B , 3, R4, R5, R7 and R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein L is -CH 2 CH 2 -; A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 3 , R , R 5 , R 7 and R 9 are hydrogen; R 8 is cyano; X is CH; Y is CH; Z is CH; and D, R A , and R B are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is cyano; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is heterocyclecarbonyl; and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 , R 9 , X, Y and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1- pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomo ⁇ holinyl, and l,l-dioxidothiomo ⁇ holin-4-yl; and D, L, R A , R B , R 3 , R , R 5 , R 7 , R 9 , X, Y and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 , R 9 , X, Y and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 3 , R-j, R 5 , R and R are hydrogen; R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; X is CH; Y is CH; Z is CH; and D, R A and RB are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is heterocyclecarbonyl; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R», R 5 , R 7 and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; R 8 is heterocyclecarbonyl wherein the heterocycle of heterocarbonyl is selected from the group consisting of azetidinyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl.; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R-t, R 5 , R 7 and R 9 are as defined in formula (II)
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R ⁇ are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1- pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomo ⁇ holinyl, and l,l-dioxidothiomo ⁇ holin-4-yl; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R , R 5 , R 7 and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R] and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R-i, R5, R7 and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 3 , R , R 5 , R 7 and R 9 are hydrogen; R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; X is N; Y is CH; Z is CH; and D, R A and R B are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 , Rg, R , X, Y and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R g is cyano; and D, L, R A , R B , R 3 , R ⁇ R 5 ,R 7 , R , X, Y and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R , R 5 , and R are independently selected from hydrogen, alkyl, alkylcarbonyl, and halogen; Rg and R 9 are independently selected from hydrogen, alkoxy
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3 -hydroxy- 1 -pyrrolidinyl, (3S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrol
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle substituted with 0, 1 or 2 substituents selected from alkyl; R 3 , R-i, R 5 , R , and R 9 are hydrogen; R 8 is cyano; X is CH; Y is CH; and Z is CH.
  • compounds of the present invention have formula (II) wherein L is -CH 2 CH 2 -; A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 is heterocycle; R-j, R 5 , R and R are hydrogen; R 8 is cyano; X is CH; Y is CH; and Z is CH.
  • compounds of the present invention have formula (II) wherein L is -CH 2 CH 2 -; A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3 -hydroxy- 1 -pyrrolidinyl, (3S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrol
  • compounds of the present invention have formula (II) wherein L is -CH 2 CH 2 -; A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R 3 is heterocycle selected from 2-furyl, 3-pyridinyl, and 2-thienyl wherein the heterocycle is substituted with 0, 1, or 2 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, or oximyl; R , R 5 , R and R 9 are hydrogen; R 8 is cyano; X is CH;Y is CH; and Z is CH.
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R 8 is cyano; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R , R5, R7 and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R 8 is cyano; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R g is heterocyclecarbonyl; and D, L, R A , R B , R 3 , R , R 5 , R 7 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl.
  • R 8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; and D, L, R A , R B , R 3 , R ⁇ R5, R ,
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1 ,1- dioxidothiomo ⁇ holinyl; R 8 is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridin
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l-pyrrolidinyl, (3 S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidinyl, (c
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; and D, L, R A , R B , R 3 , R-t, R5, R 7 , R 9 , X,
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1 ,1- dioxido thiomo ⁇ holinyl; R 3 , R 4 , R 5 , R 7 and R 9 are hydrogen; R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; X is CH; Y is CH; Z is CH;
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R 8 is heterocyclecarbonyl; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R ⁇ R 5 , R 7 , and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; Rg is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3-hydroxy-l -pyrrolidinyl, (3 S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidin
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl.
  • R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl;
  • X is N;
  • Y is CH;
  • Z is CH; and
  • D, L, R A , R B , R 3 , R , R 5 ,R 7 , and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3-hydroxy-l -pyrrolidinyl, (3S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidin
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; R 3 , R , R 5 , R 7 and R 9 are hydrogen; R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; X is N;
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3 -hydroxy- 1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-di
  • compounds of the present invention have formula (II) wherein A is carbonyl; Ri and R 2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and Rg is selected from the group consisting of cyano and heterocyclecarbonyl; and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 , and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is carbonyl; Ri and R 2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and Rg is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; and D, L, R A , R B , R 3 , R . R 5 , R , and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is carbonyl; R ⁇ and R 2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; Rg is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1- piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro- l(2H)-pyridinyl, 4-thiomo ⁇ holinyl, and l,l-dioxidothiomo ⁇ holin-4-yl; and D, L, R A , R B , R 3 , R 4 , R5, R 7 ,
  • compounds of the present invention have formula (II) wherein A is carbonyl; and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R 8 is selected from cyano or heterocyclecarbonyl; and D, L, R A , R B , R3, R 4 , R 5 , R 7 , R 9 , X, Y and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is carbonyl; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; Rg is selected from cyano or heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3-
  • compounds of the present invention have formula (II) wherein A is carbonyl; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; R 8 is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1 -azetidinyl, 4-mo ⁇ holiny
  • compounds of the present invention have formula (II) wherein A is carbonyl; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy- 1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2 S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2
  • compounds of the present invention have formula (HI)
  • R 6 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • R 8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl or (NR A R B )carbonyl;
  • R 9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • X is selected from CH, CRx or N;
  • Y is selected from CH, CRy or N;
  • Z is selected from CH, CRz or N;
  • Rx, R Y and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R ⁇ )sulfonyl; and
  • R A , D, L, R A , R B , R I , R 2 , R 3 , R 4 , and R 5 are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is a covalent bond; and D, L, R A , R B , R I , R 2 , R 3 , R , R5, e, R 8 , R9, X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is a covalent bond; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is selected from cyano or heterocyclecarbonyl; and D, L, R A , R B , R3, R-t, R5, Re, R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; Rg is selected from cyano or heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1- piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro- l(2H)-pyridinyl, 4-thiomo ⁇ holinyl, and 1 , 1 -dioxidothiomo ⁇ holin-4-yl; D, L, R A , R B , R 3 , Rj, R5, Re, R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; Rg is selected from cyano or heterocyclecarbonyl; and D, L, R A , R B , R 3 , R , R 5 , Re, R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R 8 is selected from cyano or heterocyclecarbonyl wherein the heterocycle is selected from 1-azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyri
  • compounds of the present invention have formula (III) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-
  • compounds of the present invention have formula (III) wherein A is carbonyl; and D, L, R A , R B , Ri, R2, R3, R ⁇ t, R5, Re, R 8 , R9, X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is cyano; and D, L, R A , RB, R3, R4, R5, R ⁇ , R9, X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein L is -CH 2 CH 2 -; A is carbonyl; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 3 is methyl, R , R 5 , Re and R 9 are hydrogen; R 8 is cyano; X is CH; Y is CH; Z is CH; and D, R A and R B are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; Rg is heterocyclecarbonyl; and D, L, R A , R B , R 3 , R 4 , R 5 , R 6 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is heterocyclecarbonyl wherein the heterocycle is selected from 1-azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1- pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomo ⁇ holinyl, and 1 , 1 -dioxidothiomo ⁇ holin-4-yl; and D, L, R A , R B , R 3 , R , R 5 , R 6 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R 8 is cyano; and D, L, R A , R B , R 3 , R- t , R 5 , Re, R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1 ,1- dioxidothiomo ⁇ holinyl; R 8 is cyano; and D, L, R A , R B , R 3 , R.;, R 5 , R 6 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; R) and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-
  • compounds of the present invention have formula (III) wherein L is -CH 2 CH 2 -; A is carbonyl; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l- pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; R 3 is methyl; R , R 5 , Re and R 9 are hydrogen; R 8 is cyano; X is CH; Y is CH; Z is CH; and D, L, R A and R
  • compounds of the present invention have formula (III) wherein L is -CH 2 CH 2 -; A is carbonyl; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidiny
  • compounds of the present invention have formula (III) wherein A is carbonyl; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; Rg is heterocyclecarbonyl; and D, L, R A , R B , R 3 , R 4 , R5, Re, R9, X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; R ⁇ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R 8 is heterocyclecarbonyl wherein the heterocycle is selected from 1-azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1
  • compounds of the present invention have formula (III) wherein A is carbonyl; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5
  • R 7 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • R 8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl or (NR A R B )carbonyl;
  • R 9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • X is selected from CH, CRx or N;
  • Y is selected from CH, CRy or N;
  • Z is selected from CH, CRz or N;
  • Rx, Ry and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A , R B , (NR A R ⁇ )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl; and
  • D, L, R A , RB, R I , R 2 , R 3 , R 4 and R 5 are as defined in formula (I).
  • compounds of the present invention have formula (IV) wherein A is a covalent bond; and D, L, R A , R B , R,, R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (IV) wherein A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is cyano; and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (IV) wherein L is -CH2CH2-; A is a covalent bond; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 3 , R 4 , R 5 , R 7 and R 9 are hydrogen; R 8 is cyano; X is CH; Y is CH; Z is CH; and D, R A and R B are as defined in formula (I).
  • Re is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • Rg is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl or (NR A R ⁇ )carbonyl;
  • R 9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • X is selected from CH, CRx or N;
  • Y is selected from CH, CR Y or N
  • Z is selected from CH, CR Z or N;
  • Rx, RY and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl; and A, D, L, R A , R B , Ri, R 2 , R 3 , R , R 5 are as defined in formula (I).
  • compounds of the present invention have formula (V) wherein A is a covalent bond; and D, L, R A , R B , Rj, R 2 , R 3 , i, R 5 , Re, R 8 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (IV) wherein A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is cyano; and D, L, R A , R B , R 3 , ⁇ , R 5 , Re, R , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (IV) wherein L is -CH 2 CH 2 -; A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 3 , R-j, R 5 , Re and R 9 are hydrogen; R is cyano; X is CH; Y is CH; Z is CH; and D, R A and R B are as defined in formula (I).
  • R 5 , Re, and R are selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • R 8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl and (NR A R B )carbonyl;
  • R 9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbon
  • X is selected from CH, CRx or N;
  • Y is selected from CH, CRY or N;
  • Z is selected from CH, CRz or N;
  • Rx, R Y and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R ⁇ , (NR A R ⁇ )alkyl, (NR A R B )carbonyl or (NR A R ⁇ )sulfonyl; and
  • R A , D, L, R A , R B , Ri, R 2 , and R 3 are as defined in formula (I).
  • compounds of the present invention have formula (VI) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; P, Q, D, L, R A , R B , and R 3 , are as defined in formula (I) and R 5 , Re, R 7 , Rg, and R 9 are defined as in formula (VI).
  • compounds of the present invention have formula (VI) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R 8 is cyano; and P, Q, D, L, R A , R B , and R 3 , are as defined in formula (I) and R 5 , Re, R 7 , and R 9 are defined as in formula (VI).
  • compounds of the present invention have formula (VI) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- di
  • compounds of the present invention have formula (VI) wherein L is -CH 2 CH 2 -; A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1 , 1 -dioxidothiomo ⁇ holinyl; R 3 , R 5 , R ⁇ , R and R 9 are hydrogen; Rg is cyano; X is CH;Y is CH; and Z is CH.
  • compounds of the present invention have formula (VI) wherein L is -CH 2 CH 2 -; A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3 -hydroxy- 1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrol
  • compounds of the present invention have formula (VII) (VII), or a pharmaceutical acceptable salt, ester, amide, or prodrug thereof, wherein
  • R ⁇ R 6 , and R 7 are selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • Rg is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl or (NR A R B )carbonyl;
  • R 9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • X is selected from CH, CR X or N;
  • Y is selected from CH, CR Y or N;
  • Z is selected from CH, CRz or N;
  • Rx, Ry and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbony
  • L, A, D, Ri, R 2 , R 3 , R A , and R B are as defined in formula (I).
  • compounds of the present invention have formula (VII) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; P, Q, D, L, R A , R B , and R 3 , are as defined in formula (I) and R 4 , R ⁇ , R 7 , Rg, and R 9 are defined as in formula (VII).
  • compounds of the present invention have formula (VII) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R 8 is cyano; and P, Q, D, L, R A , R B , and R 3 , are as defined in formula (I) and j, Re, R 7 , and R9 are defined as in formula (VII).
  • compounds of the present invention have formula (VII) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,
  • compounds of the present invention have formula (VII) wherein L is -CH 2 CH 2 -; A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; R 3 , R 4 , R ⁇ , R7 and R 9 are hydrogen; Rg is cyano; X is CH;Y is CH; and Z is CH.
  • compounds of the present invention have formula (VII) wherein L is -CH 2 CH 2 -; A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3-hydroxy-l -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyr
  • the present invention also provides, pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I- VII) in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method of selectively modulating the effects of the histamine-3 receptors in a mammal comprising administering an effective amount of a compound of formula (I- VII).
  • the present invention provides a method of treating or preventing a disorder ameliorated by modulating the histamine-3 receptors in a mammal comprising administering an effective amount of a compound of formula (I -VII).
  • the present invention provides a method of treating a disorder selected from acute myocardial infarction, asthma, bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric disorders, cutaneous carcinoma, drug abuse, depression, gastrointestinal disorders, inflammation, jet lag, medullary thyroid carcinoma, melanoma, allergic rhinitis, Meniere's disease, migraine, mood and attention alteration, motion sickness, neurogenic inflammation, obsessive compulsive disorder, pain, Parkinson's disease, schizophrenia, seizures, septic shock, Tourette's syndrome, vertigo, or wakefulness.
  • a disorder selected from acute myocardial infarction, asthma, bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric disorders, cutaneous carcinoma, drug abuse, depression, gastrointestinal disorders, inflammation, jet lag, medullary thyroid carcinoma, melanoma, allergic rhinitis, Meniere's disease, migraine, mood and attention alteration, motion sickness, neurogenic inflammation, obsessive compulsive disorder, pain, Parkinson
  • the present invention provides a method of treating Alzheimer's disease by administering an effective amount of a compound of formula (I-VII).
  • the present invention provides a method of treating attention-deficit hyperactivity disorder by administering an effective amount of a compound of formula (I- VII).
  • the present invention provides a method of treating epilepsy by administering an effective amount of a compound of formula (I- VII).
  • the present invention provides a method of treating narcolepsy by administering an effective amount of a compound of formula (I- VII).
  • the present invention provides a method of treating obesity by administering an effective amount of a compound of formula (I- VII).
  • the present invention provides a method of treating a disorder selected from mild cognitive impairment, deficits of memory, and deficits of learning and dementia by administering an effective amount of a compound of formula (I- VII).
  • Representative compounds of the invention include, but are not limited to: 2R)-2-methylpyrrolidinyl]ethyl ⁇ - 1 -benzofuran-5-yl)benzonitrile; -pyrrolidinyl)ethyl]- 1 -benzofuran-5-yl ⁇ benzonitrile; -methyl- 1 -pyrrolidinyl)ethyl]- 1 -benzofuran-5-yl ⁇ benzonitrile; -piperidinyl)ethyl]- 1 -benzofuran-5-yl ⁇ benzonitrile; iethylamino)ethyl]-l-benzofuran-5-yl ⁇ benzonitrile; -methyl- 1 -piperidinyl)ethyl]- 1 -benzofuran-5-yl ⁇ benzonitrile; 3R)-3-hydroxypy ⁇ Olidinyl]ethyl ⁇ -l-benzofuran-5-yl)benz
  • H 3 receptor ligands histamine-3 receptor ligands
  • Sprague-Dawley rat brain cortices were homogenized (1 g tissue/10 mL buffer) in 50 mM Tris-HCl/5 mM EDTA containing protease inhibitor cocktail (Calbiochem) using a polytron set at 20,500 ⁇ m. Homogenates were centrifuged for 20 minutes at 40,000 ⁇ g. The supernatant was decanted, and pellets were weighed. The pellet was resuspended by polytron homogenization in 40 mL 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and centrifuged for 20 minutes at 40,000xg.
  • the membrane pellet was resuspended in 6.25 volumes (per gram wet weight of pellet) of 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and aliquots flash frozen in liquid N 2 and stored at -70 °C until used in assays.
  • Rat cortical membranes (12 mg wet weight/tube) were incubated with ( 3 H)-N- ⁇ -methylhistamine (-0.6 nM) with or without H 3 receptor antagonists in a total incubation volume of 0.5 mL of 50 mM Tris-HCl/5 mM EDTA (pH 1.1).
  • Test compounds were dissolved in DMSO to provide a 20 mM solution, serially diluted and then added to the incubation mixtures prior to initiating the incubation assay by addition of the membranes. Thioperamide (3 ⁇ M) was used to determine nonspecific binding. Binding incubations were conducted for 30 minutes at 25 °C and terminated by addition of 2 mL of ice cold 50 mM Tris-HCl (pH 1.1) and filtration through 0.3% polyethylenimine-soaked Unifilter plates (Packard). These filters were washed 4 additional times with 2 mL of ice-cold 50 mM Tris- HCl and dried for 1 hour. Radioactivity was determined using liquid scintillation counting techniques. Results were analyzed by Hill transformation and Ki values were determined using the Cheng-Prusoff equation.
  • the compounds of the present invention bind to the histamine-3 receptors and therefore may have utility in the treatment of diseases or conditions ameliorated with histamine-3 receptor ligands.
  • Compounds of the present invention are histamine-3 receptor ligands that modulate function of the histamine-3 receptor by antagonizing the activity of the receptor. These compounds may be inverse agonists that inhibit the basal activity of the receptor or they may be antagonists that completely block the action of receptor-activating agonists. These compounds may also be partial agonists that partially block or partially activate the histamine-3 receptor receptor or they may be agonists that activate the receptor.
  • the compounds of this invention can be prepared by a variety of synthetic procedures.
  • Benzofurans of general formula (5) wherein L, Ri, R 2 , R 3 , R t , R 5 , Re and R are as defined in formula (I), may be prepared as described in Scheme I.
  • Phenols of general formula (1) may be treated with sodium hypochlorite, sodium iodide and sodium hydroxide in a solvent such as methanol to provide iodides of general formula (2).
  • Iodides of general formula (2) may be treated with substituted propargyl alcohols, dichlorobis(triphenylphosphine)palladium, copper iodide, a base such as triethylamine in a solvent such as DMF with heat to provide benzofurans of general formula (3).
  • Alcohols of general formula (3) may be treated with methanesulfonyl chloride or methanesulfonyl anhydride, a base such as triethylamine, diisopropylethylamine or N-methylmo ⁇ holine in a solvent such as dichloromethane or THF to provide mesylates of general formula (4).
  • Mesylates of general formula (4) may be treated with secondary or primary amines in solvents such as DMF or THF with heat to provide amines of general formula (5).
  • mesylates of general formula (4) may be treated with secondary or primary amine hydrochlorides in the presence of a base such as triethylamine, diisopropylethylamime or N-methylmo ⁇ holine in a solvent such as DMF or THF with heat to provide benzofurans of general formula (5).
  • a base such as triethylamine, diisopropylethylamime or N-methylmo ⁇ holine in a solvent such as DMF or THF with heat to provide benzofurans of general formula (5).
  • Benzofurans of general formula (10), wherein L, Ri, R 2 , R 3 , R-i, R 5 , R 7 , Rg, R , X, Y and Z are as defined in formula (II), may be prepared as described in Scheme 2.
  • Halides of general formula (6) may be treated with boronic acids of general formula (7), under Suzuki conditions such as tetrakis(triphenylphosphine)palladium, a base such as aqueous sodium carbonate in a solvent such as toluene with heat to provide tert-butyldimethylsilyl protected alcohols of general formula (8).
  • Protected alcohols of general formula (8) may be treated with tetrabutylammonium fluoride in a solvent such as THF to provide phenols of general formula (9).
  • Phenols of general formula (9) may be treated using conditions as described in Scheme 1 to provide benzofurans of general formula (10).
  • Benzofurans of general formula (12) wherein L, Ri, R 2 , R 3 , R , R 5 , Re, X, Y, Z, Rg, and R 9 are as defined in formula (III), may be prepared as described in Scheme 3.
  • Boronic acids of general formula (11) may be treated with halides as described in Scheme 2 to provide compounds of general formula (11a).
  • Compounds of general formula (11a) may be treated with tetra-butylammonium fluoride and then as described in Scheme 1 and Scheme 2 to provide benzofurans of general formula (12).
  • Chromenes of general formula (19), wherein L, Ri, R 2 , R 3 , Rt, R 5 , R 7 , R 8 , R 9 , X, Y and Z are as defined by formula (II), may be prepared as described in Scheme 4.
  • Boronic acids of general formula (13) may be treated with halides of general formula (6), tetrakis(triphenylphosphine)palladium, a base such as aqueous sodium carbonate in a solvent such as toluene with heat to provide compounds of general formula (14).
  • Compounds of general formula (14) may be treated with n-butyl lithium, N, N, N', N'- tetramethylethylenediamine followed by DMF or acetyl chloride to provide compounds of general formula (15) which may be treated with [2-(dimethylamino)-2-oxoethyl]lithium in a solvent such as THF to provide compounds of general formula (16).
  • Compounds of general formula (16) may be treated with acetic acid with heat to provide chromenes of general formula (17).
  • Chromenes of general formula (17) may be treated with butyl lithium, N, N, N', N'-tetramethylethylenediamine followed by ethylene oxide or trimethylene oxide to provide alcohols of general formula (18).
  • Alternatively (17) may be treated with butyl lithium, N, N, N', N'-tetrarnethylethylenediamine and (2-bromoethoxy) tert- butyldimethylsilane followed by tetrabutylammonium fluoride deprotection to provide alcohols of general formula (18).
  • Alcohols of general formula (18) may be converted to the respective mesylate and further reacted with amines as described in scheme 1 to provide chromenes of general formula (19).
  • chromenes of general formula (24) wherein L, R ls R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R are as defined in formula (II), may be prepared as described in scheme 5.
  • Compound of general structure (21) may be prepared from Scheme 4 by substituting compound of general structure (20) for compound of general formula (14).
  • Compound of general formula (20) may be treated with n-butyl lithium followed by DMF or acetyl chloride to provide compounds of general formula (20a).
  • Compounds of general formula (20a) may be treated with [2-(dimethylamino)-2-oxoethyl]lifhium followed by acetic acid and heat to provide chromenes of general formula (21).
  • Chromenes of general formula (21) may be treated with n-butyl lithium, N, N, N', N'-tetramethylethylenediamine followed by ethylene oxide or trimethylene oxide to provide alcohols which may be treated with methanesulfonyl chloride, a base such as triethylamine, diisopropylethylamine or N-methylmo ⁇ holine in a solvent such as dichloromethane or THF to provide mesylates which may be treated with secondary or primary amines in solvents such as DMF or THF with heat to provide amines of general formula (22).
  • Amines of general formula (22) may be treated with tetrabutylammonium fluoride followed by treatment with triflic anhydride, pyridine and boronic acids of general formula (23), dichlorobis(triphenylphosphine)palladium, cesium carbonate in a solvent such as DMF with heat to provide compound of general formula (24).
  • chromenes of general structure (28), wherein Ri, R 2 , R 3 , R 4 , R 5 , R ⁇ and R 7 are as defined by formula (III), may be prepared as described in Scheme 6.
  • Phenols of general formula (25) may be treated with compounds of general formula (26) and hydrobromic acid in acetic acid with heat to provide compounds of general formula (27), which may be treated with amines as described in Scheme 4 to provide chromenes of general formula (28).
  • Chromenes of general formula (30) wherein L, Ri, R2, R3, R4, R5, R-, Rs, R9, X, Y and Z are as defined in formula (III), may be prepared as described in Scheme 7.
  • Boronic acids of general formula (29) may be treated as described in Scheme 4 to provide Chromenes of general formula (30).
  • Alcohols of general formula (34) may be treated with methanesulfonyl chloride with bases such as triethylamine, diisopropylethylamine or N-methylmo ⁇ holine in solvents such as dichloromethane or THF to provide mesylates of general formula (35).
  • Mesylates of general formula (35) may be treated with secondary or primary amines in a solvent such as DMF or THF with heat to provide amines of general formula (36).
  • Dihydrofurans of general formula (38) wherein Ri, R 2 , R3, i, R5, Re, R_, R 9 , X, Y and Z are as defined in formula (IV), may be prepared as described in Scheme 9.
  • Iodides of general formula (37) may be treated as described in Scheme 8 to provide dihydrofurans of general formula (38).
  • Benzothiophenes of general formula (43) wherein L, R ⁇ , R2, R 3 , R», R 5 , R 7 , R 8 , R 9 , X, Y and Z are defined in formula (I), may be prepared as described in Scheme 10.
  • Compounds of general formula (39) may be treated with poly-phosphoric acid with heat to provide benzothiophenes of general formula (40).
  • Benzothiophenes of general formula (40) may be treated with boronic acids, tetrakis(triphenylphosphine)palladium, a base such as aqueous sodium carbonate in a solvent such as toluene with heat to provide compounds of general formula (41).
  • Compounds of general formula (41) may be treated with n-butyl lithium, N, N, N', N'-tetramethylethylenediamine followed by ethylene oxide to provide alcohols of general formula (42).
  • Alcohols of general formula (42) may be converted to the mesylate and then further treated with amines as described in Scheme 1 to provide benzothiophenes of general formula (43).
  • Benzothiophenes of general formula (45) wherein Ri, R 2 , R 3 , R 4 , R 5 , Re, Rg, R 9 and X, Y and Z are defined in formula (I), may be prepared as described in Scheme 1 1.
  • Compounds of general formula (44) may be processed as described in Scheme 10 to provide compounds of general formula (45).
  • Benzofurans of general formula (49) wherein R ⁇ , R 2 , R 3 , R , R 5 , Re, and R are as defined in formula (I), may be prepared as described in Scheme 12.
  • Alkynes of general formula (48) may be treated with a phenol of general formula (2), a palladium catalyst such as palladium(II) acetate, a triarylphoshine such as triphenylphoshine or tris(2-mefhylphenyl)phosphine, copper iodide, and a base such as diisopropylamine in a solvent such as acetonitrile followed by heat to provide benzofurans of general formula (49).
  • a palladium catalyst such as palladium(II) acetate
  • a triarylphoshine such as triphenylphoshine or tris(2-mefhylphenyl)phosphine
  • copper iodide copper iodide
  • a base such as diisopropylamine in a solvent such as acetonitrile followed by heat to provide benzofurans of general formula (49).
  • Example 1A 4'-hvdroxy-3'-iodor 1 , 1 '-biphenyl1-4-carbonitrile
  • 4-hydroxy-4'-cyanobiphenyl 6.00 g, 30.8 mmol
  • sodium iodide 4.61 g, 30.8 mmol
  • sodium hydroxide 1.23 g, 30.8 mmol
  • methanol 90 mL
  • an aqueous solution of sodium hypochlorite 47 mL of 5.25% CloroxTM, 2.29 g, 30.8 mmol
  • Example IB 4-[2-(2-hvdroxyethylH-benzofuran-5-yl]benzonitrile
  • a solution of Example 1A (5.19 g, 16.2 mmol), triethylamine (5.60 mL, 40.4 mmol) and 3-butyn-l-ol (1.90 g, 27.2 mmol) in dimethylformamide (13 mL) at 20 °C was added cuprous iodide (0.46 g, 2.4 mmol) and bis-triphenylphosphine palladium dichloride (0.56 g, 0.80 mmol).
  • dichloromethane 10 mL
  • methane sulfonyl chloride 0.79 g, 4.5 mmol
  • the mixture was stirred for 30 min., diluted with dichloromethane, washed with water, dried (Na2SO 4 ), filtered and concentrated under reduced pressure. The residue was chromatographed on silica with dichloromethane to give the titled compound (0.66 g, 89%).
  • 2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl) - 1 -benzofuran-5-yl benzonitrile A suspension of Example IC (0.19 g, 0.55 mmol), (2R)-2-methylpyrrolidine hydrobromide (0.17 g, 1.0 mmol) and sodium carbonate (0.23 g, 2.2 mmol) in acetonitrile (0.4 mL) was heated to 50 °C with stirring for 48 hours. The reaction was cooled to ambient temperature, diluted with acetonitrile and centrifuged. The supernatant liquid was removed and the solids washed with acetonitrile.
  • Example 2 4- ⁇ 2-r2-(l -pyrrolidinyDethyl]- 1 -benzofuran-5-yl ⁇ benzonitrile
  • the product from Example IC and pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 3 4- ⁇ 2-[2-(2-methyl-l-pyrrolidinyl)ethyl]-l-benzofuran-5-yl ⁇ benzonitrile
  • the product from Example 1 C and 2-methyl-pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 4 4-(2-[2-(l-piperidinyl)ethyll-l-benzofuran-5-yl ⁇ benzonitrile
  • the product from Example IC and piperidine were processed as described in Example ID to provide the titled compound.
  • ⁇ NMR (300 MHz, CD 3 OD) ⁇ 7.88 (m, IH), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, IH), 3.65 (m, 2H), 3.55 (m, 2H), 3.33 (m, 2H), 3.05 (m, 2H), 2.0 (m, 2H), 1.5-1.9 (m, 4H);
  • Example 5 4-(2- 2-(diethylamino)ethvn-l-benzofuran-5-v benzonitrile
  • the product from Example 1 C and diethylamine were processed as described in Example ID to provide the titled compound.
  • Example 6 4-(2-[2-(2-methyl-l-piperidinyl)ethyll-l-benzofuran-5-yl ⁇ benzonitrile
  • the product from Example IC and 2-methylpiperidine were processed as described in Example ID to provide the titled compound.
  • Example 7 4-(2- ⁇ 2-[( ' 3R)-3-hvdroxypyrrolidinyl1ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and 3-(R)-hydroxypyrrolidine were processed as described in Example ID to provide the titled compound.
  • ⁇ NMR (300 MHz, CD 3 OD) ⁇ 7.88 (m, IH), 7.80 (m, 4H), 7.60 (m, 2H), 6.80 (s, IH), 4.55 (bs, IH), 3.8-3.9 (m, 4H), 3.25-3.5 (m, 4H), 2.05-2.4 (m, 2H); MS (DCI) m/z 333 (M+H) + .
  • Example 8 4- ⁇ 2- 2-(lH-imidazol-l-yl)ethyl]-l-benzofuran-5-yllbenzonitrile
  • the product from Example IC and imidazole were processed as described in Example ID to provide the titled compound.
  • Example 9 4-(2-(2-[(3S)-3-(dimethylamino)pyrrolidinyl]ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and 3-(S)-(dimethylamino)pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 10 4-(2- ⁇ 2-r(2S)-2-(hvdroxymethyl)pyrrolidinyl1ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example 1 C and 2-(S)-(hydroxymethyl)pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 11 4-(2- ⁇ 2- -2,6-dimethylpiperidinyl]ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and -dimethylpiperidine were processed as described in Example ID to provide the titled compound.
  • Example 12 4-(2- ⁇ 2-r(2R.5R)-2.5-dimethylpyrrolidinyl1ethvU-l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and (2R,5R)-dimethylpyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 13 4- (2-[2-f 1 -azepanvDethyl]- 1 -benzofuran-5 -yl ⁇ benzonitrile
  • the product from Example IC and azepine were processed as described in Example ID to provide the titled compound.
  • Example 14 4-
  • the product from Example IC and 4-methylpiperidine were processed as described in Example ID to provide the titled compound.
  • Example 15 4-(2-(2-r2-pyrrolidine methyl carboxylatelethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and (L)-proline methyl ester were processed as described in Example ID to provide the titled compound.
  • Example 16 4-(2- 2-(3.6-dihvdro-l(2H)-pyridinyl)ethyl]-l-benzofuran-5-yl ⁇ benzonitrile
  • the product from Example IC and 1,2,3,6-tetrahydropyridine were processed as described in Example ID to provide the titled compound.
  • Example 17 4-(2- ⁇ 2-f(2R)-2-(hvdroxymethyl)pyrrolidinyl1ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and (D)-prolinol were processed as described in Example ID to provide the titled compound.
  • ⁇ NMR (300 MHz, CD 3 OD) ⁇ 7.87 (m, IH), 7.82 (m, 4H), 7.58 (m, 2H), 6.80 (s, IH), 3.95 (m, 2H), 3.72 (m, 2H), 3.58 (m, IH), 3.35-3.4 (m, 4H), 1.95-2.3 (m, 4H); MS (DCI) m/z 347 (M+H) + .
  • Example 18 4-(2-f2-rtert-butyl(methyl aminolethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and tert-butyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 19 4-(2- ⁇ 2-[isopropyl(methyl)aminolethyl. -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and isopropyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 20 4-(2- ⁇ 2- isobutyl(methyl)amino]ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example 1 C and isobutyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 21 4-(2-(2-rethyl(isopropyl)amino]ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and ethyl(isopropyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 22 4-(2- j2-rethyl(propyl)amino]ethvU - 1 -benzofuran-5-yl)benzonitrile
  • the product from Example IC and ethyl (propyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 23A 4'-(4-mo ⁇ holinylcarbonyl)[l. -biphenyl]-4-ol
  • 4-hydroxy-biphenyl-4'-carboxylic acid 5.35 g, 25.0 mmol
  • mo ⁇ holine 2.39 g, 27.5 mmol
  • triethylamine 3.5 mL, 25 mmol
  • dichloromethane 100 mL
  • l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was stirred for 16 hours, diluted with aqueous NaH 2 PO 4 and filtered.
  • Example 23B 3-iodo-4'-(4-mo ⁇ holinylcarbonyl)r 1.1 '-biphenyll-4-ol
  • Example 23 C 2- ⁇ 5- 4-(4-mo ⁇ holinylcarbonyl)phenyl]-l-benzofuran-2-yl ⁇ ethanol
  • MS (DCI) m/z 352 (M+H) + .
  • Example 23 D 2-
  • the product from Example 23C was processed as described in Example IC to provide the titled compound.
  • Example 23E 4-(4- ⁇ 2- 2-(2-methyl-l-pyrrolidinyl)ethyll-l-benzofuran-5-yl ⁇ benzoyl)mo ⁇ holine
  • the product from Example 23 D and 2-methyl-pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 24 4-(4- ⁇ 2- 2-(l-piperidinyl)ethyl]-l-benzofuran-5-yl ⁇ benzoyl)mo ⁇ holine
  • the product from Example 23 D and piperidine were processed as described in Example ID to provide the titled compound.
  • Example 25 N.N-diethyl-N-(2- ( 5 -f 4-(4-morpholinylcarbonyl)phenv ⁇ - 1 -benzofuran-2-yl ⁇ ethyllamine
  • the product from Example 23D and diethylamine were processed as described in Example ID to provide the titled compound.
  • Example 26 4-(4- ⁇ 2- 2-(2-methyl- 1 -piperidinvDethyl]- 1 -benzofuran-5-yl ⁇ benzoyl)mo ⁇ holine
  • the product from Example 23D and 2-methyl-piperidine were processed as described in Example ID to provide the titled compound.
  • Example 27 (3R)-l-(2-
  • the product from Example 23D and 3-(R)-pyrrolidinol were processed as described in Example ID to provide the titled compound.
  • Example 29 4-[4-(2- ⁇ 2-[-2.6-dimethylpiperidinyl]ethyl ⁇ -l-benzofuran-5-yl)benzoyllmorpholine
  • the product from Example 23D and -dimethylpiperidine were processed as described in Example ID to provide the titled compound.
  • Example 30 4-(4- ⁇ 2- 2-(azepanyl)ethyll-l-benzofuran-5-yl ⁇ benzoyl)mo ⁇ holine
  • the product from Example 23D and azepane were processed as described in Example ID to provide the titled compound.
  • Example 31 4-(4- .2-r2-(4-methyl- 1 -piperidinvDethyll- 1 -benzofuran-5-yl ⁇ benzoyl)mo ⁇ holine
  • the product from Example 23D and 4-methyl piperidine were processed as described in Example ID to provide the titled compound.
  • Example 32 4-(4-(2-r2-(4-mo ⁇ holine)ethyl]-l-benzofuran-5-yl ⁇ benzoyl ' )mo ⁇ holine
  • the product from Example 23D and mo ⁇ holine were processed as described in Example ID to provide the titled compound.
  • Example 33 4-(4-(2-r2-(3,6-dihvdro-l(2H)-pyridinyl ethyl]-l-benzofuran-5-yl ⁇ benzoyl)mo ⁇ holine
  • the product from Example 23D and 1,2,3,6-tetrahydropyridine were processed as described in Example ID to provide the titled compound.
  • Example 34 4-(4- ⁇ 2- 2-(2S)-pyrrolidinylmethano ⁇ ethvn-l-benzofuran-5-yl ⁇ benzoyl mo ⁇ holine
  • the product from Example 23D and 2-(S)-(hydroxymethyl)pyrrolidine were processed as described in Example ID to provide the titled compound.
  • ⁇ NMR (300 MHz, CD 3 OD) 8 7.81 (m, IH), 7.73 (m, 2H), 7.55 (m, 2H), 7.50 (dm 2H, J 8.4Hz), 6.77 (s, IH), 3.3-4.0 (m, 17H), 1.9-2.3 (m, 4H); MS (DCI) m/z 434 (M+H) + .
  • Example 35 N-(tert-butyl)-N-methyl-N-(2- ⁇ 5-
  • the product from Example 23 D and tert-butyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 36 N-isopropyl-N-methyl-N-(2- ⁇ 5- 4-(4-mo ⁇ holinylcarbonyl)phenyl]- 1 -benzofuran-2- yllethvDamine
  • the product from Example 23D and isopropyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 37 N-isobutyl-N-methyl-N-(2-(5-[4-(4-mo ⁇ holinylcarbonyl)phenyl1-l-benzofuran-2- vUethvDamine
  • the product from Example 23 D and isobutyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 38 N-ethyl-N-isopropyl-N-(2- ⁇ 5- 4-(4-mo ⁇ holinylcarbonyl)phenyll-l-benzofuran-2- yl ⁇ ethvDamine
  • the product from Example 23D and isopropyl(ethyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 39 N,N-dimethyl-N-(2- ⁇ 5-[4-(4-mo ⁇ holinylcarbonyl)phenyll- 1 -benzofuran-2-yl ⁇ ethvDamine
  • Example 40 N-ethyl-N-(2- ⁇ 5- 4-(4-mo ⁇ holinylcarbonvDphenyl]- 1 -benzofuran-2-yl ⁇ ethvD-N- propylamine
  • the product from Example 23D and ethyl(propyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 41 A 3-(2-bromoethyD-6-hydroxy-4-methyl-2H-chromen-2-one To a solution of resorcinol (7.03 g, 64.0 mmol) in a solution consisting of HBr (104 mL, 422 mmol) and glacial acetic acid (10 mL) at 0 °C was slowly added 2-acetylbutyrolactone (5.8 mL, 54 mmol). The mixture was warmed to ambient temperature and then heated to reflux for 2 hours. The mixture was cooled to ambient temperature and diluted with water (350 mL). The mixture was filtered and the solid dried in vacuo overnight to give the titled compound (15.5 g, 85%).
  • Example 41B 6-hydroxy-4-methyl-3-[ " 2-(l-pyrrolidinyDethyl]-2H-chromen-2-one
  • a solution of Example 41 A (0.20 g, 0.70 mmol) and pyrrolidine (0.50 mL, 6.0 mmol) in DMF (2 mL) was heated to 75 °C for 16 hours, cooled to ambient temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate was dried (MgS0 4 ), filtered, concentrated under reduced pressure and chromatographed on silica with 10 % methanol in dichloromethane to give the titled compound (0.48 g, 25%).
  • Example 41C To a solution of Example 41B (0.105 g, 0.38 mmol), N-phenyltrifluoromethane sulfonimide (0.143 g, 0.38 mmol) in dichloromethane (2 mL) at 0 °C was added triethylamine (0.68 mL, 0.48 mmol). The mixture was stirred at ambient temperature for 12 hours, diluted with diethyl ether (40 mL) and washed sequentially with aqueous NaOH (IN, 2 x 30 mL), water and brine, dried (MgS0 ), filtered and evaporated to provide the triflate.
  • Example 42 4- ⁇ 4-methyl-2-oxo-3-r2-(l-piperidinvDethyl]-2H-chromen-6-yl ⁇ benzonitrile
  • the product from Example 41 A and piperidine were processed as described in Examples 41B and 41C to provide the titled compound.
  • Example 43 4- ⁇ 3-[2-(diethylamino)ethyl1-4-methyl-2-oxo-2H-chromen-6-yl ⁇ benzonitrile
  • the product from Example 41 A and diethylamine were processed as described in Examples 41B and 41C to provide the titled compound.
  • Example 44A 4-[(6-chloro-3-pyridinvDcarbonyllmo ⁇ holine To a solution of chloronicotinoyl chloride (3.52 g, 2.00 mmol) and triethylamine (3.1 mL, 2.22 mmol) in dichloromethane (5 mL) at 0 °C was slowly added mo ⁇ holine (1.75 mL, 2.00 mmol). The mixture was warmed to ambient temperature, washed with water (2 x 25 mL), brine (1 x 25 mL), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The product was chromatographed on silica with ethyl acetate to give the titled compound (4.0 g, 88%). MS (DCI) m/z 227 (M+H) + .
  • Example 44B 4-f 5-(4-mo ⁇ holinylcarbonyD- 1 ,6-dihvdro-2-pyridinyl1phenol
  • Example 44C 2-iodo-4- 5-(4-mo ⁇ holinylcarbonvD-2-pyridinyl]phenol
  • a mixture of Example 44B (4.25 g, 15.0 mmol) sodium iodide (2.36 g, 15.7 mmol) and sodium hydroxide (0.63 g, 15.7 mmol) was stirred in methanol (90 mL) with heating until a clear solution was obtained. The solution was then cooled to 0 °C and to this was slowly added sodium hypochlorite (22 mL of 5.25%, 1.15 g, 15.5 mmol) (CloroxTM) over 45 minutes.
  • sodium hypochlorite 22 mL of 5.25%, 1.15 g, 15.5 mmol
  • Example 44D 2- ⁇ 5-[5-(4-mo ⁇ holinylcarbonyD-2-pyridinyl]-l -benzofuran-2 -vPethanol
  • a solution of Example 44C (2.85 g, 6.95 mmol), triethylamine (2.4 mL, 17.4 mmol), and 3-butyn-l-ol (0.73 g, 10.4 mmol) in dimethylformamide (15 mL) at 20 °C was added cuprous iodide (0.2 g, 1.0 mmol) and bis-triphenylphosphine palladium dichloride (0.24 g, 0.35 mmol). The mixture was stirred for one hour, then heated to 65 °C for 16 hours.
  • Example 44E 2- .5-[5-(4-mo ⁇ holinylcarbonvD-2-pyridinyl]- 1 -benzofuran-2-yl ⁇ ethyl methanesulfonate
  • the product from Example 44D was processed as described in Example IC to provide the titled compound.
  • Example 44F 4-[(6- ⁇ 2- 2-(l-pyrrolidinvDethyl]-l-benzofuran-5-yl ⁇ -3-pyridinvDcarbonyl]mo ⁇ holine
  • the product from Example 44E and pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 44E The product from Example 44E and 2-(R)-methylpyrrolidine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 420 (M+H) + .
  • Example 46 4-[(6- ⁇ 2-f2-( 1 -piperidinvDethyll- 1 -benzofuran-5-yl) -3-pyridinvDcarbonyl]mo ⁇ holine
  • the product from Example 44E and piperidine were processed as described in Example ID to provide the titled compound.
  • Example 47 4-[(6-(2-r2-(N,N-diethvDethyl]-l-benzofuran-5-yl ⁇ -3-pyridinvDcarbonyl1mo ⁇ holine
  • the product from Example 44E and diethylamine were processed as described in Example ID to provide the titled compound.
  • Example 48 (3R)-l-r2-(5-f5-( ' 4-morpholinylcarbonyl)-2-pyridinyl1-l-benzofuran-2-yllethvD-3- pyrrolidinol
  • the product from Example 44E and 3-(R)-hydroxypyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 49 4-(r6-(2-(2-[(2R.5R)-2.5-dimethylpyrrolidinyl]ethvD-l-benzofuran-5-vD-3- pyridinyl]carbonyl ⁇ mo ⁇ holine
  • the product from Example 44E and (2R,5R)-dimethylpyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 50 4-(r6-(2-(2-[-2,6-dimethylpiperidinyl1ethvU-l-benzofuran-5-vD-3- pyridinyl]carbonyl ⁇ mo ⁇ holine
  • the product from Example 44E and -dimethylpiperidine were processed as described in Example ID to provide the titled compound.
  • Example 51 4-([6-r2-(2-[l-azepanyl]ethyl)-l-benzofuran-5-yD-3-pyridinyl]carbonyllmorpholine
  • the product from Example 44E and azepine were processed as described in Example ID to provide the titled compound.
  • Example 52 4-r.6-l2-r2-(4-methyl-l-piperidinvDethyl]-l-benzofuran-5-vU-3- pyridinvDcarbonyllmo ⁇ holine
  • the product from Example 44E and 4-methylpiperidine were processed as described in Example ID to provide the titled compound.
  • Example 53 4-[(6-(2-r2-(4-mo ⁇ holinyl)ethyl1-l-benzofuran-5-vU-3-pyridinyl)carbonyl1mo ⁇ holine
  • the product from Example 44E and mo ⁇ holine were processed as described in Example ID to provide the titled compound.
  • Example 54 N-(tert-butvD-N-methyl-N-(2- ⁇ 5-[5-(4-m ⁇ holinylcarbonvD-2 -pyridinyl]-! -benzofuran-2- yl. ethvDamine
  • the product from Example 44E and tert-butyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 55 N-isobutyl-N-methyl-N-(2- (5-[5-(4-mo ⁇ holinylcarbonvD-2-pyridinyl]- 1 -benzofuran-2 - yl) ethvDamine
  • the product from Example 44E and isob ⁇ tyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 56 N-isopropyl-N-methyl-N-(2-(5-r5-(4-mo ⁇ holinylcarbonyl)-2-pyridinyll-l-benzofuran-2- yl ⁇ ethvDamine
  • the product from Example 44E and isopropyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 57 N-ethyl-N-isopropyl-N-(2- ⁇ 5-r5-(4-mo ⁇ holinylcarbonyD-2 -pyridinyl]- 1-benzo furan-2- yl ⁇ ethvDamine
  • the product from Example 44E and ethyl(isopropyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 58 N.N-dimethyl-N-(2- ⁇ 5-[5-(4-mo ⁇ holinylcarbonyD-2 -pyridinyl]- l-benzofuran-2- yl) ethvDamine
  • the product from Example 44E and dimethylamine were processed as described in Example ID to provide the titled compound.
  • Example 59 N-ethyl-N-propyl-N-(2- (5-r5-(4-mo ⁇ holinylcarbonvD-2-pyridinyl1- 1 -benzofuran-2 - yll ethvDamine
  • the product from Example 44E and ethyl(propyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 60 8-(2- ⁇ 5-f5-(4-mo ⁇ holinylcarbonyl)-2-pyridinyl1-l-benzofuran-2-vUethvD-l,4-dioxa-8- azaspiro[4.5]decane
  • the product from Example 44E and l,4-dioxa-8-azaspiro[4.5]decane were processed as described in Example ID to provide the titled compound.
  • Example 61 5-(2-(5-[5-(4-mo ⁇ holinylcarbonyD-2-pyridinyl1-l -benzofuran-2-yl ⁇ ethvD-2-oxa-5- azabicyclo[2.2. l]heptane
  • the product from Example 44E and 2-oxo-5-azabicyclo[2.2.1]heptane were processed as described in Example ID to provide the titled compound.
  • Example 62 (2S)-l-(2- ⁇ 5-[5-(4-mo ⁇ holinylcarbonyD-2-pyridinyl1-l-benzofuran-2-yl ⁇ ethvD-2- pyrrolidinol
  • the product from Example 44E and 2-(R)-hydroxymethylpyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 63 N-allyl-N-(2-(5-[5-C4-morpholinylcarbonvD-2-pyridinvn-l-benzofuran-2-yllethvDamine
  • the product from Example 44E and allylamine were processed as described in Example ID to provide the titled compound.
  • ⁇ NMR 300 MHz, CD 3 OD
  • ⁇ 8.70 m, IH
  • 7.96 m, 3H
  • 7.59 7.59
  • J 8.7 Hz, IH
  • 6.81 s, IH
  • 5.95 m, IH
  • 5.55 m, 2H
  • MS (DCI) m/z 392 (M+H) + MS (DCI) m/z 392 (M+H) + .
  • Example 64 3-[(2-(5-[5-(4-mo ⁇ holinylcarbonvD-2-pyridinvn-l-benzofuran-2-yl ⁇ ethvDamino]-l- propanol
  • the product from Example 44E and 3-amino-l-propanol were processed as described in Example ID to provide the titled compound.
  • Example 44E The product from Example 44E and propylamine were processed as described in Example ID to provide the titled compound.
  • Example 66 4-(2- ⁇ 2-[(3R)-3-(dimethylamino)pyrrolidinyl]ethyl ⁇ -l-benzofuran-5-vDbenzonitrile
  • the product from Example IC and 3-(R)-(dimethylamino)pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 67A 4-(2-[(E)-2-methoxyethenyl1-2.3-dihvdro-l-benzofuran-5-yl ⁇ benzonitrile
  • a solution of Example 1A (0.20 g, 0.623 mmol), 1 -methoxybutadiene (0.18 g, 2.18 mmol), palladium diacetate (0.007 g, 0.031 mmol), sodium bicarbonate (0.261 g, 3.11 mmol) and tetrabutyl ammonium chloride (0.173 g, 0.623 mmol) was heated at 60° C in DMF (3 mL) under an atmosphere of nitrogen for 36 hours.
  • Example 67B 4- [2 -(2-oxoethvD-2.3 -dihvdro- 1 -benzofuran-5 -yl]benzoni trile
  • Example 67C 4-[2-(2-hvdroxyethvD-2,3-dihydro-l-benzofuran-5-yllbenzonitrile A solution of Example 67B (0.25 g, 0.95 mmol) and sodium borohydride (0.054 g, 1.42 mmol)in methanol (5 mL) was stirred for 1 hour, cooled on ice and quenched with aqueous NaHCO 3 (50 mL).
  • Example 67D 2-[5-(4-cvanophenvD-2,3-dihvdro-l-benzofuran-2-yl]ethyl methanesulfonate
  • methanesulfonyl chloride 0.075 mL, 0.96 mmol
  • triethylamine 0.13 mL, 9.4 mmol
  • the mixture was stirred for 30 minutes, diluted with CH 2 C1 2 (75 mL), washed with water (3 x 100 mL), dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure.
  • Example 67E 4-(2- ⁇ 2-r(2R)-2-methylpyrrolidinyl1ethvU-2,3-dihvdro-l-benzofuran-5-vDbenzonitrile
  • a solution of Example 67D (0.2 g, 0.58 mmol), R-2-methylpyrrolidine-(L)-tartrate 1.45 mmol) and cesium carbonate (0.95 g) in acetonitrile (5 mL) was heated to 60°C for 48 hours under an atmophere of nitrogen.
  • the reaction was allowed to come to ambient temperature, diluted with CH 2 CI 2 (100 mL), washed with aqueous NaHCO 3 (2 x 100 mL), H 2 O (1 x 100 mL), brine (100 mL), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure.
  • the residue was purified by on silica using CHCl 3 /CH 3 OH/NH 4 OH (95:5:0.5) to provide the titled compound (0.14 g, 72%).
  • Example 68 A (4-fluorophenvD(4-hydroxy-3-iodophenvDmethanone (4-Fluorophenyl)(4-hydroxyphenyl)methanone (20.0 g, 92.5 mmol) in concentrated ammonium hydroxide (770 mL) was allowed to stir at 25°C for 15 minutes and then treated with potassium iodide (74.79 g, 450.5 mmol) and iodine (23.48 g, 92.5 mmol) in water (185 mL). The reaction mixture was allowed to stir at 25°C for 18 hours and then filtered.
  • Example 68A The product from Example 68A (6.5 g, 18.5 mmol) was sequentially treated with a 0.1M solution of the product from Example 68B in acetonitrile (230 mL, 23.0 mmol), Pd(OAc) 2 (0.127 g, 0.566 mmol), tris(4-methylphenyl)phosphine (0.344 g, 1.130 mmol), and copper iodide (1.08 g, 95.72 mmol). After stirring at 25 °C for 10 minutes, the reaction mixture was treated with diisopropyl amine (26.6 mL, 189 mmol) and then heated at 60 °C in an inert atmosphere for 16 hours.
  • Example 69A f3-fluoro ⁇ henvD 4-hvdroxyphenvDmefhanone (3-fluorophenyl)(4-methoxyphenyl)methanone (1.0 g, 4.34 mmol) in 50 mL DCM at -78 °C while stirring was treated with 1M boron tribromide (13.03 mL, 13.03 mmol) dropwise over 20 minutes. The mixture was allowed to warm to 25°C and stir for 18 hours. The mixture was treated with water (1 mL) and stirred for 5 minutes, followed by additional water (2 mL) and stirred for 10 minutes, and finally treated with more water (50 mL) and stirred for 20 minutes.
  • Example 69B (3 -fluorophenvD(4-hydroxy-3 -iodophenyDmethanone
  • the product from Example 69A, potassium iodide and iodine were processed as described in Example 68A to provide the title compound.
  • 'HNMR 300 MHz, CD 3 OD
  • Example 69C (3-fluorophenyl)(2-
  • the product from Example 69B and a 0.1M solution of the product from Example 68B were processed as described in Example 68C to provide the title compound.
  • Example 70A (2-fluorophenvD(4-hydroxy-3-iodophenyDmethanone (2-Fluorophenyl)(4-hydroxyphenyl)methanone, potassium iodide and iodine were processed as described in Example 68A to provide the title compound.
  • MS (DCI) m/z 343 (M+H) + , 360 (M+NH 4 ) + .
  • Example 70B (2-fluorophenvP(2- ⁇ 2- (2R)-2-methyl-l-pyrrolidinyl]ethvP-l-benzofuran-5-vPmethanone
  • the product from Example 70 A and a 0.1M solution of the product from Example 68B were processed as described in Example 68C to provide the title compound.
  • Example 71 A 4-(benzyloxy)benzoyl chloride 4-Benzyloxybenzoic acid (15.0 g, 65.72 mmol) in dichloromethane (150 mL) and dimethylformamide (075 mL) was cooled to 0 °C. After 30 minutes, the mixture was treated with neat oxalyl chloride (11.5 mL, 131.44 mmol) dropwise over 25 minutes. The resulting mixture was stirred at room temperature for 120 minutes followed by evaporation of solvent under reduced pressure to provide the title compound as a light yellow solid (18.2 g, 1 12% yield).
  • Example 7 IB 4-(benzyloxy)-N-methoxy-N-methylbenzamide
  • the product from Example 71 A (18 g, 72.96 mmol) in DCM at room temperature was treated with N,O-dimethylhydroxylamine hydrochloride (7.83 g, 80.26 mmol) slowly.
  • the mixture was cooled to 0 °C, stirred for 30 minutes, and treated with triethylamine (25.47 mL, 182.41 mmol) dropwise.
  • the mixture was allowed to warm to 25 °C, stirred for 16 hours, and treated with DCM (150 mL).
  • the mixture was washed with saturated NaHC0 3 , brine, and water.
  • Example 7 ID 4-hydroxy-3-iodo-N-methoxy-N-methylbenzamide
  • the product from Example 71C (10.3 g, 56.84 mmol) in concentrated ammonium hydroxide (400 mL) was stirred at 25 °C for 15 minutes and then treated with KI (45.96 g, 276.83 mmol) and I 2 (14.43 g, 56.84 mmol) in water (65 mL). After stirring at room temperature for 16 hours, the solvent was removed under reduced pressure and the residure was redissolved in DCM (500 mL) and washed with water (350 mL x2). The organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure.
  • Example 7 IE N-methoxy-N-methyl-2- ⁇ 2-[(2R -2-methyl-l-pyrrolidinyl]ethvU-l-benzofuran-5- carboxamide
  • the product from Example 71D (1 1.6 g, 37.77 mmol) in acetonitrile (50 mL) was treated sequentially with a 0.12M solution of the product from Example 68B (378 mL, 45.33 mmol), Pd(OAc) 2 (0.254 g, 1.13 mmol), tris(4-methylphenyl)phosphine (0.518 g, 1.699 mmol), and diisopropyl amine (39.7 mL, 283.3 mmol).
  • Example 7 IF (3-chlorophenyP(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl ⁇ -l-benzofuran-5-vPmethanone
  • the product from Example 71 E (0.05 g, 0.158 mmol) in 5 mL of anhydrous THF at 0 °C was treated with 3 -chloropheny .magnesium bromide (1.58 mL, 0.79 mmol). The mixture was allowed to slowly warm to 25°C and stir under nitrogen for 18 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with DCM (50 mL x2). The organic phases were combined, dried, filtered, and the filtrate evaporated under reduced pressure.
  • the residue was purified by preparative HPLC on a Waters Nova- Pak HR C18 column (40 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 12 minute (15 minute run time) at a flow rate of 70 mL/minute to provide the title compound.
  • Example 72 (4-chlorophenyP(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl ⁇ -l-benzofuran-5-vPmethanone
  • the product from Example 71E and 4-chlorophenylmagnesium bromide were processed as described in Example 71F to provide the title compound.
  • Example 71E and 4-methoxyphenylmagnesium bromide were processed as described in Example 71F to provide the title compound.
  • Example 74 (4-fluoro-3-methylphenvP(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPmethanone
  • the product from Example 71E and (4-fluoro-3-methyl)phenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • Example 75 cyclopropyl(2- ⁇ 2- (2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-vPmethanone
  • the product from Example 71E and cyclopropylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • Example 76 3-ethyl-l-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl ⁇ -l-benzofuran-5-yl)-l-pentanone
  • the product from Example 71E and 2-ethylbutylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • Example 77 (4-chloro-3-methylphenvP(2- (2-[Y2R)-2-methyl- 1 -pyrrolidinyl]ethyl) - 1 -benzofuran-5- vPmethanone
  • the product from Example 71E and 4-chloro-3-methylphenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • Example 78 (2-(2-r(2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-vPr4- (methylthio)phenyllmethanone
  • the product from Example 71 E and 4-(methylthio)phenylmagnesium bromide were processed as described in Example 71F to provide the title compound.
  • Example 79 4-(dimethylamino)phenyll(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPmethanone
  • the product from Example 71 E and 4-(dimethylamino)phenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • Example 80 (4-methv.phenvD.2- l2-IY2R)-2-methyl- 1 -pyrrolidinyl]ethyl) - 1 -benzofuran-5 -vPmethanone
  • the product from Example 71 E and 4-methylphenylmagnesium bromide were processed as described in Example 71F to provide the title compound.
  • Example 81 (3,5-difluorophenvP(2-(2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPmethanone
  • the product from Example 71E and 3,5-difluorophenylmagnesium bromide were processed as described in Example 71F to provide the title compound.
  • Example 71 E and 2-methoxyphenylmagnesium bromide were processed as described in Example 71F to provide the title compound.
  • 'HNMR 300 MHz, CD 3 OD
  • Example 71 E and 3-methoxyphenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • 'HNMR 300 MHz, CD 3 OD
  • 8 1.42 (d, 3H), 1.72 (m, IH), 2.10 (m, 2H), 2.35 (m, IH), 3.30 (m, 4H), 3.55 (m, IH), 3.80 (m, 2H), 3.83 (s, 3H), 6.83 (s, IH), 7.2 (m, IH), 7.30 (m, 2H), 7.45 (m, IH), 7.60 (m, 2H), 7.80 (dd, IH), 8.02 (d, IH); MS (ESI) m/z 364 (M+H) + .
  • Example 84 (2-(2-[(2R)-2-methyl-l -Pyrrolidinyllethyl)-l-benzofuran-5-vP(phenvPmethanone
  • the product from Example 7 IE and phenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • Example 85B 2-(2-hvdroxyethvD-l-benzofuran-4-ol
  • the product from Example 85A (0.2 g, 0.85 mmol) in 5 mL of DMF under nitrogen was treated with palladium bis(triphenylphosphine) dichloride (30 mg, 0.043 mmol), copper iodide (24 mg, 0.13 mmol), triethylamine (0.2 g, 2.12 mmol) and 3-butyn-l-ol (0.11 g, 1.53 mmol). The mixture was heated at 60°C for 14 hours.
  • Example 85C 2-(2-hvdroxyethvP- 1 -benzofuran-4-yl trifluoromethanesulfonate
  • the product from Example 85B (0.1 g, 0.56 mmol) in 10 mL of CH 2 C1 2 at 0°C was treated with triethylamine (0.11 g, 1.12 mmol), DMAP (7 mg, 0.056 mmol) and N-phenyl- trifluoromethanesulfonimide (0.22 g, 0.62 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 100 mL of CH 2 CI 2 and washed twice with water (2x100 mL) and brine (100 mL).
  • Example 85D 4- 2-(2-hvdroxyethvP-l -benzofuran-4-yl1benzonitrile
  • the product from Example 85C (0.1 g, 0.32 mmol) in 8 mL of benzene/ethanol (2:1), was treated with 4-cyanophenylboronic acid (0.052 g, 0.35 mmol), palladium diacetate (0.0032 mmol), bipheny-2yl-dicyclohexylphosphine (0.0048 mmol) and Na 2 CO 3 (2M, 0.87 mmol) and heated at 75 °C for 14 hours.
  • Example 85E 2-r4-(4-cyanophenvP-l -benzofuran-2 -yl]ethyl methanesulfonate
  • CH 2 C1 2 10 mL
  • methanesulfonyl chloride 68 mg, 0.59 mmol
  • After 45 minutes at room temperature the reaction was diluted with 50 mL CH 2 C1 2 and the mixture was washed with water (2x50 mL). The organic phase was dried over sodium sulfate and evaporated to provide the title compound (99% yield).
  • Example 85F 4-(2- (2-F(2R)-2-methyl- 1 -pyrrolidinyllethyl) - 1 -benzofuran-4-vDbenzonitrile
  • the product from Example 85E (0.086 g, 0.25 mmol), (2R)-2-methylpyrrolidine-L- tartaric acid (0.12 g, 0.5 mmol) and cesium carbonate (0.41 g, 1.26 mmol) in 2 mL of MeCN were combined and heated at 45 °C for two days.
  • the mixture was diluted with 100 mL of CH 2 CI 2 and washed with a saturated solution of sodium bicarbonate (50 mL), water (50 mL) and brine (50 mL).
  • Example 86A 4-iodobenzene- 1.3 -diol
  • iodine monochloride 8.2 g, 50.5 mmol
  • dry diethyl ether 100 mL
  • resorcinol 5.5 g, 49.9 mmol
  • dry ether 50 mL
  • 100 mL of water and 1.0 g of sodium sulfite was added.
  • the organic phase was separated and the aqueous phase was washed with 100 mL of ether, the combine ether phase was dried over sodium sulfate and evaporated under reduced pressure.
  • Example 86B 2-(2-hvdroxyethyD-l-benzofuran-6-ol
  • the product from Example 86A was processed as described in Example 85B to provide the title compound.
  • 'HNMR 300 MHz, CDC1 3 ) ⁇ 3.00 (m, 2H), 3.98 (m, 2H), 6.40 (s, IH), 6.73 (m, IH), 6.90 (d, IH), 7.30 (m, IH).
  • MS (CDI) m/z 179 (M+H) + .
  • Example 86B The product from Example 86B was processed as described in Example 85C to provide the title compound.
  • Example 86D 4-[2-(2-hvdroxyethvD-l-benzofuran-6-yl1benzonitrile
  • the product from Example 86C was processed as described in Example 85D to provide the title compound.
  • 'HNMR (300 MHz, CDC1 3 ) 8 3.15 (m, 2H), 4.00 (m, 2H), 6.52 (s, IH), 6.95 (m, IH), 7.35 (m, 2H), 7.52 (m, 2H), 7.70(m, 2H); MS (CDI) m/z 264 (M+H) + .
  • Example 86D The product from Example 86D was processed as described in Example 85E to provide the title compound.
  • 'HNMR 300 MHz, CDCI 3 ) ⁇ 2.65 (m, 2H), 2.99 (s, 3H), 3.95
  • Example 86F 4-(2-
  • the product from Example 86E was processed as described in Example 85F to provide the title compound.
  • 'HNMR 300 MHz, CDC1 3 ) ⁇ 1.20 (d, 3H), 1.58 (m, 4H), 2.20- 2.50 (m, 5H), 2.78 (m,2H), 6.52 (s, IH), 7.40 (m, IH), 7.58 (m, IH), 7.60 (s, IH), 7.73 (m, 4H); MS (CSI) m/z 331 (M+H) + .
  • Example 87A 4-hvdroxy-3-iodobenzonitrile
  • a 2000 mL round-bottom flask containing 10.0 g (84 mmol) of 4-cyanophenol, 450 mL cone ammonium hydroxide was added and contents were allowed to stir at 25 °C for 15 min.
  • the reaction mixture was allowed to stir at 25 °C for 18h at which time contents were filtered.
  • the filtrate was concentrated under reduced pressure and redissolved in 500 mL dichloromethane.
  • Example 87B 2-(2-[(2R)-2-methylpyrrolidin-l-yllethvI ⁇ -l-benzofuran-5-carbonitrile
  • the product from Example 87A (10.0 g, 40.81 mmol) was sequentially treated with 0.1M (2R)-l-(3-butynyl)-2-methylpyrrolidine in acetonitrile (490 mL, 48.9 mmol), Pd(OAc) 2 (0.275 g, 1.22 mmol), Ptol 3 (0.747 g, 2.44 mmol), and copper iodide (1.16 g, 6.122 mmol).
  • Example 87C N'-hvdroxy-2- ⁇ 2- (2R)-2-methylpyrrolidin-l-yl]ethvU-l-benzofuran-5-carboximidamide
  • EtOH 200 mL
  • the product from Example 87B (2.5 g, 9.83 mmol) in EtOH (200 mL) was stirred at 25°C for 10 minutes.
  • the mixture was treated with hydroxylamine hydrochloride (1.71 g, 24.6 mmol) and potassium carbonate (4.49 g, 32.48 mmol) and the resulting mixture was heated at 95°C for 16h with stirring.
  • the reaction mixture was subsequently cooled, filtered through celite, and concentrated under reduced pressure.
  • the crude product was purified with flash chromatography to provide the title compound (1.43 g, 51% yield).
  • MS (ESI) m/e 288 (M+H) + .
  • Example 87D 3-(2- ⁇ 2-rf2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-5-(thien-2-ylmethvP-1.2.4- oxadiazole
  • the product from Example 87C (0.06 g, 0.209 mmol) in acetone (10 mL) was treated with triethylamine (34.9 ⁇ L, 0.25 mmol) and stirred at 25°C for 10 minutes.
  • the mixture was slowly treated with thien-2-ylacetyl chloride (25.7 ⁇ L, 0.25 mmol) and stirred at 25°C for 18h.
  • Example 88 4- 3-(2-(2-r(2R)-2-methylpyrrolidin-l-yl]ethyl)-l-benzofuran-5-vP-L2,4-oxadiazol-5- yllbenzonitrile 4-Cyanobenzoyl chloride was processed as described in Example 87D to provide the title compound.
  • Example 89 5-(4-chlorophenvP-3-.2-(2-F(2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole 4-Chlorobenzoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 408 (M+H) + .
  • Example 90 5-(2-chlorophenvP-3-(2-l2-r(2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole 2-Chlorobenzoyl chloride was processed as described in Example 87D to provide the title compound.
  • Example 91 5-(4-fluorobenzvP-3-(2- ⁇ 2-[ " (2R)-2-methylpyrrolidin-l-yl1ethyl)-l-benzofuran-5-yl)-1.2,4- oxadiazole (4-Fluorophenyl)acetyl chloride was processed as described in Example 87D to provide the title compound.
  • Example 92 5-(4-methoxybenzvP-3-(2-(2- r2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole (4-Methoxyphenyl)acetyl chloride was processed as described in Example 87D to provide the title compound.
  • Example 93 3-(r3-(2-l2-rf2R)-2-methyl p yrrolidin-l-yl]ethyl)-l-benzofuran-5-vD-1.2.4-oxadiazol-5- yllmethyl ) benzonitrile 3-Cyanobenzoyl chloride was processed as described in Example 87D to provide the title compound.
  • Example 95 5-(4-fluorophenvP-3-(2-(2-r(2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole 4-Fluorobenzoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 392 (M+H) + .
  • Example 96 5-(3-chloro-4-fluorophenvP-3-(2- ⁇ 2- (2R)-2-methylpyrrolidin-l-yl1ethyl)-l-benzofuran-5- vP-1 ,2,4-oxadiazole 3-Chloro-4-fluorobenzoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 426 (M+H) + .
  • Example 97 5-(chloromethvP-3-(2-(2-f(2R -2-methylpyrrolidin-l-yl1ethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole Chloroacetyl chloride was processed as described in Example 87D to provide the title compound.
  • Butanoyl chloride was processed as described in Example 87D to provide the title compound.
  • 'HNMR 300 MHz, CD 3 OD
  • 8 1.42-1.48 m, 10H
  • 1.78 m, IH
  • 2.10 m, 2H
  • 2.38 m, I H
  • 3.21 -3.90 m, 7H
  • 4.96, 6.83 s, IH
  • 7.59 d, IH
  • Example 99 5-ethyl-3-(2- ⁇ 2-r(2R -2-methylpyrrolidin-l-yl]ethyl)-l-benzofuran-5-vP-l,2.4-oxadiazole Propanoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 326 (M+H) + .
  • Example 101 4-(3-bromo-2- ⁇ 2-[(2R)-2-methylpyrrolidin-l-vnethyl)-l-benzofuran-5-yPbenzonitrile
  • the product from Example ID 2.5 g (5.2 mmol) and trifluoroacetic acid (40 mL) (TFA) were combined and stirred at 25 °C for 10 min.
  • the mixture was slowly treated with a solution of Br 2 (450 ⁇ L, 7.8 mmol) in TFA (10 mL).
  • the mixture was allowed to stir at 25 °C for lh and then treated with saturated aqueous Na 2 SO 3 .
  • the mixture was concentrated and redissolved in 50 mL ethyl acetate.
  • Example 102 4-(3-(2-fi.u-vP-2- ⁇ 2-r(2R)-2-methylpyrrolidin-l-yl1ethyl ⁇ -l-benzofuran-5-vPbenzonitrile
  • DME dimethoxye thane
  • Pd(PPh 3 ) 4 0.008 g, 0.0073 mmol
  • 2-furylboronic acid 0.041 g, 0.317 mmol
  • 1M Na 2 CO3 (1 mL
  • Example 104 4-[2-(2-[(2R)-2-methyl-l-py ⁇ olidinyl]ethyl)-3-(3-thienvP-l-benzofuran-5-yllbenzonitrile 3-Thienylboronic acid was processed as described in Example 102 to provide the title compound.
  • 'HNMR 300 MHz, CD 3 OD
  • Example 105 4-(3-r2-formyl-3-thienvP-2--.2-r(2R)-2-methyl-l-pyrrolidinvnethyl)-l-benzofuran-5- vPbenzonitrile 2-Formyl-3-thienylboronic acid was processed as described in Example 102 to provide the title compound. MS (ESI) m/e 441 (M+H) + .
  • Example 106A 4'-methoxy-3-methyl- 1 , 1 '-biphenyl-4-carbonitrile 4-Bromo-2-methylbenzonitrile (4.9 g, 25.0 mmol), Pd(PPli 3 ) (578 mg) in benzene (50 mL) and 2.0 M aqueous solution of Na 2 CO (25 mL, 50.0 mmol) was treated with 4- methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) and heated at 75 °C for 17 hours. The mixture was allowed to cool to room temperature and the phases were separated. The aqueous phase was extracted with diethyl ether (3x40 mL).
  • Example 106B 4'-hydroxy-3 -methyl- 1 , 1 '-biphenyl-4-carbonitrile
  • the product from Example 106A (5.60 g, 25.4 mmol) in CH 2 C1 2 (120 mL) at 78 °C was treated with 1.0 M BBr (in CH 2 CI 2 , 76 mL, 76.0 mmol) dropwise over 1 hour.
  • the mixture was warmed to 0 °C (ice bath) and treated with water (0.5 mL). After 10 minutes, additional water was added (2.0 mL), ice bath was removed, and 5.0 mL of water was added. The mixture was then treated with another 20 mL of water and allowed to stir for 45 minutes.
  • Example 106C 4 ' -hydroxy-3 ' -iodo-3 -methyl- 1.1 ' -biphenyl-4-carboni trile The product from Example 106B (4.67 g, 22.3 mmol), Nal (3.343 g, 22.3 mmol), and NaOH (892 mg, 22.3 mmol) were combined in methanol (70 mL) at 0 °C and treated with bleach (5.25%, 31.6 g) dropwise over 30 minutes. After being stirred at 0 °C for 80 minutes, the mixture was quenched with 10% aqueous sodium thiosulfate (10 mL).
  • the mixture was acidified with 1M aqueous HC1 (25 mL), neutralized with dipotassium hydrogen phosphate, recooled to 0 °C, and filtered.
  • the solids were rinsed with water, then mostly dissolved in 50% EtOAc / hexanes and filtered. When this filtrate was mostly concentrated crystals began to form.
  • the solids were slurried with 20% EtOAc/hexanes, collected by filtration, and washed with 10% EtOAc / hexanes followed by hexanes to provide the impure title compound as a light tan powder (52% yield).
  • Example 106D 2-methyl-4-(2-
  • the product from Example 106C (670 mg, 2.00 mmol), palladium (II) acetate (22 mg, 0.10 mmol), tri-o-tolylphosphine (61 mg, 0.20 mmol), copper (I) iodide (114 mg, 0.60 mmol), and diisopropylamine (2.8 mL, 20 mmol) were dissolved into a 0.1M MeCN solution of (R)-l-but-3-ynyl-2-methylpyrrolidine (30 mL, 3.0 mmol) and heated at 55 °C overnight.
  • Example 107 A 4'-hydroxy-3 '-iodo-2-methyl-l .1 '-biphenyl-4-carbonitrile 4'-Hydroxy-2-methyl-l, -biphenyl-4-carbonitrile was processed as described in Example 106C to provide the title compound as a light tan powder (69% yield).
  • Example 107B 3-methyl-4-(2-(2- ( f 2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile
  • the product from Example 107 A was processed as described in Example 106D to provide the impure title compound as an orange-brown foam (42% yield), a portion of which was purified by HPLC to provide the TFA salt.
  • Example 108 4-(6-methyl-2-(2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-yl)benzonitrile and 4-(4-methyl-2-j2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile
  • Example 108B 4-(6-methyl-2- ⁇ 2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile and 4-(4-methyl-2- ⁇ 2-[(2R -2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-vPbenzonitrile
  • the 7.6: 1 mixture of Example 108A was processed as described Example 106D, except that after concentration the residue was partitioned between CH 2 CI 2 and 10% aqueous ammonia.
  • Example 109 4-(7-methyl-2-
  • Example 109 A 4'-hydroxy-5 '-iodo-3 ' -methyl- 1 , 1 '-biphenyl-4-carbonitrile 4 '-hydroxy-3' -methyl- 1, 1 '-biphenyl-4-carbonitrile (875 mg, 4.18 mmol) was dissolved into DMF (20 mL) and treated with N-iodosuccinimide (1.012 g, 4.5 mmol). The solution was stirred at room temperature for four days.
  • Example 109B 4-(7-methyl-2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-vPbenzonitrile
  • the product from Example 109A was processed as described for Example 106D to provide the title compound as a brown-orange gum (44%> yield), a portion of which was purified by HPLC [Waters Nova-Pak HR C18 column (40 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100% MeCN / 0.1 %> aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL / min.] to provide the TFA salt.
  • Example 1 10A 3 ' -fluoro-4 ' -hydroxy-5 ' -iodo- 1.1 ' -biphenyl-4-carboni trile 3 '-Fluoro-4' -hydroxy- l,l '-biphenyl-4-carbonitrile (320 mg, 1.50 mmol) was dissolved into DMF (7 mL) and treated with N-iodosuccinimide (360 mg, 1.60 mmol). The solution was stirred at room temperature overnight. Then the mixture was poured into an aqueous mixture of Na 2 S03 and Na 2 C03, adjusted to pH 9 with aqueous potassium dihydrogen phosphate, and extracted with ether. The combined organic phases were dried (Na 2 S0 ) and concentrated to provide the title compound as a pinkish solid (100 % yield). MS (ESI APCI negative ion detection) m/z 338 (M-H) " .
  • Example HOB 4-(7-fluoro-2- ⁇ 2-[(2R)-2-methyl-l -pyrrolidinyljethyl) -l-benzofuran-5-vPbenzonitrile
  • the product from Example 110A was processed as described for Example 106D, except that after the solution was heated overnight, it was heated for an additional eight hours at 80 °C.
  • the reaction mixture was cooled to room temperature and chromatographed through a short column of silica with 1 :8 hexanes / CH 2 CI 2 , followed by a 0 to 2% gradient of MeOH / CH 2 CI 2 .
  • Example 1 11A 3 -fluoro-4' -methoxy- 1.1 '-biphenyl-4-carbonitrile
  • 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) was added to a solution of 4-bromo-2-fluorobenzonitrile (5.00 g, 25.0 mmol) and tetrakis(triphenylphosphine)palladium (578 mg, 0.50 mmol) in benzene (50 mL).
  • the resulting mixture was treated with a 2.0 M aqueous solution of Na 2 CO 3 (25 mL, 50 mmol) and heated briefly at reflux, then at 65 °C overnight.
  • the mixture was cooled to room temperature and treated with 6.0 M aqueous NaOH.
  • the aqueous phase was separated and extracted with ether.
  • First the original organic phase and then the ethereal wash were filtered through diatomaceous earth.
  • the collection flask was changed and the solids remaining atop the diatomaceous earth were washed through with EtOAc.
  • the ethereal wash was concentrated and refiltered as before.
  • the combined EtOAc rinses were combined and concentrated to provide the title compound as a yellow powder (92% yield).
  • Example 11 IB 3 -fluoro-4' -hydroxy- 1 , 1 '-biphenyl-4-carbonitrile The product from Example 11 1 A was processed as described in Example 106B, except that the extraction was conducted with EtOAc, to provide the title compound as a tan powder (100% yield).
  • Example 1 1 1 C 3 -fluoro-4 ' -hydroxy-3 ' -iodo- 1 , 1 '-biphenyl-4-carbonitrile
  • the product from Example 11 IB was processed as described for Example 106C, except that the solids collected after cold-filtering were rinsed consecutively with 50% aqueous methanol and water, and dried under reduced pressure to provide the title compound as an off-white powder (86% yield).
  • Example 1 1 1 D 2-fluoro-4-(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyllethyl ⁇ -l-benzofuran-5-vPbenzonitrile
  • the product from Example 11 IC was processed as described for Example 106D, except that the solution was heated at 50 °C overnight and then at 80 °C for eight hours.
  • the reaction mixture was cooled to room temperature and chromatographed through a short column of silica with a 0 to 2% gradient of MeOH / CH 2 CI 2 .
  • Example 112A 4-bromo-2-iodophenol 4-Bromophenol was processed as described in Example 106C, except that after neutralization the mixture was was partitioned between 20%> EtOAc/hexanes (250 mL) and brine (50 mL) and the aqueous phase was separated and reextracted until nearly all the product was removed (TLC). The combined organic phases were washed with brine, dried (Na 2 S0 ), and concentrated to provide the (90% pure) title compound (100% yield). A portion was purified by chromatography on silica using a 25 to 80% gradient of CH 2 CI 2 / hexanes. 'HNMR (300 MHz, d 6 -DMSO) ⁇ 6.83 (d, 1 H), 7.36 (dd, 1 H), 7.79 (d, 1 H), 10.59
  • Example 112B 2-(5-bromo-l-benzofuran-2-vPethanol
  • the product from Example 1 12A (26.9 g, 90% pure, 80 mmol), 3-butyn-l-ol (6.05 mL, 79.9 mmol), and copper (I) oxide (7.15 g, 50.0 mmol) were suspended in a mixture of pyridine (40 mL) and 1 -methyl-2-pyrrolidinone (160 mL) and heated at 70 °C overnight, then at 100 °C for 3.5 hours. The mixture was cooled towards room temperature, diluted with ether and filtered.
  • the filtrate was diluted with additional ether and washed consecutively with 5% aqueous ammonia, 0.5 M aqueous NaOH, and brine. It was dried (Na 2 SO ), concentrated, and reconcentrated from EtOAc. 2:1 Hexanes/CH 2 ⁇ 2 was added to the resulting syrup and the mixture was cooled to -78 °C. Upon warming towards room temperature, the pure title compound crystallized as an off-white microcrystalline solid. It was collected by filtration and washed with 4: 1 hexanes / CH 2 CI 2 , then hexanes (8%> yield).
  • Example 112C 3-[2-(2-hydroxyethvP- 1 -benzofuran-5-yllbenzonitrile
  • the product from Example 112B(193 mg, 0.80 mmol), 3-cyanophenylboronic acid (147 mg, 1.00 mmol), and tetrakis(triphenylphosphine)palladium (35 mg, 0.030 mmol) were suspended into dioxane (3 mL) and then treated with 1.0 M aqueous Na 2 C0 3 (2.1 mL, 2.1 mmol). The mixture was heated at 90 °C for 3.5 hours, then cooled to room temperature, partitioned between EtOAc and water, worked up as usual, dried (Na 2 SO ), and concentrated.
  • Example 1 12D 2-[5-(3-cvanophenyl)-l-benzofuran-2-yl]ethyl methanesulfonate
  • the product from Example 112C (170 mg, 0.65 mmol) and triethylamine (100 ⁇ L, 0.72 mmol) were dissolved into CH2CI2 (3 mL) and cooled to 0°C.
  • the solution was treated with methanesulfonyl chloride (55 ⁇ L, 0.71 mmol), and after 10 minutes it was permitted to slowly warm to room temperature. More methanesulfonyl chloride (10 ⁇ L, 0.13 mmol) and triethylamine (10 ⁇ L, 0.072 mmol) were added.
  • the mixture was stirred until the reaction was nearly complete and then washed consecutively with water and brine, dried (Na 2 S0 4 ), concentrated, and used without further purification in the next step.
  • Example 1 12E 3-(2- (2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl ⁇ - 1 -benzofuran-5-yDbenzonitrile
  • the crude product from Example 1 12D, the mono-(L)-tartaric acid salt of (2R)-2- methylpyrrolidine (306 mg, 1.3 mmol), and CS 2 CO 3 (652 mg, 2.0 mmol) were stirred in an approximately 0.2 M MeCN solution of (2R)-2-methylpyrrolidine (1.6 mL, 0.3 mmol). The mixture was heated at 40 °C overnight.
  • Example 1 13 A 2-r5-(4-fluorophenvD-benzofuran-2-yll-ethanol 4-Fluorophenylboronic acid was processed as described in Example 1 12C to provide the title compound as a white microcrystalline solid (19% yield).
  • 'HNMR 300 MHz, d 6 - DMSO
  • ⁇ 2.94 t, 2 H
  • 3.77 dt, 2 H
  • 4.84 t, 1 H
  • 7.28 (dd, 2 H) 7.48 (dd, 1 H), 7.56 (d, 1 H), 7.70 (dd, 2 H), 7.78 (d, 1 H).
  • Example 1 13B (2R)-1 - (2-r5-C4-fluorophenvP- 1 -benzofuran-2 -yllethyl) -2-methylpyrrolidine
  • the product from Example 1 13A was processed as described in Example 112D and Example 112E to provide the title compound as an orange-tan syrup (60% yield).
  • Example 114 (2R)-l- ⁇ 2-[5-(3.4-dichlorophenyP-l-benzofuran-2-yl]ethyl) -2-methylpyrrolidine 3,4-Dichlorophenylboronic acid was processed as described Examples 1 12C, 112D, and 112E except that in the procedure in Example 1 12E the reaction was conducted at 60 °C overnight, and after the ethereal extracts were filtered through diatomaceous earth the filtrate was concentrated and semi-purified by HPLC [Waters Nova-Pak HR C 18 column (40 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL / min.] to provide the title compound (62% yield) as a TFA salt.
  • HPLC Waters Nova-Pak HR C 18 column (40 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10%
  • Example 115 A (2R)-l-[2-(5-bromo-l -benzofuran-2 -vPethyl]-2-methylpyrrolidine 4-Bromo-2-iodophenol (2.99 g, 90 % pure, 9 mmol), palladium (II) acetate (112 mg, 0.50 mmol), triphenylphosphine (262 mg, 1.0 mmol), copper (I) iodide (571 mg, 3.0 mmol), and diisopropylamine (14 mL, 100 mmol) were dissolved into a 0.09 M MeCN solution of (R)-l-but-3-ynyl-2-methylpyrr ⁇ lidine (120 mL, 10.8 mmol) and stirred at room temperature three days, then at 80 °C overnight.
  • the reaction mixture was cooled to room temperature, concentrated, and chromatographed through a short column of silica with 2: 1 hexanes / CH 2 CI 2 followed by a 0 to 1% gradient of MeOH / CH2CI2.
  • the appropriate fractions were concentrated, and the residue extracted with MeOH.
  • the extracts were concentrated and partitioned between CH 2 Cl 2 and 1 M aqueous Na 2 C0 3 , worked up as usual, dried (Na 2 S0 4 ), and concentrated to provide the title compound as a dark red syrup (26 % yield).
  • Example 115B (2R)-2-methyl- 1 - ⁇ 2-[5-(2-methylphenvP- 1 -benzofuran-2-yllethyl ⁇ pyrrolidine
  • a portion (-330 ⁇ L) of a solution of the product from Example 115A (650 mg, 2.1 mmol) and tetrakis(triphenylphosphine)palladium (125 mg, 0.1 1 mmol) in benzene (6.2 mL) was added to a mixture of (2-methylphenyl)boronic acid ( ⁇ 24 mg, -0.18 mmol) in ethanol (150 ⁇ L).
  • the mixture was treated with 2.0 M aqueous Na 2 CU 3 (200 ⁇ L, 0.4 mmol), and the reaction vial was sealed, placed on a heater-stirrer apparatus, and heated at 75 °C for four days.
  • the mixture was cooled to room temperature, diluted with 1 :1 MeOH / DMSO (1 mL), filtered, and purified by HPLC [Waters Nova-Pak HR C18 column (25 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL / min.] to provide the title compound.
  • MS (APCI) m/z 320 (M+H) + .
  • Example 1 16 (2R)-2-methyl-l- ⁇ 2-[5-(3-methylphenvP-l-benzofuran-2-yl]ethyl ⁇ pyrrolidine (3-Methylphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 320 (M+H) + .
  • Example 117 (2R)-2 -methyl- 1 - ⁇ 2-[5-(4-methylphenvP- 1 -benzofuran-2-yllethyl ⁇ pyrrolidine (4-Methylphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (APCI) m/z 320 (M+H) + .
  • Example 118 methyl 4-(2- (2-r(2R)-2-methyl- 1 -pyrrolidinyl]ethyl ⁇ - 1 -benzofuran-5-vPbenzoate (4-Methoxycarbonylphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 364 (M+H) + .
  • Example 119 (2R)- 1 - (2-[5-f 2-methoxyphenvP- 1 -benzofuran-2-yl]efhyl ⁇ -2-methylpyrrolidine (2-Methoxyphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound.
  • Example 120 (2R)- 1 - j2-[5-(3-methoxyphenvD- 1 -benzofuran-2 -yllethyl) -2-methylpyrrolidine (3-Methoxyphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 336 (M+H) + .
  • Example 121 (2R)-l- ⁇ 2-r5-(4-methoxyphenyP-l-benzofuran-2-vnethy ) -2-methylpyrrolidine (4-Methoxyphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (ESI) m/z 364 (M+H) + .
  • Example 122 (2R)-l-(2-[5-(3-fluorophenvP-l-benzofuran-2-yl]ethyl) -2-methylpyrrolidine (3-Fluorophenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (ESI) m/z 324 (M+H) + .
  • Example 123 (2R)-l-(2-[5-(2-chlorophenyP-l-benzofuran-2-yl1ethyl) -2-methylpyrrolidine (2-Chlorophenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 340 (M+H) + .
  • Example 124 (2R)-l-(2-[5-(3-chlorophenvP-l-benzofuran-2-yl]ethyl)-2-methylpyrrolidine (3-Chlorophenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 340 / 342 (M+H) + .
  • Example 125 l- ⁇ 2-[5-.4-chlorophenyP-benzofuran-2-yll-ethyl) -2-methylpyrrolidine (4-Chlorophenyl)boronic acid was processed as described in Example 115B to provide the title compound.
  • MS (ESI) m/z 340 / 342 (M+H) + .
  • Example 126 (2R)-2-methyl- 1 -(2- (5-[3-(trifluoromethvDphenyl]- 1 -benzofuran-2 -yl) ethvPpyrrolidine (3-Trifluoromethylphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (APCI) m/z 374 (M+H) + .
  • Example 127 (2R)-2-methyl-l-(2-(5-[4-(trifluoromethvPphenyll-l-benzofuran-2-yl)ethvDpyrrolidine (4-Trifluoromethylphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 374 (M+H) + .
  • Example 128 (2R -2-mefhyl-l -(2- ⁇ 5-[3-(trifluoromethoxy)phenyl]- 1 -benzofuran-2-yl) ethvDpyrrolidine (3-Trifluoromethoxyphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 390 (M+H) + .
  • Example 129 ( " 2R -2-methyl-l -(2- ⁇ 5-[4-(trifluoromethoxy)phenyl]-l-benzofuran-2-yl) ethvPpyrrolidine (4-Trifluoromethoxyphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (APCI) m/z 390 (M+H) + .
  • Example 130 " 2R 1 - (2-T5-(3 ,4-dimethylphenvD- 1 -benzoiuran-2-yllethyl) -2-methylpyrrolidine (3,4-Dimethylphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (ESI) m/z 334 (M+H) + .
  • Example 131 C2R -l-(2-[5-(3.5-dichlorophenvP-l-benzofuran-2-ynethyl)-2-methylpyrrolidine (3,5-Dichlorophenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (APCI) m/z 374 / 376 (M+H) + .
  • Example 132 (2R)-l-(2-[5-(3.5-dimethylphenyP-l-benzofuran-2-yl]ethyl)-2-methylpyrrolidine (3,5-Dimethylphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 334 (M+H) + .
  • Example 133 [4-(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yPphenyl1methanol A solution (1.2 mL) of the product from Example 115A (350 mg, 1.1 mmol) in benzene (3.6 mL) was added to a mixture of palladium (II) acetate (11 mg, 0.05 mmol), and biphen-2-yl-dicyclohexylphosphine (28 mg, 0.08 mmol).
  • reaction mixture was then treated with 4-(hydroxymethyl)phenylboronic acid (87 mg, 0.57 mmol) in ethanol (500 ⁇ L) followed by 2M aqueous Na 2 C ⁇ 3 (500 ⁇ L). The mixture was stirred thoroughly overnight.
  • Example 134 3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yPpyridine 3-(l,3,2-Dioxaborinan-2-yl)pyridine was processed as described in Example 133 to provide the title compound (1% yield).
  • Example 135 (2R)-1 -(2-15-1 2-( " 4-fluorophenvPvinyl]-l-benzofuran-2-yl)ethvP-2-methylpyrrolidine trans-2-(4-Fluorophenyl)vinylboronic acid was processed as described in Example 133 to provide the title compound (4% yield). MS (ESI APCI) m/z 350 (M+H) + .
  • Example 136A 1 -(4'-hydroxy- 1 , 1 '-biphenyl-3 -vPethanone 4-Iodophenol (5.39 g, 24.5 mmol) and 3-acetylphenylboronic acid (4.42 g, 26.95 mmol) were mixed in N,N-dimethylformamide (15 mL) and treated with 1.0 M aqueous Na 2 C0 3 (75 mL) and palladium (II) acetate (110 mg, 0.49 mmol). The suspension was heated at 55°C for one hour and then brought to room temperature. CH 2 C1 2 (100 mL) was added to the mixture which was then filtered.
  • Example 136B 1 -(4'-hydroxy-3 '-iodo- 1 , 1 '-biphenyl-3 -vPethanone
  • the product from Example 136A (5.76 g, 27 mmol) was suspended in concentrated aqueous ammonia (400 mL) and treated with a solution of potassium iodide (23.3 g, 140 mmol) and iodine (7.24 g, 28.5 mmol) in water (100 mL).
  • the mixture was treated with a second solution of potassium iodide (15.8 g, 95 mmol) and iodine (4.83 g, 19 mmol) in water (50 mL).
  • Example 136C l-[3-(2- ⁇ 2-[(2R -2-methyl-l-pyrrolidinyl1ethyl ⁇ -l-benzofuran-5-vPphenyl]ethanone
  • the product from Example 136B (1.15 g, 3.40 mmol), palladium (II) acetate (38 mg, 0.17 mmol), biphen-2-yl-dicyclohexylphosphine (119 mg, 0.34 mmol), diisopropylamine (4.8 mL, 34 mmol), and copper (I) iodide (76 mg, 0.40 mmol) were suspended in a 0.09 M MeCN solution of (R)-l-but-3-ynyl-2-methylpyrrolidine (45 mL, 4.0 mmol).
  • N,N- dimethylformamide (10 mL) was added, and the mixture was heated at 45 °C overnight, cooled to room temperature, partitioned between CH 2 CI 2 (100 mL) and 5% aqueous ammonia (100 mL), worked up as usual but with 5% aqueous ammonia, filtered, and concentrated. The residue was dissolved into CH 2 CI 2 and washed consecutively with water and brine, dried (Na 2 S0 4 ), concentrated, and chromatographed through silica with a gradient of 0 to 4% MeOH / CH 2 CI 2 .
  • Example 137 l-[3-(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl ⁇ -l-benzofuran-5-yPphenyl1ethanol
  • the product from Example 136C (46 mg, 0.12 mmol) in ethanol (2 mL) and tetrahydrofuran (0.5 mL) was treated with sodium borohydride.
  • the mixture was concentrated and passed through a short column of silica with a gradient of 2 to 10% MeOH / CH2CI2.
  • Example 138 2-[3-(2- ⁇ 2-r(2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-yDphenyl1-2-propanol
  • the product from Example 136C (87 mg, 0.25 mmol) was dissolved into tetrahydrofuran (5 mL), treated with 3 M methylmagnesium bromide in ether (0.3 mL, 0.9 mmol), stirred overnight, quenched with 0.5 M aqueous dipotassium hydrogen phosphate, and diluted with EtOAc and a little CH 2 CI 2 .
  • the resulting emulsion was sonicated, and the aqueous phase was separated and extracted with EtOAc.
  • Example 139 1 -D-(2- (2-[(2R -2-methyl- 1 -pyrrol idinyll ethyl) - 1 -benzofuran-5-vPphenyllethanone oxime The product from Example 136C (240 mg, 0.5 mmol) and hydroxylamine hydrochloride (139 mg, 2.00 mmol) were dissolved into methanol (2 mL) and treated with Na 2 C0 3 (318 mg, 3.0 mmol). The suspension was stirred at room temperature overnight and then heated at 70 °C three days. The mixture was cooled to room temperature and filtered, the solids being rinsed with 50%, MeOH / CH 2 CI 2 .
  • Example 140 1 -[3-(2-
  • Example 141 l-[3-(2-(2-[(2R -2-methyl-l-pyrrolidinyl]ethyl ⁇ -l-benzofuran-5-yl)phenyl1ethanone O- ethyloxime O-Ethylhydroxylamine was processed as described in Example 139 to provide the title compound as an orange gum (56% yield).
  • Example 142 1 [3-(2-
  • Example 143 A ethyl 4'-hydroxy- 1 , 1 '-biphenyl-3-carboxylate 4-Iodophenol and 3-ethoxycarbonylphenylboronic acid were processed as described in Example 136A, except that the reaction was done overnight at room temperature and the chromatography was conducted twice with 50% CH 2 CI 2 / hexanes followed by a gradient of 0 to 1% MeOH / CH 2 CI 2 to provide the title compound as a white powder (71% yield).
  • Example 143B ethyl 4'-hydroxy-3'-iodo- 1 , 1 '-biphenyl-3-carboxylate
  • the product from Example 143A (7.71 g, 31.8 mmol) was dissolved into N,N- dimethylformamide (30 mL), diluted with concentrated aqueous ammonia (320 mL), and treated with a solution of potassium iodide (27.72 g, 167 mmol) and iodine (8.48 g, 33.4 mmol) in water (100 mL) all at once. After the mixture was stirred for one hour, the ammonia was removed under reduced pressure on a rotary evaporator.
  • Example 143C ethyl 3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yPbenzoate
  • the product from Example 143B was treated as described for Example 136C, except that the reaction was conducted at 65 °C to provide the title compound as a viscous dark brown oil (52% yield).
  • MS (ESI APCI) m/z 378 (M+H) + .
  • Example 144 3-(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yPbenzoic acid
  • the product from Example 143C (755 mg, 2 mmol) was dissolved into ethanol (20 mL) and treated with 2 M aqueous NaOH (2 mL). The mixture was heated at 55 °C for 40 minutes, cooled to room temperature, concentrated, and partitioned between isopropanol and a mixture of 1 M aqueous potassium dihydrogen phosphate and brine. The aqueous phase was separated and extracted with isopropanol, and the combined organic phases were washed with a mixture of pH 6 potassium phosphate buffer and brine.
  • the aqueous phase was separated and extracted with isopropanol, and the combined organic phases were washed with brine. Again, the aqueous phase was separated and extracted with isopropanol, and the combined organic phases were diluted with EtOAc, and filtered. The filtrate was dried (Na 2 S0 ) and concentrated. The residue was chromatographed on silica with 50%, EtOAc / CH 2 CI 2 , followed by 10% MeOH / 45% EtOAc / CH 2 C1 2 , followed by 30% MeOH / CH 2 C1 2 .
  • Example 145 N-methoxy-N-me thyl-3 -(2- (2-[(2R)-2-methyl- 1 -pyrrolidinyllethyl) - 1 -benzofuran-5 - yPbenzamide
  • the product from Example 144 was suspended in CH 2 C1 2 (25 mL) and treated with 2 M oxalyl chloride in CH 2 C1 2 (3.0 mL, 6.0 mmol). After the bubbling had subsided, N,N- dimethylformamide (300 ⁇ L) was added slowly over 15 minutes. After an additional hour, more N,N-dimethylformamide (100 ⁇ L) was added. After another 30 minutes, the mixture was concentrated and dissolved into CH 2 C1 2 (5 mL).
  • N,O-Dimethylhydroxylamine hydrochloride (488 mg, 5.0 mmol) and pyridine (1 mL) were added, the reaction flask was placed in a water bath, and the mixture was stirred overnight, concentrated, diluted with 1 ,2- dichloroethane (5 mL), heated at 85 °C for four hours, concentrated, and partitioned between CH 2 CI 2 and water. Saturated aqueous NaHC0 3 was added until the pH of the aqueous phase exceeded seven. Then the aqueous phase was separated and extracted with CH 2 CI 2 .
  • Example 146 1 -[3 -(2- ⁇ 2-[(2R)-2-methyl- 1 -pyrrolidinyllethyl) - 1 -benzofuran-5-vPphenyl]- 1 -propanone
  • the product from Example 145 (20 mg, 0.05 mmol) was dissolved into tetrahydrofuran (900 ⁇ L), cooled to 0 °C, and treated with 1.0 M ethylmagnesium bromide in tetrahydrofuran (150 ⁇ L, 150 ⁇ mol). The reaction mixture was then stirred at room temperature overnight, quenched by the addition of saturated aqueous NH 4 C1, and diluted with EtOAc.
  • aqueous phase was separated and extracted with EtOAc, and the combined organic phases were washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, concentrated, and purified by HPLC [Waters Nova-Pak HR CI 8 column (25 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL / min.] to provide the title compound (44% yield).
  • Example 147 cvclopropyl[3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPphenyl]methanone
  • the product from Example 145 and cyclopropylmagnesium bromide were processed as described in Example 146 to provide the title compound (48% yield).
  • Example 148 3-methyl-l-[3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPphenyl]-l- butanone
  • the product from Example 145 and isobutylmagnesium chloride were processed as described in Example 146, except that after reacting overnight additional isobutylmagnesium chloride (400 mol%>) was added and the reaction mixture was stirred for four more hours, to provide the title compound (19% yield).
  • Example 149 3-(2-j2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzaldehvde
  • the product from Example 145 and cyclopentylmagnesium bromide were processed as described in Example 146, except that additional cyclopentylmagnesium bromide was added after the reaction had stirred overnight (400 mol%) and after another four hours (600 mol%>). The reaction mixture was allowed to stir for three additional days (16% yield).
  • Example 150 r3-(2-(2-r(2R)-2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-vDphenyllC2- thienvDmethanone
  • the product from Example 145 and 2-thienyllithium were processed as described in Example 146 to provide the title compound (53% yield).
  • Example 151 (3-fluorophenyD[3-(2-
  • the product from Example 145 and 3-fluorophenylmagnesium bromide were processed as described in Example 146 to provide the title compound (46% yield).
  • Example 152 [3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl ⁇ -l-benzofuran-5-vPphenyl]methanol
  • the product from Example 144 (167 mg, 0.48 mmol) was dissolved into 1 M BH 3 in tetrahydrofuran (2 mL, 2 mmol), stirred at room temperature overnight, quenched with 0.5 M aqueous dipotassium hydrogen phosphate, and diluted with EtOAc.
  • the organic phase was separated and washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na 2 SO ), concentrated, and chromatographed through a short column of silica with a gradient of 0 to 5% MeOH / CH 2 C1 2 , and through a second short column of silica with a gradient of 0 to 5% MeCN / CH 2 CI 2 , collecting and concentrating the material with a mass ion corresponding to a borane complex.
  • Example 153 A 4-benzyl-2-iodophenol 4-Benzylphenol was processed as described in Example 143B, except that neutralization after the reaction was complete was not conducted and the chromatography was conducted with a gradient of 25 to 33% CH 2 CI 2 / hexanes to provide the title compound (42% yield).
  • 'HNMR 300 MHz, CDC1 3 ) 8 3.88 (s, 2 H), 5.13 (s, 1 H), 6.90 (d, 1 H), 7.05 (dd, 1 H), 7.13-7.33 (m, 5 H), 7.47 (d, 1 H).
  • Example 153B (2R)-l -r2-(5-benzyl-l-benzofuran-2-vPethyl]-2-methylpyrrolidine
  • the product from Example 153 A was treated as described in Example 136C, except that the reaction was conducted at room temperature for one day, then at 65 °C overnight, and worked up as follows: The reaction mixture was brought to room temperature, concentrated, suspended in CH 2 CI 2 and mixed with 10% aqueous ammonia, and filtered through diatomaceous earth. The filtrate was diluted with water and the aqueous phase was separated and extracted with CH 2 CI 2 .
  • Example 154 1 -(2-
  • Example 154A 4-( 1 H-imidazol- 1 -vP-2-iodophenol 4-Imidazol-l-ylphenol was processed as described in Example 143B, except that after removal of the ammonia under reduced pressure, the mixture was diluted with brine and extracted with 33% isopropanol / EtOAc. The organic extracts were combined and partially concentrated before being washed with brine. The brine phase was separated and extracted as before. The combined organic phases were then concentrated until only some unseparated N,N-dimethylformamide and water remained, and set aside overnight. The crystals which formed were collected by filtration and washed with 2: 1 EtOAc / ether. The filtrate was concentrated and diluted with brine.
  • Example 154B 1 (2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vP-l H-imidazole
  • the product from Example 154 A was processed as described in Example 136C except that the reaction was carried out at 80 °C for six hours, additional alkyne solution (10 moP/o) was added, and after an additional 2.3 hours the reaction was brought to room temperature, concentrated, and chromatographed through a short column of silica covered with a layer of diatomaceous earth with a gradient of 0 to 10% 2 M NH 3 in MeOH / CH 2 C1 2 .
  • Example 155 4-(3-bromo-2- ⁇ 2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl ⁇ -l-benzofuran-5-vP-2- methylbenzonitrile
  • the product of Example 106D was processed as described in Example 101 to provide the title compound as a brownish-orange gum (18% yield).
  • Example 156A 4-(3-chloro-2- ⁇ 2-r(2R)-2-methyl-l-pyrrolidinyllethyl ⁇ -l-benzofuran-5-yl)benzonitrile and Example 156B 4-(3.6-dichloro-2- ⁇ 2-[(2R)-2 -methyl- l -pyrrolidinyl]ethyl)-l-benzofuran-5-vDbenzonitrile
  • the mono-(L)-tartaric acid salt of the product of Example ID 120 mg, 0.25 mmol
  • N-chlorosuccinimide 53 mg, 0.40 mmol
  • the reaction mixture was poured into aqueous Na 2 S0 3 , made alkaline with aqueous Na 2 CU 3 , and extracted with CH 2 CI 2 .
  • the combined organic phases were washed with brine, dried (Na 2 SO 4 ), concentrated, and purified by HPLC [Waters Nova-Pak HR C 18 column (40 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100%) MeCN / 0.1% aqueous TFA over 12 min (15 min run time) at a flow rate of 70 L / min.] to provide the title chloro (57% yield) and dichloro (12% yield) compounds as brown gums.
  • Example 157 4-(3-iodo-2- ⁇ 2-f(2R)-2-methyl-l-pyrrolidinyllethyl ⁇ -l-benzofuran-5-yPbenzonitrile
  • the mono-(L)-tartaric acid salt of the product of Example ID and N-iodosuccinimide were processed as in Example 156, except that a large excess of N-iodosuccinimide (2.4 molar equivalents) was utilized, to provide the title compound as a tan gum (18% yield).
  • Example 158 4-(2- ⁇ 2-[(2R)-2-methyl-5-oxo-l-pyrrolidinyllethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the mono-(L)-tartaric acid salt of the product of Example ID (96 mg, 0.20 mmol) was suspended in acetone (10 mL) and treated with a solution of KMnO (158 mg, 1.0 mmol) and MgSO 4 (120 mg, 1.0 mmol) in water (5 mL) over 30 minutes. After the pu ⁇ le color had disappeared, the solids were filtered off.
  • the filtrate was diluted with EtOAc, washed with aqueous potassium dihydrogen phosphate, concentrated, and purified by HPLC [Waters Nova-Pak HR C18 column (25 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL / min.] to provide the title compound (2 % yield).
  • Example 159 4-(3-acetyl-2- ⁇ 2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile
  • the product of Example ID 330 mg, 1.0 mmol was dissolved into CH 2 C1 (500 ⁇ L) and cooled to 0 °C.
  • Acetyl chloride 140 ⁇ L, 2.0 mmol
  • 1 M SnCl 4 in CH 2 C1 2 1.5 mL, 1.5 mmol
  • the mixture was partitioned between 20%> EtOAc / CH2CI 2 and 0.5 M aqueous dipotassium hydrogen phosphate.
  • the aqueous phase and solids were separated and extracted with CH 2 CI 2 , and the organic phases were combined and worked up as usual but with an aqueous dipotassium hydrogen phosphate wash, dried (Na 2 S0 4 ), and concentrated.
  • the residue was then resubjected to the same reaction conditions used previously except with additional CH 2 CI 2 (7 mL), stirred for five days, and worked up as before.
  • the concentrated residue was chromatographed through silica (MeOH / EtOAc / CH 2 C1 ) to afford an inseparable mixture of product and starting material.
  • Example 160 cyclopropyl[4-(2-(2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPphenyllmethanone
  • the product from Example ID (330 mg, 1.0 mmol) was dissolved into tetrahydrofuran (1 mL), treated with -0.7 M cyclopropylmagnesium bromide in tetrahydrofuran (2 mL, -1.4 mmol) and copper (I) iodide (a few milligrams), and heated at 45 °C for one day and at 60 °C for two days.
  • Example 161 A 2-[5-(3.5-Dimethyl-isoxazol-4-vD-benzofuran-2-yl]-ethanol To a well stirred suspension of the product from Example 112B (1.446 g, 6.00 mmol), 3,5-dimethylisoxazole-4-boronic acid (2.09 g, 6.6 mmol) (Frontier Scientific, chemical abstracts number 16114-47-9), palladium (II) acetate (0.07 g, 0.3 mmol), and biphen-2-yl- dicyclohexylphosphine (0.15 g, 0.6 mmol) in toluene (20 mL) was added 10 mL of isopropanol and 10 mL of water.
  • Example 161B 2-[5-(3.5-dimethyl-4-isoxazolyl)-l -benzofuran-2 -yllethyl methanesulfonate To a well stirred solution of the product from Example 161A (643 mg, 2.5 mmol) and methanesulfonic anhydride (522 mg, 3 mmol), in 3 mL of dichloromethane at 0 °C was added 0.53 mL (3.75 mmol) of triethylamine slowly.
  • reaction was allowed to warm to 23 °C and poured into dichloromethane, then washed with aqueous sodium phosphate (buffered to pH 8), dried over sodium sulfate, then concentrated in vacuo to provide the title compound as an oil.
  • Example 161C 3.5-dimethyl-4-(2-(2-[(2R)-2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-vDisoxazole
  • Mono-(L)-tartaric acid salt of (R)-2- methylpyrrolidine (0.82 g, 3.5 mmol) was converted to the free base by shaking with 1 mL of toluene, 0.5 L of 50%, wt/vol sodium hydroxide, and 2 mL of brine.
  • the toluene layer was decanted by pipette and added to the 3.3 mL aliquot of the product from Example 16 IB. After stirring for one week at room temperature, the reaction was poured into dichloromethane and washed with aqueous ammonia, dried over sodium sulfate, and purified by flash chromatography, eluting with 97:3 dichloromethane/methanol/0.1% NH 3 , to give 225 mg (69%) of the title compound as a clear oil.
  • Example 162A 4-[2-(2-azidoe thy!)- 1 -benzofuran-5-yl]benzonitrile Methanesulfonic acid (109 mg, 0.32 mmol), the product from Example IC and sodium azide (83 mg, 1.28 mmol) was stirred in DMF for 4 days, then poured into dichloromethane and washed with water. The crude product was purified by flash chromatography, eluting with 2: 1 dichloromefhane/hexane to provide the title compound as a clear syrup (65 mg, 71%,).
  • Example 162B 4-[2-(2-aminoethvD-l-benzofuran-5-yllbenzonitrile
  • the product from Example 162A was dissolved in 3 mL of tetrahydrofuran, and treated with triphenylphosphine (262 mg, 1 mmol) was added, along with 0.5 mL water. After 3 days, the reaction was poured into dichloromethane and washed with aqueous ammonia.
  • Example 163 4-(2- ⁇ 2-[(2R)-2-ethyl-l-pyrrolidinyl1ethyl ⁇ -l -benzofuran-5-vPbenzonitrile The product from Example IC and (2R)-ethylpyrrolidine (Andres, Jose M.; Herraiz- Sierra, Ignacio; Pedrosa, Rafael; Perez-Encabo, Alfonso; Eur.J.Org.Chem.; vol.
  • Example ID 9; 2000; ppl 719 - 1726; chemical abstracts number 123168-37-6 hydrochloride salt)were processed as described in Example ID to provide the titled compound, except that potassium carbonate was substituted for sodium carbonate, and the reaction was run at 60°C, then worked up by pouring into toluene.
  • the organic phase was extracted with 7:2: 1 of water/N- methylpyrrolidinone/10% aqueous methanesulfonic acid, and the aqueous phase then covered with isopropyl acetate and adjusted to pH 1 1 with 50% aqueous NaOH. After shaking and separation of the layers, the isopropanol extract was saved, then combined with a second isopropanol extract of the aqueous layer.

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Abstract

Compounds of formula (I), or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, which are useful for the modulation of the histamine-3 receptors in mammals and which are useful for the treatment of disorders ameliorated by histamine-3 receptor ligands.

Description

NOVEL AMINES AS HISTAMINE-3 RECEPTOR LIGANDS AND THEIR THERAPEUTIC APPLICATIONS
TECHNICAL FIELD This invention relates to compounds useful for treating diseases or conditions caused by or exacerbated by histamine-3 receptor activity, pharmaceutical compositions containing such compounds and methods of treatment using such compounds.
BACKGROUND OF THE INVENTION Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) which are commonly treated with antagonists of histamine or "antihistamines." It has also been established that histamine receptors exist in at least two distinct types, referred to as Hi and H2 receptors.
A third histamine receptor (H3 receptor) is believed to play a role in neurotransmission in the central nervous system, where the H3 receptor is thought to be disposed presynaptically on histaminergic nerve endings (Nature, 302, 832-837 (1983)). The existence of the H3 receptor has been confirmed by the development of selective H3 receptor agonists and antagonists (Nature, 327, 117-123 (1987)) and has subsequently been shown to regulate the release of other neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs, cardiovascular system and gastrointestinal tract.
A number of diseases or conditions may be treated with histamine-3 receptor ligands wherein the H3 ligand may be an antagonist, agonist or partial agonist. Such diseases or conditions include cardiovascular disorders such as acute myocardial infarction; memory processes, dementia and cognition disorders such as Alzheimer's disease and attention-deficit hyperactivity disorder; neurological disorders such as Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions; cancer such as cutaneous carcinoma, medullary thyroid carcinoma and melanoma; allergic rhinitis; respiratory disorders such as asthma; sleep disorders such as narcolepsy; vestibular dysfunction such as Meniere's disease; gastrointestinal disorders, inflammation, migraine, motion sickness, obesity, pain, and septic shock. SUMMARY OF INVENTION In its principle embodiment, the present invention is directed to compounds of formula (I):
(I), or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein
A is selected from carbonyl or a covalent bond;
D is selected from O or S;
L is selected from lower alkylene, fluoroalkylene, or hydroxyalkylene;
P and Q taken together form a covalent bond or are both hydrogen;
Ri and R2 are each independently selected from hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, alkenyl, or alkynyl; or
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle;
R3 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl, or (NRARB)sulfonyl;
R-j, R5, Re and R are each independently selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl, (NRARB)sulfonyl, -L2R20, or -R2oL3R22;
L2 is selected from alkylene, alkenylene, O, S, S(O), S(O)2, C(=O), C=(NOR2ι), or N(RA);
L3 is selected from a covalent bond, alkylene, alkenylene, O, S, C(=0), N(=OR2ι), or N(RA); R2o is selected from aryl, heterocycle, or cycloalkyl;
R ι is selected from hydrogen or alkyl;
R22 is selected from aryl, heterocycle, or cycloalkyl;
RA and RB are each independently selected from hydrogen, alkyl, alkylcarbonyl or formyl; provided that at least one of R4, R5, Rg, or R7 is aryl, heterocycle, cycloalkyl, -L2R2o or -R2oL3R22.
The compounds can be incorporated into pharmaceutical compositions and can be useful in methods for treating or preventing disorders related to histamine-3 receptor modulation. The compounds, compositions comprising the compounds, and methods for treating or preventing disorders by administering the compounds are further described herein.
DETAILED DESCRIPTION OF THE INVENTION The present invention discloses compounds and compositions thereof which are useful for selectively modulating the effects of the histamine-3 receptors in a mammal. The compounds of the invention can be used for treating and preventing disorders modulated by the histamine-3 receptor. Typically, the disorders are those that are ameliorated by selectively modulating the histamine-3 receptors in a mammal. One method of the invention provides for treating a disorder selected from acute myocardial infarction, asthma, bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric disorders, cutaneous carcinoma, drug abuse, depression, gastrointestinal disorders, inflammation, jet lag, medullary thyroid carcinoma, melanoma, allergic rhinitis, Meniere's disease, migraine, mood and attention alteration, motion sickness, neurogenic inflammation, obsessive compulsive disorder, pain, Parkinson's disease, schizophrenia, seizures, septic shock, Tourette's syndrome, vertigo, or wakefulness. The method can be particularly useful for treating Alzheimer's disease, attention-deficit hyperactivity disorder, epilepsy, narcolepsy, and cognitive and memory-related disorders, for example, mild cognitive impairment, deficits of memory, and deficits of learning and dementia.
Definition of Terms As used for the present invention, the following terms have the meanings ascribed. The term "alkenyl," as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
The term "alkenylene" means a divalent group derived from a straight or branched chain hydrocarbon of from 2 to 10 carbon atoms containing at least one double bond. Representative examples of alkenylene include, but are not limited to, -CH=CH-, -C(=CH2)- -CH=CH2CH2-, -CH2CH2C(=CH2)CH2-, -CH2CH2C(=CHCH3)CH2-, and -CH=C(CH3)CH2-.
The term "alkoxy," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term "alkoxyalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl and methoxymethyl.
The term "alkoxycarbonyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.
The term "alkyl," as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
The term "alkylcarbonyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-l-oxopropyl, 1 -oxobutyl and 1-oxopentyl.
The term "alkylcarbonyloxy," as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy and tert-butylcarbonyloxy.
The term "alkylene" means a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH(CH3)CH2-.
The term "alkylsulfinyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl and ethylsulfinyl.
The term "alkylsulfonyl," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, ethylsulfonyl, isopropylsulfonyl and methylsulfonyl.
The term "alkylthio," as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sufur atom, as defined herein. Representative examples of alkylthio include, but are not limited to, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl and hexylsulfanyl.
The term "aryl," as used herein, refers to a monocyclic-ring system, or a bicyclic- or a tricyclic- fused ring system wherein one or more of the fused rings are aromatic. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
The aryl groups of this invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, oximyl, -NRARB, (NRARB)alkyl, (NRARB)carbonyl, and (NRARB)sulfonyl.
The term "arylalkyl," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3- phenylpropyl, and 2-naphth-2-ylethyl. The term "arylcarbonyl," as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl, phenylacetyl, 3-chlorophenylacetyl, 3-methoxyphenylacetyl, 4-fiuoro-3-methylphenylacetyl, 3-phenylpropionyl, and 2-naphthylacetyl.
The term "carbonyl," as used herein, refers to a -C(O)- group.
The term "carboxy," as used herein, refers to a -CO2H group.
The term "carboxyalkyl," as used herein, refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2- carboxyethyl, and 3-carboxypropyl.
The term "cyano," as used herein, refers to a -CN group.
The term "cyanoalkyl," as used herein, refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl and 3-cyanopropyl.
The term "cycloalkyl," as used herein, refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl .
The term "cycloalkylalkyl," as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl.
The term "fluoroalkylene" means an alkylene, as defined herein, containing 1 or fluorine atoms. Representative examples of fluoroalkylene include, but are not limited to, -CH2CH(F)-, -CH2C(F)2-, -CH2C(F)2CH2-, and -CH2CH2C(F)2-.
The term "formyl," as used herein, refers to a -C(O)H group.
The term "halo" or "halogen," as used herein, refers to -CI, -Br, -I or -F.
The term "haloalkoxy," as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2- fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
The term "haloalkyl," as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, fluoromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
The term "heterocycle" or "heterocyclic," as used herein, refers to a monocyclic or bicyclic ring system. Monocyclic ring systems are exemplified by any 3- or 4-membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5-, 6-, or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6- and 7-membered rings have from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, pyrimidinyl, pyridazinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomoφholinyl, 1,1-dioxidothiomoφholinyl (thiomoφholine sulfone), thiopyranyl, triazinyl, triazolyl, and trithianyl. More particularly, example of monocyclic ring systems can include, but are not limited to, 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2 -methyl- 1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l-pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- ( fluoromethyl)-! -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl, 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl. Bicyclic ring systems are exemplified by any of the above monocyclic heterocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic heterocyclic ring system. Representative examples of bicyclic ring systems include but are not limited to, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, indazolyl, indolyl, indolinyl, indolizinyl, naphthyridinyl, 3H-imidazo[4,5-c]pyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, isoquinolinyl, phthalazinyl, pyranopyridyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and thiopyranopyridyl .
The heterocycles of this invention are substituted with 0, 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, arylalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, haloalkylcarbonyl, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl.
The term "heterocyclealkyl," as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyridin-3- ylmethyl and 2-pyrimidin-2-ylpropyl.
The term "heterocyclecarbonyl," as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclecarbonyl include, but are not limited to, lH-imidazol- 1 -ylcarbonyl, 4-moφholinylcarbonyl, 1-piperidinylcarbonyl and cyclopentylaminocarbonyl.
The term "hydroxy," as used herein, refers to an -OH group.
The term "hydroxyalkyl," as used herein, refers to one or two hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyproρyl and 2-ethyl-4- hydroxyheptyl.
The term "hydroxyalkylene" means an alkylene, as defined herein, containing 1 or hydroxy groups. Representative examples of hydroxyalkylene include, but are not limited to, -CH2CH(OH)-, -CH2CH(OH)CH2-, -CH2CH2CH(OH)-, and -CH2CH(OH)CH(OH)-.
The term "lower alkylene" as used herein, is a subset of alkylene as defined herein and means a straight or branched chain hydrocarbon group containing from 1 to 6 carbon atoms. Representative examples of lower alkylene are -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, and -CH2CH2CH2CH .
The term "mercapto," as used herein, refers to a -SH group.
The term "nitro," as used herein, refers to a -NO2 group.
The term "-NRARB," as used herein, refers to two groups, RA and RB, which are appended to the parent molecular moiety through a nitrogen atom. RA and RB are each independently selected from hydrogen, alkoxy, alkyl, alkylcarbonyl, and formyl. Representative examples of -NRARB include, but are not limited to, acetylamino, amino, formylamino, dimethylamino, and methylamino.
The term "(NRARB)alkyl," as used herein, refers to a -NRARβ group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NRARβ)alkyl include, but are not limited to, (amino)methyl, (dimethylamino)methyl and (ethylamino)methyl.
The term "(NRARB)carbonyl," as used herein, refers to a -NRARB group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRARB)carbonyl include, but are not limited to, aminocarbonyl, dimethylaminocarbonyl and ethylaminocarbonyl.
The term "(NRARB)sulfonyl," as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of aminosulfonyl include, but are not limited to, aminosulfonyl, dimethylaminosulfonyl and ethylaminosulfonyl.
The term "oximyl" as used herein , refers to a group wherein R99 and Rioo are independently selected from hydrogen and alkyl.
The term "oxo," as used herein, refers to a =O moiety.
The term "oxy," as used herein, refers to a -O- moiety. The term "sulfinyl," as used herein, refers to a -S(O)- group.
The term "sulfonyl," as used herein, refers to a -SO2- group.
Compounds of the present invention include at least those compounds of formula (I) wherein one substituent represented by R , R5, R6 or R7 are selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl, (NRARB)sulfonyl, -L2R2o, or -R20L3R22. and the other substituents represented by R4, R5, Re and R7 is selected from hydrogen or alkyl. Particular groups for the substituents represented by R^ R5, Re and R can be selected from hydrogen, alkyl, heterocycle, -L2R2o, and -R20L3R22.
Compounds of the present invention also can have the formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached form heterocycle; R3, R , R5, and R are hydrogen; and R$ is L2R20.
Heterocycles formed by R\ and R2 can include, but are not limited to, azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl. (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl. Particular examples of heterocycles for compounds of the invention are, for example, 1-azepanyl, (3S)-3-
(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l-pyrrolidinyl, (2R)-2-methyl-5 -oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl- 1 -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl. The (2R)-2-methyl-l -pyrrolidinyl group may be preferred. Groups for R6 can include, but are not limited to, a group represented by the formula L2R20, alkylcarbonyl, heterocycle, or a group represented by R2oL3R22. Where Rό is L2R20, particular groups for the position can include, but are not limited to, those wherein L2 is C(=O) and R2o is aryl; L2 is C(=O) and R2o is cycloalkyl; L2 is alkylene or alkenylene and R20 is aryl. Specific aryl groups for R20 include, but are not limited to, phenyl that is substituted with 0, 1, 2 or 3 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NRARB)carbonyl, or NRARβ.
Heterocycle groups suitable for Rό are, for example, furyl, imidazolyl, isothiazolyl, isothiazolinyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, quinolinyl, quinolizinyl, quinoxalinyl, or quinazolinyl. The heterocycle group for R6 is substituted with 0, 1 , 2 or 3 substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, arylalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, haloalkylcarbonyl, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NRARB, (NRARβ)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl; wherein RA and RB are as defined in formula (I). Particular heterocycles for Rg are l,2,4-oxadiazol-3-yl, 3-pyridinyl, 4-isoxazolyl and lH-imidazol-1-yl, wherein the heterocycle is substituted with 0, 1 or 2 substituents selected from hydrogen, alkyl, haloalkyl, or hydroxyalkyl.
Where is R20L3R22, particular groups for the position can include, but are not limited to, those wherein R2o is heterocycle, L3 is a covalent bond or alkylene and R22 is aryl; R20 is heterocycle, L3 is a covalent bond or alkylene and R22 is heterocycle, particularly 2- thienyl; R20 is aryl, particularly phenyl, L3 is C(=O) and R22 is cycloalkyl; R2o is aryl, particularly phenyl, L3 is C(=O) and R22 is aryl; and R20 is aryl, L3 is a covalent bond or alkylene and R22 is heterocycle, particularly 2-thienyl. Phenyl groups are particularly suitable for an aryl group R22. Such phenyl groups is substituted with 0, 1, 2 or 3 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NRARB)carbonyl, and NRARB. In one embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3.6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl; R3, R4, R5 and R7 are hydrogen; R^ is L2R20; L2 is C(=O); and R20 is aryl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l-pyrrolidinyl, (2R)-2-methyl-5-oxo-l-pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l-pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3, R , R5 and R7 are hydrogen; R6 is L2R20; L2 is C(=O); and R20 is aryl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R3, R*, R5 and R7 are hydrogen; R6 is L2R20; L2 is C(=O); and R20 is phenyl substituted with 0, 1, 2 or 3 substitutents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NRARB)carbonyl, or -NRARB-
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl; R3, R4, R5 and R7 are hydrogen; Rδ is L2R20; L2 is C(=O); and R2o is cycloalkyl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3 R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2 -ethyl- 1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3, R , R5 and R are hydrogen; Re is L2R20; L2 is C(=O); and R20 is cycloalkyl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R3, R4, R5 and R are hydrogen; R6 is L2R2o; L2 is C(=0); and R2o is cycloalkyl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Rt and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl; R3, R^ R5 and R are hydrogen; Rδ is L-R20. L2 is selected from alkylene and alkenylene; and R2o is aryl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3 R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3, R^ R5 and R7 are hydrogen; R6 is L2R2o; L2 is selected from alkylene and alkenylene; and R2o is aryl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R3, R^ R5 and R7 are hydrogen; and R6 is L2R20; L2 is selected from alkylene and alkenylene; and R20 is phenyl substituted with 0, 1 , 2, or 3 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NRARB)carbonyl, or -NRARB.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφho.inyl; R3) R-t, R5 and R are hydrogen; and Rό is alkylcarbonyl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3 R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l-pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3, R^ R5 and R7 are hydrogen; and R6 is alkylcarbonyl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2 -methyl- 1 -pyrrolidinyl; R3, R-(, Rs and R are hydrogen; and Re is alkylcarbonyl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl- 1 -pyrrolidinyl, 2,5-dihydro- 1 H-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl; R3, R-ι, R5 and R7 are hydrogen; and R^ is heterocycle.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3 R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3, R4, R5 and R are hydrogen; and R is heterocycle.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl; R3, R4, R5 and R are hydrogen; Re is a heterocycle selected from furyl, imidazolyl, isothiazolyl, isothiazolinyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, quinolinyl, quinolizinyl, quinoxalinyl, or quinazolinyl wherein the heterocycle is substituted with 0, 1, 2, or 3 substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, arylalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, haloalkylcarbonyl, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl; and RA and RB are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R3, R-t, R5 and R7 are hydrogen; and R6 is a heterocycle selected from l,2,4-oxadiazol-3-yl, 3-pyridinyl, 4-isoxazolyl, or lH-imidazol-1- yl wherein the heterocycle is substituted with 0, 1, or 2 substituents selected from hydrogen, alkyl, haloalkyl, or hydroxyalkyl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl; R3, R4, R5 and R are hydrogen; Re is -R2oL3R22; R20 is heterocycle; L3 is selected from a covalent bond and alkylene; and R22 is aryl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-mefhyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3, R-t, R5 and R are hydrogen; R6 is -R20L3R22; R20 is heterocycle; L3 is selected from a covalent bond and alkylene; and R22 is aryl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R3, R-,, R5 and R7 are hydrogen; R is -R2oL3R22; R20 is l,2,4-oxadiazol-3-yl; L3 is selected from a covalent bond and alkylene; and R22 is phenyl substituted with 0, 1, 2, or 3 substitutents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NRARB)carbonyl, or -NRARB.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl; R3, R-i, R5 and R are hydrogen; Re is -R2oL3R22; R20 is l,2,4-oxadiazol-3-yl; L3 is selected from a covalent bond and alkylene; and R22 is heterocycle.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l-pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethy -piperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2 -ethyl- 1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3, R4, R5 and R7 are hydrogen; R6 is -R20L3R22; R2o is 1,2,4- oxadiazol-3-yl; L3 is selected from a covalent bond and alkylene; and R22 is heterocycle.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l-pyrrolidinyl; R3, R4, R5 and R7 are hydrogen; Re is -R2oL3R22; R20 is l,2,4-oxadiazol-3-yl; L3 is selected from a covalent bond and alkylene; and R22 is 2- thienyl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl; R3, R4, R5 and R are hydrogen; R is -R20L3R22; R20 is aryl; L3 is C(=O); and R22 is cycloalkyl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l -pyrrolidinyl, (3S)-3- hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-( fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l ,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3, R4, R5 and R7 are hydrogen; Re is -R20L3R22; R20 is aryl; L3 is C(=O); and R22 is cycloalkyl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R3, R-t, R5 and R7 are hydrogen; R6 is -R20L3R22; R20 is phenyl; L3 is C(=O); and R22 is cycloalkyl. In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl; R3, R , R5 and R are hydrogen; Re is -R2oL3R22; R2o is aryl; L3 is C(=O); and R22 is aryl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3, *, R5 and R are hydrogen; R^ is -R2oL3R22; R20 is aryl; L3 is C(=O); and R22 is aryl.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R3, R-j, R5 and R are hydrogen; Re is -R20L3R22; R20 is phenyl; L3 is C(=O); and R22 is phenyl substituted with 0, 1, 2, or 3 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NRARβ)carbonyl, or -NRARB. In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl; R3, R4, R5 and R7 are hydrogen; Re is -R2oL3R22; R20 is aryl; L3 is C(=O); and R22 is heterocycle.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3, R , R5 and R7 are hydrogen; R6 is -R20L3R22; R20 is aryl; L is C(=0); and R22 is heterocycle.
In another embodiment, compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R3, R , R5 and R are hydrogen; R6 is -R20L3R22; R20 is phenyl; L3 is C(=O); and R22 is 2-thienyl.
According to another embodiment, compounds of the present invention have formula (II) (II), or a pharmaceutical acceptable salt, ester, amide, or prodrug thereof, wherein
R is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl, or (NRARB)sulfonyl;
R8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl, or (NRARB)carbonyl;
R9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NRARB, (NRARB)alkyl, (NRARB)carbonyl, or (NRARB)sulfonyl;
X is selected from CH, CRx, or N;
Y is selected from CH, CRγ; or N;
Z is selected from CH, CRz, or N;
Rx, RY and Rz groups are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl, or (NRARβ)sulfonyl; and A, D, L, RA) RB, RI, R2, R3, R , and R5 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; and D, L, RA, RB, Ri, R2, R3, Rt, R5, R7, R8, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond, Ri and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R is cyano; and D, L, RA, RB, 3, R4, R5, R7 and R9, X, Y, and Z are as defined in formula (I). In another embodiment, compounds of the present invention have formula (II) wherein L is -CH2CH2-; A is a covalent bond; Ri and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R3, R , R5, R7 and R9 are hydrogen; R8 is cyano; X is CH; Y is CH; Z is CH; and D, RA, and RB are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R8 is cyano; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R4, R5, R7 and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R8 is heterocyclecarbonyl; and D, L, RA, RB, R3, R4, R5, R7, R9, X, Y and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R8 is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1- pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl; and D, L, RA, RB, R3, R , R5, R7, R9, X, Y and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R8 is heterocyclecarbonyl wherein the heterocycle is 4-moφholinyl; and D, L, RA, RB, R3, R4, R5, R7, R9, X, Y and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH2CH2-; R\ and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R3, R-j, R5, R and R are hydrogen; R8 is heterocyclecarbonyl wherein the heterocycle is 4-moφholinyl; X is CH; Y is CH; Z is CH; and D, RA and RB are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R8 is heterocyclecarbonyl; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R», R5, R7 and R9 are as defined in formula (I). In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; R8 is heterocyclecarbonyl wherein the heterocycle of heterocarbonyl is selected from the group consisting of azetidinyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl.; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R-t, R5, R7 and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R∑ are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R8 is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1- pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R , R5, R7 and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R] and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R is heterocyclecarbonyl wherein the heterocycle is 4-moφholinyl; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R-i, R5, R7 and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH2CH2-; R\ and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R3, R , R5, R7 and R9 are hydrogen; R8 is heterocyclecarbonyl wherein the heterocycle is 4-moφholinyl; X is N; Y is CH; Z is CH; and D, RA and RB are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle and D, L, RA, RB, R3, R4, R5, R7, Rg, R , X, Y and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; Rg is cyano; and D, L, RA, RB, R3, R^ R5,R7, R , X, Y and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l-pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R8 is cyano; and D, L, RA, RB, R3, R , R5,R7, R9, X, Y and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH2CH2-; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl; R3, R , R5, and R are independently selected from hydrogen, alkyl, alkylcarbonyl, and halogen; Rg and R9 are independently selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, or oximyl; X is selected from CH and CRx; Y is selected from CH and CRy; Z is selected from CH and CRz; and R , Rγ, and Rz are independently selected from alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, or oximyl.
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH2CH2-; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3 -hydroxy- 1 -pyrrolidinyl, (3S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l - pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5- oxo-1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l-pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2R)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2S)-2- (fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-ethyl- 1 - pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)-2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa- 5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8-azaspiro[4.5]dec-8-yl; R3, R , R5, and R7 are independently selected from hydrogen, alkyl, alkylcarbonyl, and halogen; Rg and R9 are independently selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, or oximyl; X is selected from CH and CR ; Y is selected from CH and CRy; Z is selected from CH and CRZ; and Rx, RY, and Rz are independently selected from alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, or oximyl.
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH2CH2-; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle substituted with 0, 1 or 2 substituents selected from alkyl; R3, R-i, R5, R , and R9 are hydrogen; R8 is cyano; X is CH; Y is CH; and Z is CH.
In another embodiment, compounds of the present invention have formula (II) wherein L is -CH2CH2-; A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1-dioxidothiomoφholinyl; R3 is heterocycle; R-j, R5, R and R are hydrogen; R8 is cyano; X is CH; Y is CH; and Z is CH. In another embodiment, compounds of the present invention have formula (II) wherein L is -CH2CH2-; A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3 -hydroxy- 1 -pyrrolidinyl, (3S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-mefhyl-l- pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5- oxo-1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l -pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2R)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2S)-2- (fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-(fiuoromethyl)- 1 -pyrrolidinyl, (2R)-2-ethyl- 1 - pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)-2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa- 5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8-azaspiro[4.5]dec-8-yl; R3 is heterocycle; R , R5, R7 and R9 are hydrogen; R8 is cyano; X is CH; Y is CH; and Z is CH.
In another embodiment, compounds of the present invention have formula (II) wherein L is -CH2CH2-; A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R3 is heterocycle selected from 2-furyl, 3-pyridinyl, and 2-thienyl wherein the heterocycle is substituted with 0, 1, or 2 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, or oximyl; R , R5, R and R9 are hydrogen; R8 is cyano; X is CH;Y is CH; and Z is CH.
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R8 is cyano; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R , R5, R7 and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; R8 is cyano; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R4, R5, R7 and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; Rg is cyano; X is N; Y is CH; Z is CH; and D, L, RA, RB, R , R , R5, R7 and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; Rg is heterocyclecarbonyl; and D, L, RA, RB, R3, R , R5, R7, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl. (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl; R8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl; and D, L, RA, RB, R3, R^ R5, R , R9, X, Y, and Z are as defined in formula (I). In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1- dioxidothiomoφholinyl; R8 is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5- dihydro-lH-pyrrolyl, 1 -pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1,1- dioxidothiomoφholin-4-yl; and D, L, RA, RB, R3, R , R5, R , R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l-pyrrolidinyl, (3 S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l - pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5- oxo-1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l -pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2R)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2S)-2- (fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-ethyl- 1 - pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)-2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa- 5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8-azaspiro[4.5]dec-8-yl; R8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1- dioxidothiomoφholinyl; and D, L, RA, RB, R3, R4, R5, R , R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l-pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl. (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; Rg is heterocyclecarbonyl wherein the heterocycle is selected from 1- azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5- dihydro-lH-pyrrolyl, 1 -pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1,1- dioxidothiomoφholin-4-yl; and D, L, RA, RB, R3, R , R5, R7, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; R8 is heterocyclecarbonyl wherein the heterocycle is 4-moφholinyl; and D, L, RA, RB, R3, R-t, R5, R7, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- ( fluoromethyl)- 1 -pyrrolidinyl, (2R)-2 -ethyl- 1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l ,4-dioxa-8- azaspiro[4.5]dec-8-yl; Rg is heterocyclecarbonyl wherein the heterocycle is 4-moφholinyl; and D, L, RA, RB, R3, R4, R5, R7, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1- dioxido thiomoφholinyl; R3, R4, R5, R7 and R9 are hydrogen; R8 is heterocyclecarbonyl wherein the heterocycle is 4-moφholinyl; X is CH; Y is CH; Z is CH; and D, L, RA and RB are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2 -methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2 -ethyl- 1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3, R4, R5, R and R9 are hydrogen; Rg is heterocyclecarbonyl wherein the heterocycle is 4-moφholinyl; X is CH; Y is CH; Z is CH; and D, L, RA and RB are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R8 is heterocyclecarbonyl; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R^ R5, R7, and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH2CH2-; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl; Rg is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1 , 1 -dioxidothiomoφholin-4-yl; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R , R5, R7, and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH2CH2-; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3-hydroxy-l -pyrrolidinyl, (3 S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l - pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5- oxo-1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l -pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2R)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2S)-2- (fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-ethyl- 1 - pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2 S)-2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa- 5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8-azaspiro[4.5]dec-8-yl; R8 is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1- piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro- l(2H)-pyridinyl, 4-thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R , R5, R7, and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH2CH2-; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl. (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl; R8 is heterocyclecarbonyl wherein the heterocycle is 4-moφholinyl; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R , R5,R7, and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH2CH2-; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3-hydroxy-l -pyrrolidinyl, (3S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l - pyrrolidinyl, (2R)-2-methyl-l-pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5- oxo-1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l-pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2R)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2S)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l- pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2 S)-2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa- 5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8-azaspiro[4.5]dec-8-yl; R8 is heterocyclecarbonyl wherein the heterocycle is 4-moφholinyl; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R , Rs,R7, and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH2CH2-; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl; R3, R , R5, R7 and R9 are hydrogen; R8 is heterocyclecarbonyl wherein the heterocycle is 4-moφholinyl; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R4, R5, R , and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH2CH2-; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3 -hydroxy- 1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l - pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5- oxo-1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l-pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2R)-2-(methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2- (fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-ethyl- 1 - pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)-2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa- 5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8-azaspiro[4.5]dec-8-yl; R3, R4, R5, R7 and R9 are hydrogen; R8 is heterocyclecarbonyl wherein the heterocycle is 4-moφholinyl; X is N; Y is CH; Z is CH; and D, L, RA, RB, R3, R4, R5, R , and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is carbonyl; Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and Rg is selected from the group consisting of cyano and heterocyclecarbonyl; and D, L, RA, RB, R3, R4, R5, R7, and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is carbonyl; Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and Rg is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl; and D, L, RA, RB, R3, R . R5, R , and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is carbonyl; R\ and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; Rg is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1 -azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1- piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro- l(2H)-pyridinyl, 4-thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl; and D, L, RA, RB, R3, R4, R5, R7, and R9 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is carbonyl; and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R8 is selected from cyano or heterocyclecarbonyl; and D, L, RA, RB, R3, R4, R5, R7, R9, X, Y and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is carbonyl; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; Rg is selected from cyano or heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1 , 1 -dioxidothiomoφholin-4-yl; D, L, RA, RB, R3, R4, R5, R7, R9, X, Y and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is carbonyl; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl; R8 is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1 -azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl; and D, L, RA, RB, R3, R , R5, R7, R9, X, Y and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (II) wherein A is carbonyl; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy- 1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2 S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l-pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-( fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; Rg is selected from cyano or heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl; D, L, RA, RB, R3, R-t, R5, R7, R9, X, Y and Z are as defined in formula (I).
According to another embodiment, compounds of the present invention have formula (HI)
(HI), or a pharmaceutical acceptable salt, ester, amide, or prodrug thereof, wherein
R6 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl;
R8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl or (NRARB)carbonyl;
R9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl;
X is selected from CH, CRx or N;
Y is selected from CH, CRy or N;
Z is selected from CH, CRz or N;
Rx, RY and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARβ)sulfonyl; and
A, D, L, RA, RB, RI , R2, R3, R4, and R5 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is a covalent bond; and D, L, RA, RB, RI , R2, R3, R , R5, e, R8, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is a covalent bond; R\ and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R8 is selected from cyano or heterocyclecarbonyl; and D, L, RA, RB, R3, R-t, R5, Re, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is a covalent bond; Ri and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; Rg is selected from cyano or heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1- piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro- l(2H)-pyridinyl, 4-thiomoφholinyl, and 1 , 1 -dioxidothiomoφholin-4-yl; D, L, RA, RB, R3, Rj, R5, Re, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; Rg is selected from cyano or heterocyclecarbonyl; and D, L, RA, RB, R3, R , R5, Re, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; R8 is selected from cyano or heterocyclecarbonyl wherein the heterocycle is selected from 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1 , 1 -dioxidothiomoφholin-4-yl; and D, L, RA, RB, R3, R , R5, Re, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2 -ethyl- 1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2 -ethyl- 1 -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; Rg is selected from cyano or heterocyclecarbonyl wherein the heterocycle is selected from 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1 , 1 -dioxidothiomoφholin-4-yl; and D, L, RA, RB, R3, R^ R5, Re, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is carbonyl; and D, L, RA, RB, Ri, R2, R3, R<t, R5, Re, R8, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is carbonyl; R\ and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R8 is cyano; and D, L, RA, RB, R3, R4, R5, Rό, R9, X, Y, and Z are as defined in formula (I). In another embodiment, compounds of the present invention have formula (III) wherein L is -CH2CH2-; A is carbonyl; Ri and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R3 is methyl, R , R5, Re and R9 are hydrogen; R8 is cyano; X is CH; Y is CH; Z is CH; and D, RA and RB are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is carbonyl; R\ and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; Rg is heterocyclecarbonyl; and D, L, RA, RB, R3, R4, R5, R6, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is carbonyl; R\ and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R8 is heterocyclecarbonyl wherein the heterocycle is selected from 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1- pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomoφholinyl, and 1 , 1 -dioxidothiomoφholin-4-yl; and D, L, RA, RB, R3, R , R5, R6, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is carbonyl; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R8 is cyano; and D, L, RA, RB, R3, R-t, R5, Re, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is carbonyl; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1- dioxidothiomoφholinyl; R8 is cyano; and D, L, RA, RB, R3, R.;, R5, R6, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is carbonyl; R) and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-( fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; Rg is cyano; and D, L, RA, RB, R3, Rt, R5, Re, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein L is -CH2CH2-; A is carbonyl; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l- pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl; R3 is methyl; R , R5, Re and R9 are hydrogen; R8 is cyano; X is CH; Y is CH; Z is CH; and D, L, RA and RB are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein L is -CH2CH2-; A is carbonyl; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- ( fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl- 1 -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3 is methyl; R4, R5, R6 and R9 are hydrogen; R8 is cyano; X is CH; Y is CH; Z is CH; and D, L, RA and RB are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is carbonyl; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; Rg is heterocyclecarbonyl; and D, L, RA, RB, R3, R4, R5, Re, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is carbonyl; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; R8 is heterocyclecarbonyl wherein the heterocycle is selected from 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5- dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1,1- dioxidothiomoφholin-4-yl; and D, L, RA, RB, R3, R , R5, Re, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (III) wherein A is carbonyl; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2 -ethyl- 1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R8 is heterocyclecarbonyl wherein the heterocycle is selected from 1- azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5- dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1,1- dioxidothiomoφholin-4-yl; and D, L, RA, RB, R3, R4, R5, R^ R9, X, Y, and Z are as defined in formula (I).
According to another embodiment, compounds of the present invention have formula (IV)
(IV), or a pharmaceutical acceptable salt, ester, amide, or prodrug thereof, wherein
R7 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl;
R8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl or (NRARB)carbonyl;
R9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl;
X is selected from CH, CRx or N;
Y is selected from CH, CRy or N;
Z is selected from CH, CRz or N;
Rx, Ry and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRA, RB, (NRARβ)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl; and
D, L, RA, RB, RI, R2, R3, R4 and R5 are as defined in formula (I). In another embodiment, compounds of the present invention have formula (IV) wherein A is a covalent bond; and D, L, RA, RB, R,, R2, R3, R4, R5, R7, R8, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (IV) wherein A is a covalent bond; Ri and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R8 is cyano; and D, L, RA, RB, R3, R4, R5, R7, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (IV) wherein L is -CH2CH2-; A is a covalent bond; R\ and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R3, R4, R5, R7 and R9 are hydrogen; R8 is cyano; X is CH; Y is CH; Z is CH; and D, RA and RB are as defined in formula (I).
In a further embodiment, compounds of the present invention have formula (V)
(V), or a pharmaceutical acceptable salt, ester, amide, or prodrug thereof, wherein
Re is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl;
Rg is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl or (NRARβ)carbonyl;
R9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl;
X is selected from CH, CRx or N;
Y is selected from CH, CRY or N; Z is selected from CH, CRZ or N;
Rx, RY and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl; and A, D, L, RA, RB, Ri, R2, R3, R , R5 are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (V) wherein A is a covalent bond; and D, L, RA, RB, Rj, R2, R3, i, R5, Re, R8, R9, X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (IV) wherein A is a covalent bond; Ri and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R8 is cyano; and D, L, RA, RB, R3, ^, R5, Re, R , X, Y, and Z are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (IV) wherein L is -CH2CH2-; A is a covalent bond; Ri and R2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R3, R-j, R5, Re and R9 are hydrogen; R is cyano; X is CH; Y is CH; Z is CH; and D, RA and RB are as defined in formula (I).
In a further embodiment, compounds of the present invention have formula (VI)
(VI), or a pharmaceutical acceptable salt, ester, amide, or prodrug thereof, wherein
R5, Re, and R are selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl; R8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl and (NRARB)carbonyl; R9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl;
X is selected from CH, CRx or N;
Y is selected from CH, CRY or N;
Z is selected from CH, CRz or N;
Rx, RY and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARβ, (NRARβ)alkyl, (NRARB)carbonyl or (NRARβ)sulfonyl; and
A, D, L, RA, RB, Ri, R2, and R3, are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (VI) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; P, Q, D, L, RA, RB, and R3, are as defined in formula (I) and R5, Re, R7, Rg, and R9 are defined as in formula (VI).
In another embodiment, compounds of the present invention have formula (VI) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; R8 is cyano; and P, Q, D, L, RA, RB, and R3, are as defined in formula (I) and R5, Re, R7, and R9 are defined as in formula (VI).
In another embodiment, compounds of the present invention have formula (VI) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2 -ethyl- 1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R8 is cyano; and P, Q, D, L, RA, RB, and R3, are as defined in formula (I) and R5, Re, R7, and R are defined as in formula (VI).
In another embodiment, compounds of the present invention have formula (VI) wherein L is -CH2CH2-; A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 , 1 -dioxidothiomoφholinyl; R3, R5, R^, R and R9 are hydrogen; Rg is cyano; X is CH;Y is CH; and Z is CH.
In another embodiment, compounds of the present invention have formula (VI) wherein L is -CH2CH2-; A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3 -hydroxy- 1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l- pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2 S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5- oxo-1 -pyrrolidinyl, (2S)-2-methyl-5 -oxo- 1 -pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2R)-2-(methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2- (fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-ethyl- 1 - pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2 S)-2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa- 5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8-azaspiro[4.5]dec-8-yl; R3, R5, Re, R7 and R9 are hydrogen; R8 is cyano; X is CH;Y is CH; and Z is CH.
In a further embodiment, compounds of the present invention have formula (VII) (VII), or a pharmaceutical acceptable salt, ester, amide, or prodrug thereof, wherein
R^ R6, and R7 are selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl;
Rg is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl or (NRARB)carbonyl;
R9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl; X is selected from CH, CRX or N; Y is selected from CH, CRY or N; Z is selected from CH, CRz or N; Rx, Ry and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl; and
L, A, D, Ri, R2, R3, RA, and RB are as defined in formula (I).
In another embodiment, compounds of the present invention have formula (VII) wherein A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; P, Q, D, L, RA, RB, and R3, are as defined in formula (I) and R4, R^, R7, Rg, and R9 are defined as in formula (VII).
In another embodiment, compounds of the present invention have formula (VII) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; R8 is cyano; and P, Q, D, L, RA, RB, and R3, are as defined in formula (I) and j, Re, R7, and R9 are defined as in formula (VII).
In another embodiment, compounds of the present invention have formula (VII) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l-pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l-pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2 -ethyl- 1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2 -ethyl- 1 -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R8 is cyano; and P, Q, D, L, RA, RB, and R3, are as defined in formula (I) and R-t, Re, R7, and R9 are defined as in formula (VII).
In another embodiment, compounds of the present invention have formula (VII) wherein L is -CH2CH2-; A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl; R3, R4, R^, R7 and R9 are hydrogen; Rg is cyano; X is CH;Y is CH; and Z is CH.
In another embodiment, compounds of the present invention have formula (VII) wherein L is -CH2CH2-; A is a covalent bond; R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3-hydroxy-l -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l - pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5- oxo-1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l-pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2R)-2-(methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2- (fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-ethyl- 1 - pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2 S)-2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa- 5-azabicyclo[2.2.1]hept-5-yl, or l,4-dioxa-8-azaspiro[4.5]dec-8-yl; R3, R , R6, R7 and R9 are hydrogen; Rg is cyano; X is CH;Y is CH; and Z is CH.
The present invention also provides, pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I- VII) in combination with a pharmaceutically acceptable carrier.
According to another embodiment, the present invention provides a method of selectively modulating the effects of the histamine-3 receptors in a mammal comprising administering an effective amount of a compound of formula (I- VII).
According to another embodiment, the present invention provides a method of treating or preventing a disorder ameliorated by modulating the histamine-3 receptors in a mammal comprising administering an effective amount of a compound of formula (I -VII).
According to still another embodiment, the present invention provides a method of treating a disorder selected from acute myocardial infarction, asthma, bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric disorders, cutaneous carcinoma, drug abuse, depression, gastrointestinal disorders, inflammation, jet lag, medullary thyroid carcinoma, melanoma, allergic rhinitis, Meniere's disease, migraine, mood and attention alteration, motion sickness, neurogenic inflammation, obsessive compulsive disorder, pain, Parkinson's disease, schizophrenia, seizures, septic shock, Tourette's syndrome, vertigo, or wakefulness.
According to another embodiment, the present invention provides a method of treating Alzheimer's disease by administering an effective amount of a compound of formula (I-VII). According to another embodiment, the present invention provides a method of treating attention-deficit hyperactivity disorder by administering an effective amount of a compound of formula (I- VII).
According to another embodiment, the present invention provides a method of treating epilepsy by administering an effective amount of a compound of formula (I- VII).
According to another embodiment, the present invention provides a method of treating narcolepsy by administering an effective amount of a compound of formula (I- VII).
According to still another embodiment, the present invention provides a method of treating obesity by administering an effective amount of a compound of formula (I- VII).
According to still another embodiment, the present invention provides a method of treating a disorder selected from mild cognitive impairment, deficits of memory, and deficits of learning and dementia by administering an effective amount of a compound of formula (I- VII).
Representative compounds of the invention include, but are not limited to: 2R)-2-methylpyrrolidinyl]ethyl} - 1 -benzofuran-5-yl)benzonitrile; -pyrrolidinyl)ethyl]- 1 -benzofuran-5-yl} benzonitrile; -methyl- 1 -pyrrolidinyl)ethyl]- 1 -benzofuran-5-yl} benzonitrile; -piperidinyl)ethyl]- 1 -benzofuran-5-yl}benzonitrile; iethylamino)ethyl]-l-benzofuran-5-yl}benzonitrile; -methyl- 1 -piperidinyl)ethyl]- 1 -benzofuran-5-yl } benzonitrile; 3R)-3-hydroxypyπOlidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; H-imidazol- 1 -yl)ethyl]- 1 -benzofuran-5-yl}benzonitrile; 3S)-3-(dimethylamino)pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 2S)-2-(hydroxymethyl)pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 2R,6S)-2,6-dimethylpiperidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 2R,5R)-2,5-dimethylpyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; -azepanyl)ethyl]-l-benzofuran-5-yl}benzonitrile; -methyl-l-piperidinyl)ethyl]-l-benzofuran-5-yl}benzonitrile; 2-pyrrolidine methyl carboxylate)]ethyl} - 1 -benzofuran-5-yl)benzonitrile; ,6-dihydro- 1 (2H)-pyridinyl)ethyl]- 1 -benzofuran-5-yl } benzonitrile; 2R)-2-(hydroxymethyl)pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; ert-butyl(methyl)amino]ethyl} - 1 -benzofuran-5-yl)benzonitrile; 4-(2-{2-[isopropyl(methyl)amino]ethyl}-l-benzofuran-5-yl)benzonitrile;
4-(2- {2-[isobutyl(methyl)amino]ethyl} - 1 -benzofuran-5-yl)benzonitrile;
4-(2-{2-[ethyl(isopropyl)amino]ethyl}-l-benzofuran-5-yl)benzonitrile;
4-(2- {2-[ethyl(propyl)amino]ethyl} - 1 -benzofuran-5-yl)benzonitrile;
4-(4- {2-[2-(2 -methyl- 1 -pyrrolidinyl)ethyl]- 1 -benzofuran-5-yl}benzoyl)moφholine;
4-(4- {2-[2-( 1 -piperidinyl)ethyl]- 1 -benzofuran-5-yl}benzoyl)moφholine;
N,N-diethyl-N-(2-{5-[4-(4-moφholinylcarbonyl)phenyl]-l-benzofuran-2- yl}ethyl)amine;
4-(4- {2-[2-(2 -methyl- 1 -piperidinyl)ethyl]- 1 -benzofuran-5-yl}benzoyl)moφholine;
(3R)- 1 -(2- {5-[4-(4-moφholinylcarbonyl)phenyl]- 1 -benzofuran-2 -yl} ethyl)-3- pyrrolidinol;
4-[4-(2- {2-[(2R,5R)-2,5-dimethylpyrrolidinyl]ethyl} -1 -benzofuran-5- yl)benzoyl]moφholine;
4-[4-(2-{2-[(2R,6S)-2,6-dimethylpiperidinyl]ethyl}-l-benzofuran-5- yl)benzoyl]moφholine;
4-(4-{2-[2-(azepinyl)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine;
4-(4-{2-[2-(4-methyl-l-piperidinyl)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine;
4-(4-{2-[2-(4-moφholino)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine;
4-(4- {2-[2-(3 ,6-dihydro- 1 (2H)-pyridinyl)ethyl]- 1 -benzofuran-5- yl}benzoyl)moφholine;
4-(4-{2-[2-(2S)pyrrolidinylmethanol)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine;
N-(tert-butyl)-N-methyl-N-(2-{5-[4-(4-moφholinylcarbonyl)phenyl]-l-benzofuran-2- yl}ethyl)amine;
N-isopropyl-N-methyl-N-(2- {5-[4-(4-mθφholinylcarbonyl)phenyl]- 1 -benzofuran-2- yl}ethyl)amine;
N-isobutyl-N-methyl-N-(2- {5-[4-(4-moφholinylcarbonyl)phenyl]- 1 -benzofuran-2- yl}ethyl)amine;
N-ethyl-N-isopropyl-N-(2-{5-[4-(4-moφholinylcarbonyl)phenyl]-l-benzofuran-2- yl}ethyl)amine;
N,N-dimethyl-N-(2-{5-[4-(4-moφholinylcarbonyl)phenyl]-l-benzofuran-2- yl}ethyl)amine; N-ethyl-N-(2-{5-[4-(4-moφholinylcarbonyl)phenyl]-l-benzofuran-2-yl}ethyl)-N- propylamine;
4-{4-methyl-2-oxo-3-[2-(l-pyrrolidinyl)ethyl]-2H-chromen-7-yl}benzonitrile;
4-{4-methyl-2-oxo-3-[2-(l-piperidinyl)ethyl]-2H-chromen-7-yl}benzonitrile;
4-{3-[2-(diethylamino)ethyl]-4-methyl-2-oxo-2H-chromen-7-yl}benzonitrile;
4-[(6- {2-[2-(l-pyrrolidinyl)ethyl]-l-benzofuran-5-yl}-3- pyridinyl)carbonyl]moφholine;
4- { [6-(2- {2-[(2R)-methylpyrrolidinyl]ethyl} - 1 -benzofuran-5-yl)-3- pyridinyl]carbonyl}moφholine;
4-[(6-{2-[2-(l-piperidinyl)ethyl]-l-benzofuran-5-yl}-3- pyridinyl)carbonyl]moφholine;
4-[(6- {2-[2-(N,N-diethyl)ethyl]- 1 -benzofuran-5-yl} -3-pyridinyl)carbonyl]moφholine;
(3R)- 1 -(2- {5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]- 1 -benzofuran-2 -yl} ethyl)-3- pyrrolidinol;
4-{[6-(2-{2-[(2S,5S)-2,5-dimethylpyrrolidinyl]ethyl}-l-benzofuran-5-yl)-3- pyridinyl]carbonyl}moφholine;
4- { [6-(2- {2-[(2R,6S)-2,5-dimethylpiperidinyl]ethyl} - 1 -benzofuran-5-yl)-3- pyridinyljcarbonyl} moφholine;
4- { [6-(2- {2-[ 1 -azepanyljethyl} - 1 -benzofuran-5-yl)-3-pyridinyl]carbonyl}moφholine;
4-[(6- {2-[2-(4-methyl- 1 -piperidinyl)ethyl]- 1 -benzofuran-5-yl} -3- pyridinyl)carbonyl]moφholine;
4-[(6-{2-[2-(4-moφholinyl)ethyl]-l-benzofuran-5-yl}-3- pyridinyl)carbonyl]moφholine;
N-(tert-butyl)-N-methyl-N-(2- {5-[5-(4-moφholinylcarbonyl)-2 -pyridinyl]- 1 - benzofuran-2-yl}ethyl)amine;
N-isobutyl-N-methyl-N-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran- 2-yl}ethyl)amine;
N-isopropyl-N-methyl-N-(2- {5-[5-(4-moφholinylcarbonyl)-2 -pyridinyl]- 1- benzofuran-2-yl} ethyl)amine;
N-ethyl-N-isopropyl-N-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran- 2-yl}ethyl)amine.; N, N-dimethyl-N-(2- { 5-[5-(4-moφholinylcarbonyl)-2 -pyridinyl]- 1 -benzofuran-2- yl}ethyl)amine;
N-ethyl-N-propyl-N-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran-2-yl}et
8-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran-2-yl}ethyl)-l,4-diox8- azaspiro [4.5] decane;
5-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran-2-yl}ethyl)-2-ox5- azabicyclo[2.2.1]heptane;
(2S)-l-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran-2-yl}ethyl)-2-pyrroliι
N-allyl-N-(2- {5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]- 1 -benzofuran-2 - yl}ethyl)amine;
3-[(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l -benzofuran-2 -yl}ethyl)amino]-l - propanol;
N-(2- { 5-[5-(4-moφholinylcarbonyl)-2 -pyridinyl]- 1 -benzofuran-2-yl} ethyl)-N- propylamine;
4-(2-{2-[(3R)-3-(dimethylamino)pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile;
4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-2,3-dihydro-l-benzofuran-5- yl)benzonitrile ;
(4-fluorophenyl)(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-5- yl)methanone;
(3-fluorophenyl)(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)methanone;
(2-fluorophenyl)(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-5- yl)methanone;
(3-chlorophenyl)(2- {2-[(2R)-2 -methyl- 1 -pyrrolidinyl] ethyl} -1 -benzofuran-5- yl)methanone;
(4-chlorophenyl)(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-5- yl)methanone;
(4-methoxyphenyl)(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-5- yl)methanone;
(4-fluoro-3-methylphenyl)(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran- 5-yl)methanone; cyclopropyl(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-5- yl)methanone;
3 -ethyl- 1 -(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl } - 1 -benzofuran-5-yl)- 1 - pentanone;
(4-chloro-3-methylphenyl)(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran- 5-yl)methanone;
(2- {2-[(2R)-2-methyl-l -pyrrolidinyl]ethyl} - 1 -benzofuran-5-yl)[4- (methylthio)phenyl]methanone;
[4-(dimethylamino)phenyl](2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran- 5-yl)methanone;
(4-methylphenyl)(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)methanone;
(3,5-difluorophenyl)(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)methanone;
(2-methoxyphenyl)(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-5- yl)methanone;
(3-methoxyphenyl)(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)methanone;
(2- {2-[(2R)-2-methyl-l -pyrrolidinyl] ethyl} - 1 -benzofuran-5-yl)(phenyl)methanone;
4-(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-4-yl)benzonitrile;
2- {2- [(2R)-2-methylpyrrolidin- 1 -yl]ethyl } - 1 -benzofuran-6-carbonitrile;
3-(2- {2-[(2R)-2-methylpyrrolidin- 1 -yl]ethyl} - 1 -benzofuran-5-yl)-5-(thien-2- ylmethyl)-l ,2,4-oxadiazole;
4-[3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)-l,2,4-oxadiazol- 5-yl]benzonitrile;
5-(4-chlorophenyl)-3-(2- {2-[(2R)-2-methylpyrrolidin-l -yl]ethyl} -1 -benzofuran-5-yl)- 1,2,4-oxadiazole;
5-(2-chlorophenyl)-3-(2- {2-[(2R)-2-methylpyrrolidin-l -yljethyl} -1 -benzofuran-5-yl)- 1,2,4-oxadiazole;
5-(4-fluorobenzyl)-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)- 1,2,4-oxadiazole; 5-(4-methoxybenzyl)-3-(2- {2-[(2R)-2-methylpyrrolidin- 1 -yl]ethyl} - 1 -benzofuran-5- yl)- 1 ,2,4-oxadiazole;
3-{[3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)-l,2,4- oxadiazol-5-yl]methyl}benzonitrile;
3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)-5-phenyl-l,2,4- oxadiazole;
5-(4-fluorophenyl)-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)- 1 ,2,4-oxadiazole;
5-(3-chloro-4-fluorophenyl)-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l- benzofuran-5-yl)-l,2,4-oxadiazole;
5-(chloromethyl)-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)- 1,2,4-oxadiazole;
3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)-5-propyl- 1 ,2,4- oxadiazole;
5-ethyl-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)-l ,2,4- oxadiazole;
5-methyl-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)- 1,2,4- oxadiazole;
4-(3-bromo-2- {2-[(2R)-2-methylpyrrolidin- 1 -yl]ethyl} - 1 -benzofuran-5- yl)benzonitrile;
4-(3-(2-furyl)-2- {2-[(2R)-2-methylpyrrolidin- 1 -yl]ethyl} - 1 -benzofuran-5- yl)benzonitrile;
4-[2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-3-(3-pyridinyl)-l-benzofuran-5- yl]benzonitrile;
4-[2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} -3-(3-thienyl)- 1 -benzofuran-5 - yl]benzonitrile;
4-(3-(2-formyl-3-thienyl)-2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)benzonitrile;
2-methyl-4-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)benzonitrile;
3-methyl-4-(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-5- yl)benzonitrile; 4-(6-methyl-2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl } - 1 -benzofuran-5- yl)benzonitrile
4-(4-methyl-2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)benzonitrile;
4-(7-methyl-2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)benzonitrile;
4-(7-fluoro-2- {2-[(2R)-2-methyl-l -pyrrolidinyl]ethyl} - 1 -benzofuran-5- yl)benzonitrile;
2-fluoro-4-(2- {2-[(2R)-2-methyl-l -pyrrolidinyl]ethyl} - 1 -benzofuran-5- yl)benzonitrile;
3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile;
(2R)- 1 - {2-[5-(4-fluorophenyl)- 1 -benzofuran-2-yl]ethyl} -2-methylpyrrolidine;
(2R)-l-{2-[5-(3 ,4-dichlorophenyl)- l-benzofuran-2-yl]ethyl} -2-methylpyrrolidine;
(2R)-2-methyl-l-{2-[5-(2-methylphenyl)-l -benzofuran-2 -yl]ethyl}pyrrolidine;
(2R)-2-methyl-l-{2-[5-(3-methylphenyl)-l -benzofuran-2 -yl]ethyl}pyrrolidine;
(2R)-2-methyl- 1 - {2-[5-(4-methylphenyl)- 1 -benzofuran-2 -yl]ethyl} pyrrolidine;
4-{2-[2-(2-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-benzoic acid methyl ester;
(2R)- 1 - {2-[5-(2-methoxyphenyl)- 1 -benzofuran-2 -yl]ethyl} -2-methylpyrrolidine;
(2R)-l-{2-[5-(3-methoxyphenyl)-l-benzofuran-2-yl]ethyl}-2-methylpyrrolidine;
(2R)-l-{2-[5-(4-methoxyphenyl)-l-benzofuran-2-yl]ethyl}-2-methylpyrrolidine;
(2R)-l-{2-[5-(3-fluorophenyl)-l -benzofuran-2 -yl]ethyl} -2-methylpyrrolidine;
(2R)- 1 - {2-[5-(2-chlorophenyl)- 1 -benzofuran-2 -yl]ethyl} -2-methylpyrrolidine;
(2R)-l-{2-[5-(3-chlorophenyl)-l-benzofuran-2-yl]ethyl}-2-methylpyrrolidine;
1 - {2-[5-(4-chlorophenyl)-benzofuran-2-yl]-ethyl} -2-methylpyrrolidine;
(2R)-2-methyl-l-(2-{5-[3-(trifluoromethyl)phenyl]-l-benzofuran-2- yl} ethyl )pyrrolidine;
(2R)-2-methyl- 1 -(2- { 5-[4-(trifluoromethyl)phenyl]- 1 -benzofuran-2- yl } ethyl )pyrrolidine;
(2R)-2-methyl-l-(2-{5-[3-(trifluoromethoxy)phenyl]-l-benzofuran-2- yl}ethyl)pyrrolidine;
(2R)-2 -methyl- 1 -(2- {5-[4-(trifluoromethoxy)phenyl]- 1 -benzofuran-2- yl } ethyl )pyrrolidine ; (2R)-l-{2-[5-(3,4-dimethylphenyl)-l-benzofuran-2-yl]ethyl}-2-methylpyrrolidine;
(2R)-l-{2-[5-(3,5-dichlorophenyl)-l-benzofuran-2-yl]ethyl} -2-methylpyrrolidine;
(2R)-l-{2-[5-(3,5-dimethylphenyl)-l-benzofuran-2-yl]ethyl}-2-methylpyrrolidine;
[4-(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)phenyl]methanol;
3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)pyridine;
(2R)- 1 -(2- {5-[ 2-(4-fluorophenyl)vinylj- 1 -benzofuran-2-yl} ethyl)-2- methylpyrrolidine;
1 -[3 -(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)phenyl]ethanone;
1 -[3 -(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)phenyl]ethanol;
2-[3 -(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)phenyl]-2- propanol;
1 -[3 -(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)phenyl]ethanone oxime;
1 -[3 -(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)phenyl]ethanone O-methyloxime;
1 -[3-(2- {2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -1 -benzofuran-5-yl)phenyl]ethanone O-ethyloxime;
1 -[3 -(2- {2-[(2R)-2 -methyl- 1 -pyrrolidinyljethyl} -1 -benzofuran-5-yl)phenyl]ethanone O-(tert-butyl)oxime; ethyl 3-(2-{2-[(2R)-2-methyl-l -pyrrolidinyljethyl}- l-benzofuran-5-yl)benzoate;
3-(2- {2-[(2R)-2 -methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)benzoic acid;
N-methoxy-N-methyl-3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)benzamide;
1 -[3 -(2- {2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -1 -benzofuran-5-yl)phenyl]-l- propanone; cyclopropyl[3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)pheny 1] methanone ;
3-methyl-l-[3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-y])phenylj- 1-butanone;
3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzaldehyde;
3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)phenyl](2- thienyl)methanone; (3-fluorophenyl)[3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)pheny 1 ] methanone ;
[3-(2- {2-[(2R)-2 -methyl- 1 -pyrrolidinyl]ethyl}-l -benzofuran-5-yl)phenyl]methanol;
(2R)- 1 -[2-(5-benzyl- 1 -benzofuran-2 -yl)ethyl]-2-methylpyrrolidine;
1 -(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)- 1 H-imidazole;
4-(3-bromo-2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)-2- methy lbenzonitrile ;
4-(3-chloro-2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)benzonitrile
4-(3,6-dichloro-2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-5 - yl)benzonitrile;
4-(3-iodo-2- {2-[(2R)-2 -methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)benzonitrile;
4-(2-{2-[(2R)-2-methyl-5-oxo-l-pyrrolidinyljethyl}-l-benzofuran-5-yl)benzonitrile;
4-(3-acetyl-2- {2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -1 -benzofuran-5- yl)benzonitrile; cyclopropyl[4-(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5- yl)phenyl ] methanone ;
3 ,5-dimethyl-4-(2- {2-[(2R)-2 -methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5 - yl)isoxazole;
4-[2-(2-aminoethyl)-l-benzofuran-5-yl]benzonitrile;
4-(2-{2-[(2R)-2-ethyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile;
4-(2- {2-[(2S)-2-(fluoromethyl)- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)benzonitrile;
4-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzothien-5-yl)benzonitrile;
4-(2- {2-[(2S)-2-methylpyrrolidinyl]ethyl} - 1 -benzofuran-5-yl)benzonitrile;
(2R)-2-methyl-l-[2-(5-phenoxy-l -benzofuran-2 -yl)ethyl]pyrrolidine;
(2R)- 1 -(2- {5-[(3-fluorophenyl)thio]-l -benzofuran-2-yl}ethyl)-2-methylpyrrolidine;
3-(2-{3-[(2R)-2-methyl-l-pyrrolidinyl]propyl}-l-benzofuran-5-yl)benzonitrile;
3-(2- { [(2R)-2-methyl- 1 -pyrrolidinyljmethyl} - 1 -benzofuran-5-yl)benzonitrile;
3-(2-{4-[(2R)-2-methyl-l-pyrrolidinyl]butyl}-l-benzofuran-5-yl)benzonitrile;
4-(4-{2-[2-(2S)-methyl-l-pyrrolidinyl)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine;
4-{4-methyl-2-oxo-3-[2-(2S)-methyl-l-pyrrolidinyl ethyl] -2H-chromen-6- yl}benzonitrile; 4-{4-methyl-2-oxo-3-[2-(2R)-methyl-l-pyrrolidinyl ethyl]-2H-chromen-6- yl} benzonitrile;
4-{[6-(2-{2-[(2S)-methylpyπOlidinyl]ethyl}-l-benzofuran-5-yl)-3- pyridinyl]carbonyl}moφholine;
4-(2- {2-[(2R)-2-methylpyrrolidinyl]ethyl} -2,3-dihydro- 1 -benzofuran-5 - yl)benzonitrile;
4-(2- {2-[(2S)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-4-yl)benzonitrile;
4- {2-[2-(2(S)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} -benzonitrile;
3-(2-{2-[(2S)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile;
4-(2- {2-[(2S)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)benzonitrile;
4-(2- {2-[(2S)-2-ethyl-l -pyrrolidinyljethyl} -1 -benzofuran-5-yl)benzonitrile;
4-(2- {2-[(2R)-2 -ethyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)benzonitrile;
4-(2- {2-[2-ethyl- 1 -pyrrolidinyljethyl} -1 -benzofuran-5-yl)benzonitrile;
4-(2-{2-[(2S,5S)-2,5-dimethylpyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile;
4-(2- {2-[(trans)-2,5-dimethylpyrrolidinyl]ethyl} -1 -benzofuran-5-yl)benzonitrile;
3,5-dimethyl-4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}- isoxazole;
5-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-2-phenyl-oxazole;
2-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethylj-benzofuran-5-yl}-thiazole;
4- {2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-l H-pyrazole;
4- {2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-l-phenyl-l H-pyrazole;
1 -methyl-4- {2-[(2R)-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H- imidazole;
4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-thiazole;
2- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H-imidazole;
4- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H-benzoimidazole;
3-methyl-6-{(2R)-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-pyridazine;
2- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl-ethyl]-benzofuran-5-yl} -pyrazine;
5- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl-ethyl]-benzofuran-5-yl} -pyrimidine;
5-{2-[2-(2R)-methyl-pyrrolidin-l-yl-ethyl]-benzofuran-5-yl}-pyridazin-4-ylamine;
5-{2-[2-(2R)-methyl-pyrrolidin-l-yl-ethyl]-benzofuran-5-yl}-nicotinonitrile;
4-{2-[2-(2R)-methyl-pyrrolidin-l-yl-ethyl]-benzofuran-5-yl}-lH-indole; 4- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl-ethyl]-benzofuran-5-yl} -phthalonitrile;
5- {2-[2-(2R)-methyl-pyrrolidin-l -yl-ethyl] -benzofuran-5 -yl} -indan-1 -one; l-{2-[5-(5,6-dihydro-2H-pyran-3-yl-benzofuran-2-ylj-ethyl}-(2R)-methyl- pyrrolidine;
1 -[2-(5-cyclohept- 1 -enyl-benzofuran-2-yl)-ethyl]-2R)-methyl-pyrrolidine;
(2R)-methyl- 1 -(2- {5-[2-(l 1 H- 10-thia-dibenzo[a,d]cyclohepten-5-ylidene)-ethyl]- benzofuran-2-yl}-ethyl)-pyrrolidine;
4- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} -pyridine;
3,5-dimethyl-4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethylj-benzofuran-4-yl}- isoxazole;
5- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-4-yl} -2-phenyl-oxazole;
2-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-thiazole;
4- {2-[2-(2R)-mefhyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-4-yl} - 1 H-pyrazole;
4- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-4-yl} - 1 -phenyl- 1 H-pyrazole; 1 -methyl-4- {2-[(2R)-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-4-yl } - 1 H- imidazole;
4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-thiazole;
2-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-lH-imidazole;
4- {2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-l H-benzoimidazole;
3-methyl-6-{(2R)-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-pyridazine;
2-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-pyrazine;
5- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-4-yl} -pyrimidine; 5-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-pyridazin-4-ylamine; 5-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-nicotinonitrile;
4- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl)-ethylj-benzofuran-4-yl} - 1 H-indole;
4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-phthalonitrile;
5-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-indan-l-one;
1 - {2-[4-(5,6-dihydro-2H-pyran-3-yl)-benzofuran-2-yl]-ethyl} -(2R)-methyl- pyrrolidine; l-[2-(4-cyclohept-l-enyl-benzofuran-2-yl)-ethyl]-(2R)-methyl-pyrrolidine;
(2R)-methyl-l-(2-{4-[2-(l lH-10-thia-dibenzo[a,d]cyclohepten-5-ylidene)-ethylj- benzofuran-2-yl}-ethyl)-pyrrolidine; 4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-pyridine;
3 ,5-dimethyl-4- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} - isoxazole;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-2-phenyl-oxazole;
2- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} -thiazole;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-lH-pyrazole;
4- { 2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl } - 1 -phenyl- 1 H-pyrazole;
1 -methyl-4- {2-[2(R)-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} - 1 H- imidazole;
4- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} -thiazole;
2- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} - 1 H-imidazole;
4- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} - 1 H-benzoimidazole;
3-methyl-6-{2(R)-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-pyridazine;
2-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-pyrazine;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-pyrimidine;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-pyridazin-4-ylamine;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-nicotinonitrile;
4- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} - 1 H-indole;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-phthalonitrile;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-indan-l-one; l-{2-[6-(5,6-dihydro-2H-pyran-3-yl)-benzofuran-2-yl]-ethyl}-2(R)-methyl- pyrrolidine;
1 -[2-(6-cyclohept- 1 -enyl-benzofuran-2-yl)-ethyl]-2(R)-methyl-pyrrolidine;
2(R)-methyl-l-(2-{6-[2-(l lH-10-thia-dibenzo[a,d]cyclohepten-5-ylidene)-ethylj- benzofuran-2-yl}-ethyl)-pyrrolidine;
4- {2-[2-(2(R)-methyl-pyrrolidin-l -yl)-ethyl]-benzofuran-6-yl} -pyridine;
3 ,5-dimethyl-4- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl j-benzofuran-7-yl} - isoxazole;
5- {2-[2-(2(R)-methyl-pyrrolidin-l -yl)-ethyl]-benzofuran-7-yl} -2-phenyl-oxazole; 2-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-thiazole;
4- {2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-l H-pyrazole;
4- { 2- [2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-7-yl } - 1 -phenyl- 1 H-pyrazole; 1 -methyl-4- {2-[2(R)-(2-methyl-pyrrolidin-l -yl)-ethyl]-benzofuran-7-yl}-l H- imidazole;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-thiazole;
2- {2-[2-(2(R)-methyl-pyrrolidin-l -yl)-ethyl]-benzofuran-7-yl} -1 H-imidazole;
4- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-7-yl} - 1 H-benzoimidazole;
3-methyl-6-{2(R)-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-pyridazine;
2-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-pyrazine;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-pyrimidine;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethylj-benzofuran-7-yl}-pyridazin-4-ylamine;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-nicotinonitrile;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-lH-indole;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-phthalonitrile;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-indan-l-one; l-{2-[7-(5,6-dihydro-2H-pyran-3-yl)-benzofuran-2-yl]-ethyl}-2(R)-methyl- pyrrolidine;
1 -[2-(7-cyclohept- 1 -enyl-benzofuran-2-yl)-ethyl]-2(R)-methyl-pyrrolidine;
2(R)-methyl-l-(2-{7-[2-(l lH-10-thia-dibenzo[a,d]cyclohepten-5-ylidene)-ethylj- benzofuran-2-yl}-ethyl)-pyrrolidine;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-pyridine; l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-lH-imidazole-4,5- dicarbonitrile;
4,5-dichloro- 1 - {2-[2-(2(R)-methylpyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H- imidazole; l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-lH-benzoimidazole;
3-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-3H-imidazo[4,5- cjpyridine;
(5-hydroxymethyl-3-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-3H- imidazol-4-yl)-methanol; l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-lH-pyrrole;
1 -( 1 - {2-[2-(2(R)-methylpyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H-pyrrol-3-yl)- ethanone;
3-methyl- 1 - {2-[2-(2(R)-methylpyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} -1 H-pyrrole; l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-3,4-bis- trifluoromethyl- 1 H-pyrrole;
1 - {2-[2-(2(R)-methylpyrrolidin-l -yl)-ethyl]-benzofuran-5-yl}-l H-pyrazole;
4-methyl- 1 - {2-[2-(2(R)-methylpyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H-pyrazole;
1 - {2-[2-(2(R)-methylpyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H-pyrazole-4- carboxylic acid ethyl ester;
1 - {2-[2-(2(R)-methylpyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H-pyrazole-4- carbonitrile;
4-chloro-l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-lH-pyrazole;
3,5-dimethyl-l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-lH- pyrazole;
(4-methoxy-phenyl)-methyl- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-5- yl} -amine; benzo[l,3]dioxol-5-yl-methyl-{2-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5- yl} -amine; cyclohexyl-methyl-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}- amine; and
{ 2 - [2-(2(R)-methyl-pyrrol idin- 1 -yl)-ethyl] -benzofuran-5 -yl } -(tetrahydro-pyran-4-yl)- amine.
Determination of Biological Activity.
To determine the effectiveness of representative compounds of this invention as histamine-3 receptor ligands (H3 receptor ligands), the following tests were conducted according to methods previously described (European Journal of Pharmacology, 188:219-227 (1990); Journal of Pharmacology and Experimental Therapeutics, 275: 598-604 (1995); Journal of Pharmacology and Experimental Therapeutics, 276:1009-1015 (1996); and Biochemical Pharmacology, 22: 3099-3108 (1973)).
Briefly, male Sprague-Dawley rat brain cortices were homogenized (1 g tissue/10 mL buffer) in 50 mM Tris-HCl/5 mM EDTA containing protease inhibitor cocktail (Calbiochem) using a polytron set at 20,500 φm. Homogenates were centrifuged for 20 minutes at 40,000χg. The supernatant was decanted, and pellets were weighed. The pellet was resuspended by polytron homogenization in 40 mL 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and centrifuged for 20 minutes at 40,000xg. The membrane pellet was resuspended in 6.25 volumes (per gram wet weight of pellet) of 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and aliquots flash frozen in liquid N2 and stored at -70 °C until used in assays. Rat cortical membranes (12 mg wet weight/tube) were incubated with (3H)-N-α-methylhistamine (-0.6 nM) with or without H3 receptor antagonists in a total incubation volume of 0.5 mL of 50 mM Tris-HCl/5 mM EDTA (pH 1.1). Test compounds were dissolved in DMSO to provide a 20 mM solution, serially diluted and then added to the incubation mixtures prior to initiating the incubation assay by addition of the membranes. Thioperamide (3 μM) was used to determine nonspecific binding. Binding incubations were conducted for 30 minutes at 25 °C and terminated by addition of 2 mL of ice cold 50 mM Tris-HCl (pH 1.1) and filtration through 0.3% polyethylenimine-soaked Unifilter plates (Packard). These filters were washed 4 additional times with 2 mL of ice-cold 50 mM Tris- HCl and dried for 1 hour. Radioactivity was determined using liquid scintillation counting techniques. Results were analyzed by Hill transformation and Ki values were determined using the Cheng-Prusoff equation.
Table 1
As shown by the data in Table 1, the compounds of the present invention bind to the histamine-3 receptors and therefore may have utility in the treatment of diseases or conditions ameliorated with histamine-3 receptor ligands.
Compounds of the present invention are histamine-3 receptor ligands that modulate function of the histamine-3 receptor by antagonizing the activity of the receptor. These compounds may be inverse agonists that inhibit the basal activity of the receptor or they may be antagonists that completely block the action of receptor-activating agonists. These compounds may also be partial agonists that partially block or partially activate the histamine-3 receptor receptor or they may be agonists that activate the receptor.
Abbreviations Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: Ac for acetyl; DCM for dichloromethane; DMF for N,N- dimethylformamide; DMSO for dimethylsulfoxide; EtOAc for ethyl acetate; HPLC for high pressure liquid chromatography; Me for methyl; NMP for l-methyl-2-pyrrolidinone; i-Pr for isopropyl; TFA for trifluoroacetic acid; TosCl for p-toluenesufonyl chloride; TBDMS for tert-butyldimethylsilyl; TLC for thin layer chromatography; THF for tetrahydrofuran; TMEDA for N, N, N', N'-tetramethylethylenediamine; and p-TSA for para-toluenesulfonic acid.
Preparations of Compounds of The Present Invention The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds can be prepared.
The compounds of this invention can be prepared by a variety of synthetic procedures.
Representative procedures are shown in, but are not limited to, Schemes 1-12.
Scheme 1
Benzofurans of general formula (5), wherein L, Ri, R2, R3, Rt, R5, Re and R are as defined in formula (I), may be prepared as described in Scheme I. Phenols of general formula (1) may be treated with sodium hypochlorite, sodium iodide and sodium hydroxide in a solvent such as methanol to provide iodides of general formula (2). Iodides of general formula (2) may be treated with substituted propargyl alcohols, dichlorobis(triphenylphosphine)palladium, copper iodide, a base such as triethylamine in a solvent such as DMF with heat to provide benzofurans of general formula (3). Alcohols of general formula (3) may be treated with methanesulfonyl chloride or methanesulfonyl anhydride, a base such as triethylamine, diisopropylethylamine or N-methylmoφholine in a solvent such as dichloromethane or THF to provide mesylates of general formula (4). Mesylates of general formula (4) may be treated with secondary or primary amines in solvents such as DMF or THF with heat to provide amines of general formula (5). Alternatively mesylates of general formula (4) may be treated with secondary or primary amine hydrochlorides in the presence of a base such as triethylamine, diisopropylethylamime or N-methylmoφholine in a solvent such as DMF or THF with heat to provide benzofurans of general formula (5). Scheme 2
Benzofurans of general formula (10), wherein L, Ri, R2, R3, R-i, R5, R7, Rg, R , X, Y and Z are as defined in formula (II), may be prepared as described in Scheme 2. Halides of general formula (6) may be treated with boronic acids of general formula (7), under Suzuki conditions such as tetrakis(triphenylphosphine)palladium, a base such as aqueous sodium carbonate in a solvent such as toluene with heat to provide tert-butyldimethylsilyl protected alcohols of general formula (8). Protected alcohols of general formula (8) may be treated with tetrabutylammonium fluoride in a solvent such as THF to provide phenols of general formula (9). Phenols of general formula (9) may be treated using conditions as described in Scheme 1 to provide benzofurans of general formula (10).
Scheme 3
Benzofurans of general formula (12), wherein L, Ri, R2, R3, R , R5, Re, X, Y, Z, Rg, and R9 are as defined in formula (III), may be prepared as described in Scheme 3. Boronic acids of general formula (11) may be treated with halides as described in Scheme 2 to provide compounds of general formula (11a). Compounds of general formula (11a) may be treated with tetra-butylammonium fluoride and then as described in Scheme 1 and Scheme 2 to provide benzofurans of general formula (12).
Scheme 4
Chromenes of general formula (19), wherein L, Ri, R2, R3, Rt, R5, R7, R8, R9, X, Y and Z are as defined by formula (II), may be prepared as described in Scheme 4. Boronic acids of general formula (13) may be treated with halides of general formula (6), tetrakis(triphenylphosphine)palladium, a base such as aqueous sodium carbonate in a solvent such as toluene with heat to provide compounds of general formula (14). Compounds of general formula (14) may be treated with n-butyl lithium, N, N, N', N'- tetramethylethylenediamine followed by DMF or acetyl chloride to provide compounds of general formula (15) which may be treated with [2-(dimethylamino)-2-oxoethyl]lithium in a solvent such as THF to provide compounds of general formula (16). Compounds of general formula (16) may be treated with acetic acid with heat to provide chromenes of general formula (17). Chromenes of general formula (17) may be treated with butyl lithium, N, N, N', N'-tetramethylethylenediamine followed by ethylene oxide or trimethylene oxide to provide alcohols of general formula (18). Alternatively (17) may be treated with butyl lithium, N, N, N', N'-tetrarnethylethylenediamine and (2-bromoethoxy) tert- butyldimethylsilane followed by tetrabutylammonium fluoride deprotection to provide alcohols of general formula (18). Alcohols of general formula (18) may be converted to the respective mesylate and further reacted with amines as described in scheme 1 to provide chromenes of general formula (19).
Alternatively chromenes of general formula (24) wherein L, Rls R2, R3, R4, R5, R7, R8 and R are as defined in formula (II), may be prepared as described in scheme 5. Compound of general structure (21) may be prepared from Scheme 4 by substituting compound of general structure (20) for compound of general formula (14). Compound of general formula (20) may be treated with n-butyl lithium followed by DMF or acetyl chloride to provide compounds of general formula (20a). Compounds of general formula (20a) may be treated with [2-(dimethylamino)-2-oxoethyl]lifhium followed by acetic acid and heat to provide chromenes of general formula (21). Chromenes of general formula (21) may be treated with n-butyl lithium, N, N, N', N'-tetramethylethylenediamine followed by ethylene oxide or trimethylene oxide to provide alcohols which may be treated with methanesulfonyl chloride, a base such as triethylamine, diisopropylethylamine or N-methylmoφholine in a solvent such as dichloromethane or THF to provide mesylates which may be treated with secondary or primary amines in solvents such as DMF or THF with heat to provide amines of general formula (22). Amines of general formula (22) may be treated with tetrabutylammonium fluoride followed by treatment with triflic anhydride, pyridine and boronic acids of general formula (23), dichlorobis(triphenylphosphine)palladium, cesium carbonate in a solvent such as DMF with heat to provide compound of general formula (24).
Scheme 6
amines
Scheme 4
Alternatively chromenes of general structure (28), wherein Ri, R2, R3, R4, R5, R^ and R7 are as defined by formula (III), may be prepared as described in Scheme 6. Phenols of general formula (25) may be treated with compounds of general formula (26) and hydrobromic acid in acetic acid with heat to provide compounds of general formula (27), which may be treated with amines as described in Scheme 4 to provide chromenes of general formula (28).
Scheme 7
Chromenes of general formula (30) wherein L, Ri, R2, R3, R4, R5, R-, Rs, R9, X, Y and Z are as defined in formula (III), may be prepared as described in Scheme 7. Boronic acids of general formula (29) may be treated as described in Scheme 4 to provide Chromenes of general formula (30).
Scheme 8
Compounds of general formula (36) wherein L, R\, R2, R3, R4, R5, R7, R8, R9, X, Y, and Z are as defined in formula (IV), may be prepared as described in Scheme 8. Iodides of general structure (31) may be treated with 5 -substituted- 1-methoxypentadienes and palladium acetate with heat to provide dihydrofurans of general structure (32), which may be treated with para-toluenesulfonic acid in aqueous acetone with heat to provide compounds of general formula (33). The reduction of compound of general structure (33) using sodium borohydride in solvents such as methanol may provide alcohols of general formula (34). Alcohols of general formula (34) may be treated with methanesulfonyl chloride with bases such as triethylamine, diisopropylethylamine or N-methylmoφholine in solvents such as dichloromethane or THF to provide mesylates of general formula (35). Mesylates of general formula (35) may be treated with secondary or primary amines in a solvent such as DMF or THF with heat to provide amines of general formula (36). Scheme 9
Dihydrofurans of general formula (38) wherein Ri, R2, R3, i, R5, Re, R_, R9, X, Y and Z are as defined in formula (IV), may be prepared as described in Scheme 9. Iodides of general formula (37) may be treated as described in Scheme 8 to provide dihydrofurans of general formula (38).
Scheme 10
Benzothiophenes of general formula (43) wherein L, R\, R2, R3, R», R5, R7, R8, R9, X, Y and Z are defined in formula (I), may be prepared as described in Scheme 10. Compounds of general formula (39) may be treated with poly-phosphoric acid with heat to provide benzothiophenes of general formula (40). Benzothiophenes of general formula (40) may be treated with boronic acids, tetrakis(triphenylphosphine)palladium, a base such as aqueous sodium carbonate in a solvent such as toluene with heat to provide compounds of general formula (41). Compounds of general formula (41) may be treated with n-butyl lithium, N, N, N', N'-tetramethylethylenediamine followed by ethylene oxide to provide alcohols of general formula (42). Alcohols of general formula (42) may be converted to the mesylate and then further treated with amines as described in Scheme 1 to provide benzothiophenes of general formula (43).
Scheme 11
Benzothiophenes of general formula (45) wherein Ri, R2, R3, R4, R5, Re, Rg, R9 and X, Y and Z are defined in formula (I), may be prepared as described in Scheme 1 1. Compounds of general formula (44) may be processed as described in Scheme 10 to provide compounds of general formula (45).
Scheme 12
Benzofurans of general formula (49) wherein R\, R2, R3, R , R5, Re, and R are as defined in formula (I), may be prepared as described in Scheme 12. Primary and secondary amines may be treated with a base such as potassium carbonate (325 mesh powdered) and an alkyne of general formula (47) wherein X=C1, Br, I, OS(O)2CH3 or OTs to provide alkynes of general formula (48). Alkynes of general formula (48) may be treated with a phenol of general formula (2), a palladium catalyst such as palladium(II) acetate, a triarylphoshine such as triphenylphoshine or tris(2-mefhylphenyl)phosphine, copper iodide, and a base such as diisopropylamine in a solvent such as acetonitrile followed by heat to provide benzofurans of general formula (49).
The compounds and processes of the present invention will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.
EXAMPLES
Example 1 4-(2-{2-f(2R)-2-methyl-l -pyrrolidinyljethyl}- l-benzofuran-5-yl)benzonitrile
Example 1A 4'-hvdroxy-3'-iodor 1 , 1 '-biphenyl1-4-carbonitrile To a solution of 4-hydroxy-4'-cyanobiphenyl (6.00 g, 30.8 mmol), sodium iodide (4.61 g, 30.8 mmol) and sodium hydroxide (1.23 g, 30.8 mmol) in methanol (90 mL) at 0 °C was added an aqueous solution of sodium hypochlorite (47 mL of 5.25% Clorox™, 2.29 g, 30.8 mmol) over 45 minutes. The mixture was stirred cold for 1 hour, warmed to ambient temperature and diluted with sodium thiosulfate solution (10 mL), water (80 mL) and adjusted to a pH of 7 by addition of sodium dihydrogen phosphate. The mixture was extracted with dichloromethane (2 x 90 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated under reduced pressure to give a white powder. The solid was crystallized from dichloroethane/hexane and chromatographed on silica with dichloromethane to give the titled compound (5.19 g, 53%). MS (DCI) m/z 339[M+NH4+]+.
Example IB 4-[2-(2-hvdroxyethylH-benzofuran-5-yl]benzonitrile To a solution of Example 1A (5.19 g, 16.2 mmol), triethylamine (5.60 mL, 40.4 mmol) and 3-butyn-l-ol (1.90 g, 27.2 mmol) in dimethylformamide (13 mL) at 20 °C was added cuprous iodide (0.46 g, 2.4 mmol) and bis-triphenylphosphine palladium dichloride (0.56 g, 0.80 mmol). The mixture was stirred at 65 °C for 12 hours then cooled to ambient temperature and diluted with dichloromethane (20 mL) and hexane (100 mL). Celite (5 g) was added with stirring and the solids were removed by filtration. The filtrate was washed with water (600 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (3 x 100 mL). The combined organic solution was dried (Na2SO ), filtered and concentrated under reduced pressure to give a tan solid. The solid was chromatographed on silica with 3% methanol in dichloromethane to give the titled compound (4.02 g, 95%). MS (DCI) m/z 263 (M+H)+.
Example IC 2-|"5-(4-cvanophenvD- 1 -benzofuran-2 -yl]ethyl methanesulfonate To a solution of Example IB (0.57 g, 2.2 mmol) and triethylamine (0.9 mL, 6.5 mmol) in dichloromethane (10 mL) at 20 °C was added methane sulfonyl chloride (0.79 g, 4.5 mmol). The mixture was stirred for 30 min., diluted with dichloromethane, washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was chromatographed on silica with dichloromethane to give the titled compound (0.66 g, 89%). MS (DCI) m/z 359 (M+H)+.
Example ID 4-(2- |2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl) - 1 -benzofuran-5-yl benzonitrile A suspension of Example IC (0.19 g, 0.55 mmol), (2R)-2-methylpyrrolidine hydrobromide (0.17 g, 1.0 mmol) and sodium carbonate (0.23 g, 2.2 mmol) in acetonitrile (0.4 mL) was heated to 50 °C with stirring for 48 hours. The reaction was cooled to ambient temperature, diluted with acetonitrile and centrifuged. The supernatant liquid was removed and the solids washed with acetonitrile. The combined liquids were concentrated under reduced pressure and the residue chromatographed by reverse phase HPLC with aqueous CF3CO2H/ acetonitrile to give the titled compound (0.065 g, 34%). Η NMR (300 MHz, CD3OD) 87.88 (m, IH), 7.71 (m, 4H), 7.50 (m, 2H), 6.82 (s, IH), 3.72-3.9 (m, 2H), 3.58 (m, IH), 3.25-3.5 (m, 4H), 2.48 (m, IH), 2.05-2.2 (m, 2H), 1.75 (m, IH), 1.50 (d, J=6Hz, 3H); MS (DCI) m/z 331 (M+H)+.
Example 2 4- {2-r2-(l -pyrrolidinyDethyl]- 1 -benzofuran-5-yl} benzonitrile The product from Example IC and pyrrolidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 87.7 (m: 5H), 7.50 (d, J=8.7 Hz, IH), 7.42 (dd, J=8.7, 1.5 Hz, IH), 6.51 (s, IH), 3.1 (m 2H), 2.95 (m, 2H), 2.65 (m, 4H), 1.9 (m, 4H); MS (DCI) m/z 317 (M+H)+.
Example 3 4-{2-[2-(2-methyl-l-pyrrolidinyl)ethyl]-l-benzofuran-5-yl}benzonitrile The product from Example 1 C and 2-methyl-pyrrolidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.88 (m, IH), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, IH), 3.8-3.9 (m, 2H), 3.58 (m, IH), 3.25-3.5 (m, 4H), 2.48 (m, IH), 2.05-2.2 (m, 2H), 1.75 (m, IH), 1.50 (d, 3H, J=6 Hz); MS (DCI) m/z 331 (M+H)+.
Example 4 4-(2-[2-(l-piperidinyl)ethyll-l-benzofuran-5-yl}benzonitrile The product from Example IC and piperidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.88 (m, IH), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, IH), 3.65 (m, 2H), 3.55 (m, 2H), 3.33 (m, 2H), 3.05 (m, 2H), 2.0 (m, 2H), 1.5-1.9 (m, 4H); MS (DCI) m/z 331 (M+H)\
Example 5 4-(2- 2-(diethylamino)ethvn-l-benzofuran-5-v benzonitrile The product from Example 1 C and diethylamine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.75 (m, IH), 7.80 (m, 4H), 7.60 (m, 2H), 6.85 (s, IH), 3.6 (t, J=7.5 Hz, 2H), 3.25-3.5 (m, 6H), (t, 6H, J=6.6 Hz); MS (DCI) m/z 319 (M+H)+.
Example 6 4-(2-[2-(2-methyl-l-piperidinyl)ethyll-l-benzofuran-5-yl}benzonitrile The product from Example IC and 2-methylpiperidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.88 (m, IH), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, IH), 3.1-3.8 (m, 7H), 1.6-2.1 (m, 6H), 1.45 (d, 3H, J=6 Hz); MS (DCI) m/z 345 (M+H)+. Example 7 4-(2-{2-[('3R)-3-hvdroxypyrrolidinyl1ethyl}-l-benzofuran-5-yl)benzonitrile The product from Example IC and 3-(R)-hydroxypyrrolidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.88 (m, IH), 7.80 (m, 4H), 7.60 (m, 2H), 6.80 (s, IH), 4.55 (bs, IH), 3.8-3.9 (m, 4H), 3.25-3.5 (m, 4H), 2.05-2.4 (m, 2H); MS (DCI) m/z 333 (M+H)+.
Example 8 4-{2- 2-(lH-imidazol-l-yl)ethyl]-l-benzofuran-5-yllbenzonitrile The product from Example IC and imidazole were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 8.88 (s, IH), 7.88 (m, IH), 7.80 (m, 5H), 7.60 (m, 4H), 6.75 (s, IH), 4.1 (t, J=6.3 Hz, 2H), 3.5 (t, J=6.3 Hz, 2H); MS (DCI) m/z 314 (M+H)+.
Example 9 4-(2-(2-[(3S)-3-(dimethylamino)pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile The product from Example IC and 3-(S)-(dimethylamino)pyrrolidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.88 (m, IH), 7.80 (m, 4H), 7.58 (m, 2H), 6.80 (s, IH), 4.43 (m, IH), 3.6-3.9 (m, 4H), 3.35- 3.45 (m, 4H), 2.95 (s, 6H), 2.6 (m, IH), 2.35 (m, IH); MS (DCI) m/z 360 (M+H)+.
Example 10 4-(2-{2-r(2S)-2-(hvdroxymethyl)pyrrolidinyl1ethyl}-l-benzofuran-5-yl)benzonitrile The product from Example 1 C and 2-(S)-(hydroxymethyl)pyrrolidine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 347 (M+H)+.
Example 11 4-(2-{2- -2,6-dimethylpiperidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile The product from Example IC and -dimethylpiperidine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 360 (M+H)+.
Example 12 4-(2-{2-r(2R.5R)-2.5-dimethylpyrrolidinyl1ethvU-l-benzofuran-5-yl)benzonitrile The product from Example IC and (2R,5R)-dimethylpyrrolidine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 345 (M+H)+.
Example 13 4- (2-[2-f 1 -azepanvDethyl]- 1 -benzofuran-5 -yl} benzonitrile The product from Example IC and azepine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 345 (M+H)+.
Example 14 4-|2-[2-(4-methyl-l-piperidinyl)ethyl]-l-benzofuran-5-yl}benzonitrile The product from Example IC and 4-methylpiperidine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 345 (M+H)+.
Example 15 4-(2-(2-r2-pyrrolidine methyl carboxylatelethyl}-l-benzofuran-5-yl)benzonitrile The product from Example IC and (L)-proline methyl ester were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 375 (M+H)+.
Example 16 4-(2- 2-(3.6-dihvdro-l(2H)-pyridinyl)ethyl]-l-benzofuran-5-yl}benzonitrile The product from Example IC and 1,2,3,6-tetrahydropyridine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 329 (M+H)+.
Example 17 4-(2-{2-f(2R)-2-(hvdroxymethyl)pyrrolidinyl1ethyl}-l-benzofuran-5-yl)benzonitrile The product from Example IC and (D)-prolinol were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.87 (m, IH), 7.82 (m, 4H), 7.58 (m, 2H), 6.80 (s, IH), 3.95 (m, 2H), 3.72 (m, 2H), 3.58 (m, IH), 3.35-3.4 (m, 4H), 1.95-2.3 (m, 4H); MS (DCI) m/z 347 (M+H)+.
Example 18 4-(2-f2-rtert-butyl(methyl aminolethyl}-l-benzofuran-5-yl)benzonitrile The product from Example IC and tert-butyl(methyl)amine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 333 (M+H)+.
Example 19 4-(2-{2-[isopropyl(methyl)aminolethyl. -l-benzofuran-5-yl)benzonitrile The product from Example IC and isopropyl(methyl)amine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 319 (M+H)+.
Example 20 4-(2-{2- isobutyl(methyl)amino]ethyl}-l-benzofuran-5-yl)benzonitrile The product from Example 1 C and isobutyl(methyl)amine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 333 (M+H)+.
Example 21 4-(2-(2-rethyl(isopropyl)amino]ethyl}-l-benzofuran-5-yl)benzonitrile The product from Example IC and ethyl(isopropyl)amine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 333 (M+H)+.
Example 22 4-(2- j2-rethyl(propyl)amino]ethvU - 1 -benzofuran-5-yl)benzonitrile The product from Example IC and ethyl (propyl)amine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 333 (M+H)+.
Example 23 4-C4- .2-[2-(2 -methyl- 1 -pyrrolidinvDethyll- 1 -benzofuran-5 -yl}benzoyl)moφholine
Example 23A 4'-(4-moφholinylcarbonyl)[l. -biphenyl]-4-ol To a solution of 4-hydroxy-biphenyl-4'-carboxylic acid (5.35 g, 25.0 mmol), moφholine (2.39 g, 27.5 mmol) and triethylamine (3.5 mL, 25 mmol) in dichloromethane (100 mL) was added l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The mixture was stirred for 16 hours, diluted with aqueous NaH2PO4 and filtered. The solid was washed with 1 :2 diethyl ether/water (100 mL) then with water (400 mL). The solid was dried in vacuo to give the titled compound (5.89 g, 83%). MS (DCI) m/z 284 (M+H)+.
Example 23B 3-iodo-4'-(4-moφholinylcarbonyl)r 1.1 '-biphenyll-4-ol The product from Example 23 A was processed as described in Example 1 A to provide the titled compound. MS (DCI) m/z 410 (M+H)+.
Example 23 C 2-{5- 4-(4-moφholinylcarbonyl)phenyl]-l-benzofuran-2-yl}ethanol The product from Example 23 B was processed as described in Example IB to provide the titled compound. MS (DCI) m/z 352 (M+H)+.
Example 23 D 2-|5-r4-(4-moφholinylcarbonyl)phenyl1-l-benzofuran-2-v ethyl methanesulfonate The product from Example 23C was processed as described in Example IC to provide the titled compound.
Example 23E 4-(4-{2- 2-(2-methyl-l-pyrrolidinyl)ethyll-l-benzofuran-5-yl}benzoyl)moφholine The product from Example 23 D and 2-methyl-pyrrolidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, άVmethanol) δ 7.83 (m, IH), 7.74 (d, J=8.4 Hz, 2H), 7.57 (m, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.80 (s, IH), 3.2-3.9 (m, 7H), 2.35 (m, IH), 2.10 (m, 2H), 1.76 (m, IH), 1.48 (d, J=7.2 Hz, 3H); MS (DCI) m/z 419 (M+H)+.
Example 24 4-(4-{2- 2-(l-piperidinyl)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine The product from Example 23 D and piperidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.82 (m, IH), 7.73 (d, J=8.1 , 2H), 7.54 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.77(s, IH), 3.32-3.8 (m, 14H), 3.07 (m, 2H), 1.5-2.1 (m, 6H); MS (DCI) m/z 419 (M+H)+. Example 25 N.N-diethyl-N-(2- ( 5 -f 4-(4-morpholinylcarbonyl)phenvπ- 1 -benzofuran-2-yl } ethyllamine The product from Example 23D and diethylamine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.82 (m, IH), 7.74 (d, J=8.1, 2H), 7.54 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.80(s, IH), 3.32-3.8 (m, 16H), 1.38 (t, J=7.5Hz, 6H); MS (DCI) m/z 407 (M+H)+.
Example 26 4-(4- {2- 2-(2-methyl- 1 -piperidinvDethyl]- 1 -benzofuran-5-yl}benzoyl)moφholine The product from Example 23D and 2-methyl-piperidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.82 (m, IH), 7.74 (d, J=8.1 , 2H), 7.56 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.80 (s, IH), 3.4-3.78 (m, 15H), 1.6-2.1 (m, 6H), 1.46 (d, J=6.3 Hz, 3H); MS (DCI) m/z 433 (M+H)+.
Example 27 (3R)-l-(2-|5- 4-(4-moφholinylcarbonyl)phenyl]-l -benzofuran-2 -yl}ethyl)-3-pyrrolidinol The product from Example 23D and 3-(R)-pyrrolidinol were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.82 (m, IH), 7.73 (d, J=8.1 Hz, 2H), 7.55 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.78 (s, IH), 3.35-3.8 (m, 17H), 2.3-2.4 (m, 2H); MS (DCI) m/z 421 (M+H)+.
Example 28 4-[4-(2- {2-[(2R,5R)-2.5-dimethylpyrrolidinyl]ethyll -1 -benzofuran-5-yl benzoyl]moφholine
The product from Example 23D and (2R,5R)-dimethylpyrrolidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.82 (m, IH), 7.76 (d, J=8.1, 2H), 7.56 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.81 (s, IH), 3.3- 3.8 (m, 14H), 1.6-2.1 (m, 4H), 1.50 (d, J=6.6 Hz, 3H), 1.38 (d, J=6.6 Hz, 3H); MS (DCI) m/z 433 (M+H)+.
Example 29 4-[4-(2-{2-[-2.6-dimethylpiperidinyl]ethyl}-l-benzofuran-5-yl)benzoyllmorpholine The product from Example 23D and -dimethylpiperidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.82 (m, IH), 7.74 (d, J=8.1 , 2H), 7.56 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.80 (s, IH), 3.45-3.85 (m, 14H), 1.6-2.1 (m, 6H), 1.48 (d, J=6.3 Hz, 6H); MS (DCI) m/z 446 (M+H)+.
Example 30 4-(4-{2- 2-(azepanyl)ethyll-l-benzofuran-5-yl}benzoyl)moφholine The product from Example 23D and azepane were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.82 (m, IH), 7.73 (d, J=8.1, 2H), 7.56 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.77(s, IH), 3.3-3.8 (m, 16H), 1.6-2.1 (m, 8H); MS (DCI) m/z 433 (M+H)+.
Example 31 4-(4- .2-r2-(4-methyl- 1 -piperidinvDethyll- 1 -benzofuran-5-yl}benzoyl)moφholine The product from Example 23D and 4-methyl piperidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 8 7.82 (m, IH), 7.75 (d, J=8.1 , 2H), 7.58 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.76 (s, IH), 3.35-3.8 (m, 14H), 3.05 (m, 2H), 2.00 (m, 2H), 1.75 (m, IH), 1.49 (m, 2H), 1.05 (d, J=6.6 Hz, 3H); MS (DCI) m/z 433 (M+H)+.
Example 32 4-(4-(2-r2-(4-moφholine)ethyl]-l-benzofuran-5-yl}benzoyl')moφholine The product from Example 23D and moφholine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.82 (m, IH), 7.75 (d, J=8.1 , 2H), 7.58 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.80 (s, IH), 3.32-3.8 (m, 16H), 3.37 (t, J=7.5 Hz, 4H); MS (DCI) m/z 421 (M+H)+.
Example 33 4-(4-(2-r2-(3,6-dihvdro-l(2H)-pyridinyl ethyl]-l-benzofuran-5-yl}benzoyl)moφholine The product from Example 23D and 1,2,3,6-tetrahydropyridine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 87.83 (m, I H), 7.74 (d, J=8.1 , 2H), 7.58 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.80 (s, IH), 6.05 (m, IH), 5.79 (m, 2H), 3.4-3.8 (m, 12H), 3.41 (t, J=7.5 Hz, 4H), 2.5 (m, 2H); MS (DCI) m/z 416 (M+H)+.
Example 34 4-(4-{2- 2-(2S)-pyrrolidinylmethanoπethvn-l-benzofuran-5-yl}benzoyl moφholine The product from Example 23D and 2-(S)-(hydroxymethyl)pyrrolidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 8 7.81 (m, IH), 7.73 (m, 2H), 7.55 (m, 2H), 7.50 (dm 2H, J=8.4Hz), 6.77 (s, IH), 3.3-4.0 (m, 17H), 1.9-2.3 (m, 4H); MS (DCI) m/z 434 (M+H)+.
Example 35 N-(tert-butyl)-N-methyl-N-(2- {5-|"4-(4-moφholinylcarbonyl)phenyl]- 1 -benzofuran-2 - vUethvDamine The product from Example 23 D and tert-butyl(methyl)amine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 8 7.83 (m, IH), 7.74 (d, J=8.1, 2H), 7.55 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.81 (s, IH), 3.3- 3.8 (m, 12H), 2.93 (s, 3H), 1.48 (s, 9H); MS (DCI) m/z 421 (M+H)+.
Example 36 N-isopropyl-N-methyl-N-(2- {5- 4-(4-moφholinylcarbonyl)phenyl]- 1 -benzofuran-2- yllethvDamine The product from Example 23D and isopropyl(methyl)amine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 8 7.82 (m, IH), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.81 (s, IH), 3.3- 3.8 (m, 13H), 2.97 (s, 3H), 1.42 (d, 6.3 Hz, 3H), 1.37 (d, 6.3 Hz, 3H); MS (DCI) m/z 407 (M+H)+.
Example 37 N-isobutyl-N-methyl-N-(2-(5-[4-(4-moφholinylcarbonyl)phenyl1-l-benzofuran-2- vUethvDamine The product from Example 23 D and isobutyl(methyl)amine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 8 7.82 (m, IH), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.81 (s, IH), 3.3- 3.8 (m, 14H), 2.96 (s, 3H), 2.2 (m, IH), 1.09 (d, J=6.6 Hz, 6H); MS (DCI) m/z 421 (M+H)+.
Example 38 N-ethyl-N-isopropyl-N-(2-{5- 4-(4-moφholinylcarbonyl)phenyll-l-benzofuran-2- yl} ethvDamine The product from Example 23D and isopropyl(ethyl)amine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 8 7.83 (m, IH), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.80 (s, IH), 3.3- 3.8 (m, 15H), 1.41 (m, 9H); MS (DCI) m/z 421 (M+H)+.
Example 39 N,N-dimethyl-N-(2- {5-[4-(4-moφholinylcarbonyl)phenyll- 1 -benzofuran-2-yl} ethvDamine The product from Example 23D and dimethylamine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 378 (M+H)+.
Example 40 N-ethyl-N-(2- { 5- 4-(4-moφholinylcarbonvDphenyl]- 1 -benzofuran-2-yl} ethvD-N- propylamine The product from Example 23D and ethyl(propyl)amine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ 7.84 (m, IH), 7.74 (d, J=8.1 , 2H), 7.58 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.82(s, IH), 3.32-3.8 (m, 14H), 3.20 ( , 2H), 1.80 (m, 2H), 1.38 (t, J=7.5Hz, 3H), 1.05 (t, J=7.5Hz, 3H); MS (DCI) m/z 421 (M+H)+.
Example 41 4-{4-methyl-2-oxo-3-[2-(l-pyrrolidinvDethyl1-2H-chromen-6-yl}benzonitrile
Example 41 A 3-(2-bromoethyD-6-hydroxy-4-methyl-2H-chromen-2-one To a solution of resorcinol (7.03 g, 64.0 mmol) in a solution consisting of HBr (104 mL, 422 mmol) and glacial acetic acid (10 mL) at 0 °C was slowly added 2-acetylbutyrolactone (5.8 mL, 54 mmol). The mixture was warmed to ambient temperature and then heated to reflux for 2 hours. The mixture was cooled to ambient temperature and diluted with water (350 mL). The mixture was filtered and the solid dried in vacuo overnight to give the titled compound (15.5 g, 85%). Η NMR (300 MHz, CD3OD) δ 10.5 (s, IH), 7.6 (d, J= 8.7 Hz,lH), 6.8 (dd, J= 6.6 Hz, 11.4 Hz, IH), 6.1 (d, J= 2.1 Hz, IH), 3.6 (t, J= 7.5 Hz, 2H), 3.1 (t, J= 7.6 Hz, 2H), 2.4 (s, 3H); MS (DCI) m/z 283, 284 (M+H)+.
Example 41B 6-hydroxy-4-methyl-3-["2-(l-pyrrolidinyDethyl]-2H-chromen-2-one A solution of Example 41 A (0.20 g, 0.70 mmol) and pyrrolidine (0.50 mL, 6.0 mmol) in DMF (2 mL) was heated to 75 °C for 16 hours, cooled to ambient temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate was dried (MgS04), filtered, concentrated under reduced pressure and chromatographed on silica with 10 % methanol in dichloromethane to give the titled compound (0.48 g, 25%). MS (DCI) m/z 274 (M+H)+.
Example 41C To a solution of Example 41B (0.105 g, 0.38 mmol), N-phenyltrifluoromethane sulfonimide (0.143 g, 0.38 mmol) in dichloromethane (2 mL) at 0 °C was added triethylamine (0.68 mL, 0.48 mmol). The mixture was stirred at ambient temperature for 12 hours, diluted with diethyl ether (40 mL) and washed sequentially with aqueous NaOH (IN, 2 x 30 mL), water and brine, dried (MgS0 ), filtered and evaporated to provide the triflate. A mixture of the triflate (0.2 g, 0.49 mmol), 4-cyanophenylboronic acid (0.082 g, 0.54 mmol), Pd(PPh3)2Cl2 (0.035 g) and Cs2CO3 (0.96 g, 2.9 mmol) in DMF (5 mL) was stirred for 5 hours, diluted with ethyl acetate and washed sequentially with aqueous NaOH (IN, 3 x 25 mL), water (3 x 25 mL) and brine. The organic solution was dried (MgSO4), filtered, evaporated under reduced pressure. The residue was chromatographed on silica with dichloromethane ethyl acetate methanol to give the titled compound. NMR (300 MHz, CDC13) δ7.75 (m, 3 H) 7.5 (m, IH), 7.2 (m 2H), 7.1 (m, IH) 3.1 (m, 2H), 2.9 (m, 4H), 2.5 (s, 3H), 2.0, (m, 4H), 1.6 (m, 2 H); MS (DCI) m/z 359 (M+H)+.
Example 42 4-{4-methyl-2-oxo-3-r2-(l-piperidinvDethyl]-2H-chromen-6-yl}benzonitrile The product from Example 41 A and piperidine were processed as described in Examples 41B and 41C to provide the titled compound. NMR (300 MHz, CDC13) δ7.75 (m, 3 H) 7.6 (m, 3H), 7.2 (m, IH), 2.95 (m, 2H), 2.6 (m, 6H), 2.5 (s, 3H), 1.7 (m, 4H), 1.5 (m, 2 H); MS (DCI) m/z 373 (M+H)+.
Example 43 4-{3-[2-(diethylamino)ethyl1-4-methyl-2-oxo-2H-chromen-6-yl}benzonitrile The product from Example 41 A and diethylamine were processed as described in Examples 41B and 41C to provide the titled compound. NMR (300 MHz, CDC13) δ7.75 (m, 5H), 7.5 (m, 2H), 2.9 (m, 2H), 2.1 (m, 6H), 2.5 (s, 3H), 1.1 (t, J=9Hz, 6H); MS (DCI) m/z 361 (M+H)+.
Example 44 4- (6- {2 2-( 1 -pyrrolidinyDethyl]- 1 -benzofuran-5-yl} -3-pyridinyl)carbonyl1moφholine
Example 44A 4-[(6-chloro-3-pyridinvDcarbonyllmoφholine To a solution of chloronicotinoyl chloride (3.52 g, 2.00 mmol) and triethylamine (3.1 mL, 2.22 mmol) in dichloromethane (5 mL) at 0 °C was slowly added moφholine (1.75 mL, 2.00 mmol). The mixture was warmed to ambient temperature, washed with water (2 x 25 mL), brine (1 x 25 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The product was chromatographed on silica with ethyl acetate to give the titled compound (4.0 g, 88%). MS (DCI) m/z 227 (M+H)+.
Example 44B 4-f 5-(4-moφholinylcarbonyD- 1 ,6-dihvdro-2-pyridinyl1phenol A mixture of Example 44A (4.0 g, 17.6 mmol), Pd(Ph3P)4 (1.0 g, 0.86 mmol), 4-O-tert- butyldimethylsilyl-phenylboric acid (4.9 g, 23.6 mmol) in toluene (60 mL) and aqueous sodium carbonate (2.76 g dissolved in 25 mL water) was heated to reflux for 12 hours, then cooled to ambient temperature. The mixture was diluted with ethyl acetate (100 mL), washed with water (1 x 50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was stirred in THF (200 mL) containing tetrabutylammonium fluoride (30 mL, 1.0M, 30.0 mmol) for 16 hours. The mixture was diluted with ethyl acetate (100 mL), washed sequentially with water (1 x 50 mL), aqueous ammonium chloride (1 x 50 mL), brine (1 x 50 mL), dried (Na2S0 ), filtered and concentrated under reduced pressure to give a solid. The solid was precipitated from ethyl acetate (75 mL), filtered to provide the titled compound as a tan solid (4.27 g, 70%).
Example 44C 2-iodo-4- 5-(4-moφholinylcarbonvD-2-pyridinyl]phenol A mixture of Example 44B (4.25 g, 15.0 mmol) sodium iodide (2.36 g, 15.7 mmol) and sodium hydroxide (0.63 g, 15.7 mmol) was stirred in methanol (90 mL) with heating until a clear solution was obtained. The solution was then cooled to 0 °C and to this was slowly added sodium hypochlorite (22 mL of 5.25%, 1.15 g, 15.5 mmol) (Clorox™) over 45 minutes. While maintaining 0 °C, two sequential additions of Nal (0.3 g, 1.5 mmol) and Clorox (2.2 mL, 0.12 g, 1.5 mmol) were made both 2 hours and 4 hours later. The mixture was stirred for 12 hours at ambient temperature, quenched by the sequential addition of aqueous sodium thiosulfate (10 mL), water (800 mL) and sufficient aqueous sodium dihydrogen phosphate (NaH2PO4) to adjust the pH to 7. The mixture was extracted with dichloromethane, and the combined extracts dried (Na2SO ), filtered and concentrated under reduced pressure to give a tan foam. The product was crystallized from ethanol to give the titled compounds as a tan solid (3.78 g, 61%). MS (DCI) m/z 411 (M+H)+.
Example 44D 2- {5-[5-(4-moφholinylcarbonyD-2-pyridinyl]-l -benzofuran-2 -vPethanol To a solution of Example 44C (2.85 g, 6.95 mmol), triethylamine (2.4 mL, 17.4 mmol), and 3-butyn-l-ol (0.73 g, 10.4 mmol) in dimethylformamide (15 mL) at 20 °C was added cuprous iodide (0.2 g, 1.0 mmol) and bis-triphenylphosphine palladium dichloride (0.24 g, 0.35 mmol). The mixture was stirred for one hour, then heated to 65 °C for 16 hours. The reaction was cooled to 23 °C, diluted with dichloromethane (200 mL) and water (100 mL). The mixture was stirred with Celite then filtered. The filtrate was washed with water (1 x 50 mL), the organic phase separated, dried (Na2SO ), filtered and concentrated under reduced pressure to give a tan foam. The residue was chromatographed on silica using 5% methanol in dichloromethane to give the titled compound as a yellow solid (1.83 g, 75%). MS (DCI) m/z 353 (M+H)+.
Example 44E 2- .5-[5-(4-moφholinylcarbonvD-2-pyridinyl]- 1 -benzofuran-2-yl} ethyl methanesulfonate The product from Example 44D was processed as described in Example IC to provide the titled compound.
Example 44F 4-[(6-{2- 2-(l-pyrrolidinvDethyl]-l-benzofuran-5-yl}-3-pyridinvDcarbonyl]moφholine The product from Example 44E and pyrrolidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH), 8.24 (d, J=1.8 Hz, IH), 7.98 (m, 3H), 7.60 (d, J=8.7 Hz, IH), 6.84 (s, IH), 3.3-3.8 (m, 12H), 3.18 (m, 2H), 2.0-2.25 (m, 6H); MS (DCI) m/z 406 (M+H)+.
Example 45
4-( 6-(2-(2-r(2R)-methylpyrrolidinyl]ethyll-l-benzofuran-5-vD-3- pyridinvHcarbonyl } moφholine
The product from Example 44E and 2-(R)-methylpyrrolidine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 420 (M+H)+.
Example 46 4-[(6- {2-f2-( 1 -piperidinvDethyll- 1 -benzofuran-5-yl) -3-pyridinvDcarbonyl]moφholine The product from Example 44E and piperidine were processed as described in Example ID to provide the titled compound. ]H NMR (300 MHz, CD3OD) δ8.70 (m, IH), 8.22 (d, J=1.8 Hz, IH), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, IH), 6.82 (s, IH), 3.3-3.8 (m, 12H), 3.05 (m, 2H), 1.5-2.0 (m, 8H); MS (DCI) m/z 420 (M+H)+.
Example 47 4-[(6-(2-r2-(N,N-diethvDethyl]-l-benzofuran-5-yl}-3-pyridinvDcarbonyl1moφholine The product from Example 44E and diethylamine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH), 8.24 (d, J=l .8 Hz, IH), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, IH), 6.84 (s, IH), 3.3-3.8 (m, 12H), 1.38 (t, J=7.5 Hz, 6H); MS (DCI) m/z 408 (M+H)+.
Example 48 (3R)-l-r2-(5-f5-('4-morpholinylcarbonyl)-2-pyridinyl1-l-benzofuran-2-yllethvD-3- pyrrolidinol The product from Example 44E and 3-(R)-hydroxypyrrolidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH), 8.24 (d, J=1.8 Hz, IH), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, IH), 6.82 (s, IH), 4.55 (m, IH), 3.3-3.8 (m, 16H), 2.0-2.4 (m, 2H); MS (DCI) m/z 422 (M+H)+.
Example 49 4-(r6-(2-(2-[(2R.5R)-2.5-dimethylpyrrolidinyl]ethvD-l-benzofuran-5-vD-3- pyridinyl]carbonyl } moφholine The product from Example 44E and (2R,5R)-dimethylpyrrolidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH), 8.24 (d, J=1.8 Hz, IH), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, IH), 6.86 (s, IH), 3.3-3.8 (m, 12H), 1.2-2.4 (m, 10H); MS (DCI) m/z 434 (M+H)+.
Example 50 4-(r6-(2-(2-[-2,6-dimethylpiperidinyl1ethvU-l-benzofuran-5-vD-3- pyridinyl]carbonyl}moφholine The product from Example 44E and -dimethylpiperidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH), 8.24 (d, J=1.8 Hz, IH), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, IH), 6.86 (s, IH), 3.45-3.85 (m, 12H), 1.6-2.1 (m, 6H), 1.48 (d, J=6.3 Hz, 6H); MS (DCI) m/z 448 (M+H)+.
Example 51 4-([6-r2-(2-[l-azepanyl]ethyl)-l-benzofuran-5-yD-3-pyridinyl]carbonyllmorpholine The product from Example 44E and azepine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH), 8.24 (d, J=1.8 Hz, IH), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, IH), 6.86 (s, IH), 3.3-3.8 (m, 16H), 1.95 (m, 4H), 1.75 (m, 4H); MS (DCI) m/z 434 (M+H)+.
Example 52 4-r.6-l2-r2-(4-methyl-l-piperidinvDethyl]-l-benzofuran-5-vU-3- pyridinvDcarbonyllmoφholine The product from Example 44E and 4-methylpiperidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 88.70 (m, IH), 8.22 (d, J=1.8 Hz, IH), 7.97 (m, 3H), 7.58 (d, J=8.7 Hz, IH), 6.82 (s, IH), 3.3-3.8 (m, 14H), 3.05 (m, 2H), 1.95 (m, 2H), 1.75 (m, IH), 1.5 (m, 2H), 1.05 (d, J=6.6 Hz, 3H); MS (DCI) m/z 434 (M+H)+.
Example 53 4-[(6-(2-r2-(4-moφholinyl)ethyl1-l-benzofuran-5-vU-3-pyridinyl)carbonyl1moφholine The product from Example 44E and moφholine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 88.70 (m, IH), 8.24 (d, J=1.8 Hz, IH), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, IH), 6.82 (s, IH), 3.3-4.1 (m, 16H), 3.37 (t, J=7.5 Hz, 4H); MS (DCI) m/z 422 (M+H)+.
Example 54 N-(tert-butvD-N-methyl-N-(2-{5-[5-(4-mθφholinylcarbonvD-2 -pyridinyl]-! -benzofuran-2- yl. ethvDamine The product from Example 44E and tert-butyl(methyl)amine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 88.70 (m, IH), 8.24 (d, J=l .8 Hz, IH), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, IH), 6.85 (s, IH), 3.3-3.8 (m, 12H), 2.93 (s, 3H), 1.48 (s, 9H); MS (DCI) m/z 422 (M+H)+.
Example 55 N-isobutyl-N-methyl-N-(2- (5-[5-(4-moφholinylcarbonvD-2-pyridinyl]- 1 -benzofuran-2 - yl) ethvDamine The product from Example 44E and isobύtyl(methyl)amine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 88.70 (m, IH), 8.23 (d, J=1.8 Hz, IH), 7.98 (m, 3H), 7.59 (d, J=8.7 Hz, IH), 6.85 (s, IH), 3.0-3.8 (m, 14H), 2.98 (s, 3H), 2.2 (m, IH), 1.09 (d, J=6.6 Hz, 6H); MS (DCI) m/z 422 (M+H)+.
Example 56 N-isopropyl-N-methyl-N-(2-(5-r5-(4-moφholinylcarbonyl)-2-pyridinyll-l-benzofuran-2- yl} ethvDamine The product from Example 44E and isopropyl(methyl)amine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 88.70 (m, IH), 8.24 (d, J=1.8 Hz, IH), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, IH), 6.85 (s, IH), 3.3-3.8 (m, 13H), 2.88 (s, 3H), 1.40 (d, 6.3 Hz, 3H), 1.36 (d, 6.3 Hz, 3H); MS (DCI) m/z 408 (M+H)+.
Example 57 N-ethyl-N-isopropyl-N-(2- { 5-r5-(4-moφholinylcarbonyD-2 -pyridinyl]- 1-benzo furan-2- yl} ethvDamine The product from Example 44E and ethyl(isopropyl)amine were processed as described in Example ID to provide the titled compound. *H NMR (300 MHz, CD3OD) 88.70 (m, IH), 8.25 (d, J=1.8 Hz, IH), 7.98 (m, 3H), 7.59 (d, J=8.7 Hz, IH), 6.85 (s, IH), 3.3-3.8 (m, 15H), 1.4 (m, 9H); MS (DCI) m/z 422 (M+H)+.
Example 58 N.N-dimethyl-N-(2- { 5-[5-(4-moφholinylcarbonyD-2 -pyridinyl]- l-benzofuran-2- yl) ethvDamine The product from Example 44E and dimethylamine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) 88.70 (m, IH), 8.24 (d, J=1.8 Hz, IH), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, IH), 6.84 (s, IH), 3.35-3.8 (m, 12H), 2.98 (s, 6H); MS (DCI) m/z 380 (M+H)+.
Example 59 N-ethyl-N-propyl-N-(2- (5-r5-(4-moφholinylcarbonvD-2-pyridinyl1- 1 -benzofuran-2 - yll ethvDamine The product from Example 44E and ethyl(propyl)amine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH), 8.23 (d, J=1.8 Hz, IH), 7.98 (m, 3H), 7.58 (d, J=8.7 Hz, IH), 6.85 (s, IH), 3.2-3.8 (m, 14H), 3.20 (m, 2H), 1.80 (m, 2H), 1.38 (t, J=7.5Hz, 3H), 1.05 (t, J=7.5Hz, 3H); MS (DCI) m/z 422 (M+H)+.
Example 60 8-(2-{5-f5-(4-moφholinylcarbonyl)-2-pyridinyl1-l-benzofuran-2-vUethvD-l,4-dioxa-8- azaspiro[4.5]decane The product from Example 44E and l,4-dioxa-8-azaspiro[4.5]decane were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH), 8.24 (d, J=1.8 Hz, IH), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, IH), 6.82 (s, IH), 3.3-4.1 (m, 20H), 2.05 (m, 4H); MS (DCI) m/z 478 (M+H)+.
Example 61 5-(2-(5-[5-(4-moφholinylcarbonyD-2-pyridinyl1-l -benzofuran-2-yl}ethvD-2-oxa-5- azabicyclo[2.2. l]heptane The product from Example 44E and 2-oxo-5-azabicyclo[2.2.1]heptane were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH), 8.24 (d, J=1.8 Hz, IH), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, IH), 6.82 (s, IH), 4.1 (m, IH), 4.55 (m, IH), 3.3-4.0 (m, 14H), 2.4 (m, 2H), 2.2 (m, 2H); MS (DCI) m/z 434 (M+H)+.
Example 62 (2S)-l-(2-{5-[5-(4-moφholinylcarbonyD-2-pyridinyl1-l-benzofuran-2-yl}ethvD-2- pyrrolidinol The product from Example 44E and 2-(R)-hydroxymethylpyrrolidine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH), 8.23 (d, J=1.8 Hz, IH), 7.98 (m, 3H), 7.57 (d, J=8.7 Hz, IH), 6.82 (s, IH), 3.3-4.0 (m, 15H), 1.9-2.3 (m, 6H); MS (DCI) m/z 436 (M+H)+.
Example 63 N-allyl-N-(2-(5-[5-C4-morpholinylcarbonvD-2-pyridinvn-l-benzofuran-2-yllethvDamine The product from Example 44E and allylamine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH), 8.24 (d, J=1.8 Hz, IH), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, IH), 6.81 (s, IH), 5.95 (m, IH), 5.55 (m, 2H), 3.25-3.8 (m, 14H); MS (DCI) m/z 392 (M+H)+.
Example 64 3-[(2-(5-[5-(4-moφholinylcarbonvD-2-pyridinvn-l-benzofuran-2-yl}ethvDamino]-l- propanol The product from Example 44E and 3-amino-l-propanol were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH),
8.23 (d, J=1.8 Hz, IH), 7.98 (m, 3H), 7.59 (d, J=8.7 Hz, IH), 6.82 (s, IH), 3.20-3.8 (m, 16H), 1.92 (m, 2H); MS (DCI) m/z 410 (M+H)+.
Example 65 N-(2-{5-[5-(4-moφholinylcarbonyD-2-pyridinyl1-l -benzofuran-2 -yl}ethvD-N-propylamine
The product from Example 44E and propylamine were processed as described in Example ID to provide the titled compound. Η NMR (300 MHz, CD3OD) δ8.70 (m, IH),
8.24 (d, J=1.8 Hz, IH), 7.98 (m, 3H), 7.58 (d, J=8.7 Hz, IH), 6.82 (s, IH), 3.25-3.8 (m, 12H), 3.05 (t, J=7.5 Hz, 2H), 1.74 (m, 2H), 1.05 (t, J=7.5 Hz, 3H); MS (DCI) m/z 394 (M+H)+.
Example 66 4-(2-{2-[(3R)-3-(dimethylamino)pyrrolidinyl]ethyl}-l-benzofuran-5-vDbenzonitrile The product from Example IC and 3-(R)-(dimethylamino)pyrrolidine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 360 (M+H)+.
Example 67 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyU-2.3-dihvdro-l-benzofuran-5-vDbenzonitrile
Example 67A 4-(2-[(E)-2-methoxyethenyl1-2.3-dihvdro-l-benzofuran-5-yl}benzonitrile A solution of Example 1A (0.20 g, 0.623 mmol), 1 -methoxybutadiene (0.18 g, 2.18 mmol), palladium diacetate (0.007 g, 0.031 mmol), sodium bicarbonate (0.261 g, 3.11 mmol) and tetrabutyl ammonium chloride (0.173 g, 0.623 mmol) was heated at 60° C in DMF (3 mL) under an atmosphere of nitrogen for 36 hours. The reaction was cooled to 23° C, diluted with CH2CI2 (50 mL), filtered through Celite. The solution was concentrated under reduce pressure and the residue was purified on silica using CH2CI2 to give the titled compound (0.95 g, 55%). Η NMR (CDCI3): 3.05 (m, IH), 3.40 (m, IH), 3.60 (s, 3H), 5.00 (m, IH), 5.22 (m, IH), 6.72 (d, J=14 Hz, IH), 6.83 (d, J=7 Hz, IH), 7.38 (m, 2H), 7.65 (m, 4H); MS (DCI): 278 (M+H+), 295 (M+NH4 +).
Example 67B 4- [2 -(2-oxoethvD-2.3 -dihvdro- 1 -benzofuran-5 -yl]benzoni trile A solution of Example 67A (0.5 g, 1.8 mmol) in acetone (10 mL) and p- toluenesulfonic acid monohydrate (0.51 g, 2.1 mmol) was stirred for 45 minutes, diluted with CH2CI2 (150 mL), washed with cold aqueous sodium bicarbonate (2 x 100 mL, 10% solution), water (2 x 100 mL), dried (Na2SO ), filtered and concentrated under reduced pressure. The residue was purified on silica using CH2CI2 to give the titled compound (0.41 g, 87%). Η NMR (CDC13): 2.95 (m, 2H), 3.65 (m, 3H), 6.82 (d, J=7Hz, IH), 7.40 (m, 2H), 7.62 (m, 4H), 9.55(d, J=7Hz, IH); MS (DCI) 263 (M+), 281 (M+NH ).
Example 67C 4-[2-(2-hvdroxyethvD-2,3-dihydro-l-benzofuran-5-yllbenzonitrile A solution of Example 67B (0.25 g, 0.95 mmol) and sodium borohydride (0.054 g, 1.42 mmol)in methanol (5 mL) was stirred for 1 hour, cooled on ice and quenched with aqueous NaHCO3 (50 mL). The mixture was extracted with dichloromethane (3 x 100 mL), the organic extracts combined and washed with water (1 x 150 mL), brine (1 x 150 mL), dried (Na2S0 ), filtered and concentrated under reduced pressure to provide the titled compound (0.24 g, 95%). Η NMR (CDC13): 1.90 (m, 2H), 2.90 (m, 2H), 3.46 (m, 2H), 5.40 (m, IH), 6.85 (d, J=7Hz, IH), 7.38 (m, 2H), 7.65 (m, 4H); MS (DCI) 265 (M+), 283 (M+ NH4 +).
Example 67D 2-[5-(4-cvanophenvD-2,3-dihvdro-l-benzofuran-2-yl]ethyl methanesulfonate To a solution of Example 67C (0.23 g, 0.87 mmol) and methanesulfonyl chloride (0.075 mL, 0.96 mmol) in CH2C12 (5 mL) at 0°C was added triethylamine (0.13 mL, 9.4 mmol). The mixture was stirred for 30 minutes, diluted with CH2C12 (75 mL), washed with water (3 x 100 mL), dried (Na2S04), filtered and concentrated under reduced pressure. The residue was purified on silica using CH2CI2 to provide the titled compound (0.278 g, 90%). Η NMR (CDCI3): H NMR: 1.95 (m, 2H), 2.93 (m, 2H), 3.00 (s, 3H), 3.46 (m, 2H), 5.00 (m, IH), 6.81 (d, J=7Hz, IH), 7.40 (m, 2H), 7.65 (m, 4H); MS (DCI) 343 (M+), 361 (M+ NFL,+).
Example 67E 4-(2-{2-r(2R)-2-methylpyrrolidinyl1ethvU-2,3-dihvdro-l-benzofuran-5-vDbenzonitrile A solution of Example 67D (0.2 g, 0.58 mmol), R-2-methylpyrrolidine-(L)-tartrate 1.45 mmol) and cesium carbonate (0.95 g) in acetonitrile (5 mL) was heated to 60°C for 48 hours under an atmophere of nitrogen. The reaction was allowed to come to ambient temperature, diluted with CH2CI2 (100 mL), washed with aqueous NaHCO3 (2 x 100 mL), H2O (1 x 100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by on silica using CHCl3/CH3OH/NH4OH (95:5:0.5) to provide the titled compound (0.14 g, 72%). Η NMR (CDCI3): 1.10 (d, J=7Hz, 2H), 1.50 (m, 2H), 1.70 (m, 4H), 1.98 (m, 2H), 2.10 (m, 2H), 2.25 (m, IH), 3.00 (m, 2H), 4.60 (m, IH), 6.80 (d, J=7Hz, IH), 7.45 (m, 2H), 7.70 (m, 4H); MS(ESI) 333 (M+H+).
Example 68 (4-fluorophenvD(2-(2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl}-l-benzofuran-5-vDmethanone
Example 68 A (4-fluorophenvD(4-hydroxy-3-iodophenvDmethanone (4-Fluorophenyl)(4-hydroxyphenyl)methanone (20.0 g, 92.5 mmol) in concentrated ammonium hydroxide (770 mL) was allowed to stir at 25°C for 15 minutes and then treated with potassium iodide (74.79 g, 450.5 mmol) and iodine (23.48 g, 92.5 mmol) in water (185 mL). The reaction mixture was allowed to stir at 25°C for 18 hours and then filtered. The precipitate was dissolved in ethyl acetate, washed with water and brine, dried, filtered and the filtrate concentrated under reduced pressure to provide the title compound as a pale green solid (23.4 g, 74% yield). 'HNMR (300 MHZ, CD3OD) 8 6.91 (d, IH, J=8.9 Hz), 7.26 (t, 2H), 7.64 (d, IH, J=8.9 Hz), 7.78 (t, 2H), 8.17 (s, IH); MS (DCI) m/z 342.9 (M+H)+, 360 (M+NH4)+.
Example 68B (2R)-l^(3-butvnvD-2-methylpyrrolidine
(R)-2-methylpyrrolidine (L) tartrate (1.65 g, 7.00 mmol) and 325 mesh powdered K2CO3 (2.03 g, 14.7 mmol) in acetonitrile (60 mL) were heated at 50 °C in a sealed bottle for 24 hours. The mixture was allowed to cool to room temperature and was treated with 3- butynyl 4-methylbenzenesulfonate (1.24 mL, 7.0 mmol). The mixture was stirred for one hour at room temperature and then was heated at 50 °C for 24 hours. The mixture was allowed to cool to room temperature, filtered, and the filter cake washed with acetonitrile. The filtrate was diluted to a total volume of 70 mL with acetonitrile and used as a 0.1 M solution in subsequent steps.
Example 68C (4-fluorophenvD(2-(2-r(2R)-2-methyl-l-pyrrolidinyl1ethyl}-l-benzofuran-5-vDmethanone
The product from Example 68A (6.5 g, 18.5 mmol) was sequentially treated with a 0.1M solution of the product from Example 68B in acetonitrile (230 mL, 23.0 mmol), Pd(OAc)2 (0.127 g, 0.566 mmol), tris(4-methylphenyl)phosphine (0.344 g, 1.130 mmol), and copper iodide (1.08 g, 95.72 mmol). After stirring at 25 °C for 10 minutes, the reaction mixture was treated with diisopropyl amine (26.6 mL, 189 mmol) and then heated at 60 °C in an inert atmosphere for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate concentrated under reduced pressure. The residue was purified on silica gel using 90% DCM, 9.9% MeOH, 0.1% NH4OH to provide the title compound (1.21 g, 18.0% yield). 'HNMR (300 MHz, CD3OD) 8 1.09 (d, 3H, J=6.1 Hz), 1.46 (m, IH), 1.81 (m, 2H), 2.02-2.28 (m, 2H), 2.49 (m, 2H) 3.06 (m, 2H), 3.28 (m, 2H), 6.68 (s, IH), ), 7.27 (t, 2H), 7.58 (d, IH, J=8.9 Hz), 7.71 (d, IH, J=8.9 Hz) 7.86 (t, 2H), 7.97 (s, IH); MS (ESI) m/z 352 (M+H)+.
Example 69 (3-fluorophenvD(2-{2-r(2R)-2-methyl-l-pyrroIidinyl]ethyl}-l-benzofuran-5-vDmethanone
Example 69A f3-fluoroρhenvD(4-hvdroxyphenvDmefhanone (3-fluorophenyl)(4-methoxyphenyl)methanone (1.0 g, 4.34 mmol) in 50 mL DCM at -78 °C while stirring was treated with 1M boron tribromide (13.03 mL, 13.03 mmol) dropwise over 20 minutes. The mixture was allowed to warm to 25°C and stir for 18 hours. The mixture was treated with water (1 mL) and stirred for 5 minutes, followed by additional water (2 mL) and stirred for 10 minutes, and finally treated with more water (50 mL) and stirred for 20 minutes. The mixture was then extracted with DCM (50 mL x2). The organic layers were combined, dried, filtered, and the filtrate evaporated under reduced pressure. The residue was purified by flash chromatography to provide the title compound (0.69 g, 74% yield). 'HNMR (300 MHz, CD3OD) δ 6.92 (d, 2H, J=8.9 Hz), 7.26 (m, IH), 7.41-7.58 (m, 3H), 7.79 (d, 2H, J=8.9 Hz); MS (DCI) m/z 217 (M+H)+, 234 (M+NH )+.
Example 69B (3 -fluorophenvD(4-hydroxy-3 -iodophenyDmethanone The product from Example 69A, potassium iodide and iodine were processed as described in Example 68A to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 6.92 (d, IH, J=8.9 Hz), 7.31-7.59 (m, 4H), 7.67 (d, IH, J=8.9 Hz), 8.18 (s, IH); MS (DCI) m/z 343 (M+H)+, 360 (M+NH4)+.
Example 69C (3-fluorophenyl)(2- |2-[(2R)-2 -methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-5-vPmethanone The product from Example 69B and a 0.1M solution of the product from Example 68B were processed as described in Example 68C to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.26 (d, 3H, J=6.1 Hz), 1.57 (m, IH), 1.91 (m, 2H), 2.10-2.63 (m, 2H), 2.87 (m, 2H) 3.18 (m, 2H), 3.42 (m, 2H), 6.76 (s, IH), 7.37-7.59 (m, 5H), 7.76 (d, IH, J=8.9 Hz), 7.98 (s, IH); MS (ESI) m/z 352.1 (M+ +l).
Example 70 (2-fluorophenvD(2-{2-r(2R)-2-methyl-l-pyrrolidinyl]ethvP-l-benzofuran-5-vDmethanone
Example 70A (2-fluorophenvD(4-hydroxy-3-iodophenyDmethanone (2-Fluorophenyl)(4-hydroxyphenyl)methanone, potassium iodide and iodine were processed as described in Example 68A to provide the title compound. MS (DCI) m/z 343 (M+H)+, 360 (M+NH4)+.
Example 70B (2-fluorophenvP(2-{2- (2R)-2-methyl-l-pyrrolidinyl]ethvP-l-benzofuran-5-vPmethanone The product from Example 70 A and a 0.1M solution of the product from Example 68B were processed as described in Example 68C to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.28 (d, 3H, J=6.1 Hz), 1.59 (m, IH), 1.93 (m, 2H), 2.10-2.78 (m, 2H), 2.93 (m, 2H), 3.18 (m, 2H), 3.45 (m, 2H), 6.76 (s, IH), 7.21-7.38 (m, 2H), 7-50-7.67 (m, 3H), 7.79 (d, IH, J=8.9 Hz), 7.99 (s, IH); MS (ESI) m/z 352.1 (M+H)+.
Example 71 (3-chlorophenyl)(2- j2-|Y2R)-2 -methyl- 1 -pyrrolidinyl]ethyl} -1 -benzofuran-5 -yPmethanone
Example 71 A 4-(benzyloxy)benzoyl chloride 4-Benzyloxybenzoic acid (15.0 g, 65.72 mmol) in dichloromethane (150 mL) and dimethylformamide (075 mL) was cooled to 0 °C. After 30 minutes, the mixture was treated with neat oxalyl chloride (11.5 mL, 131.44 mmol) dropwise over 25 minutes. The resulting mixture was stirred at room temperature for 120 minutes followed by evaporation of solvent under reduced pressure to provide the title compound as a light yellow solid (18.2 g, 1 12% yield). 'HNMR (300 MHz, CDC13) δ 7.03 (d, 2H, J=8.9 Hz), 7.23-7.43 (m, 5H), 8.07 (d, 2H, J=8.9 Hz).
Example 7 IB 4-(benzyloxy)-N-methoxy-N-methylbenzamide The product from Example 71 A (18 g, 72.96 mmol) in DCM at room temperature was treated with N,O-dimethylhydroxylamine hydrochloride (7.83 g, 80.26 mmol) slowly. The mixture was cooled to 0 °C, stirred for 30 minutes, and treated with triethylamine (25.47 mL, 182.41 mmol) dropwise. The mixture was allowed to warm to 25 °C, stirred for 16 hours, and treated with DCM (150 mL). The mixture was washed with saturated NaHC03, brine, and water. The organic phase was dried, filtered, and the filtrate evaporated under reduced pressure to provide the title compound as a pale yellow solid (18.65 g, 95% yield). 'HNMR (300 MHz, CDC13) δ 3.36 (s, 3H), 3.56 (s, 3H) 6.98 (d, 2H, J=8.9 Hz), 7.33-7.46 (m, 5H), 7.76 (d, 2H, J=8.9 Hz); MS (ESI) m/z 272 (M+H)+.
Example 71 C 4-hydroxy-N-methoxy-N-methylbenzamide 10%, Palladium on charcoal (4.5 g) in methanol (10 mL) was treated with the product from Example 71B (18.60 g, 68.55 mmol) in 150 mL methanol. The mixture was placed under hydrogen atmosphere at 67 psi. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography to provide the title compound (10.3 g, 83% yield). 'HNMR (300 MHz, CD3OD) δ 3.32 (s, 3H), 3.58 (s, 3H), 6.81 (d, 2H, J=8.9 Hz). 7.59 (d, 2H, J=8.9 Hz); MS (DCI) m/z 182 (M+H)+, 199 (M+NH4)+.
Example 7 ID 4-hydroxy-3-iodo-N-methoxy-N-methylbenzamide The product from Example 71C (10.3 g, 56.84 mmol) in concentrated ammonium hydroxide (400 mL) was stirred at 25 °C for 15 minutes and then treated with KI (45.96 g, 276.83 mmol) and I2 (14.43 g, 56.84 mmol) in water (65 mL). After stirring at room temperature for 16 hours, the solvent was removed under reduced pressure and the residure was redissolved in DCM (500 mL) and washed with water (350 mL x2). The organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 90% CH2CI2, 10% MeOH, to provide the title compound as a white solid (11.6 g, 67% yield). 'HNMR (300 MHz, CD3OD) δ 3.32 (s, 3H), 3.59 (s, 3H), 6.83 (d, IH, J=8.9 Hz). 7.58 (d, IH, J=8.9 Hz), 8.06 (s, IH); MS (DCI) m/z 308 (M+H)+, 325 (M+NH4)+.
Example 7 IE N-methoxy-N-methyl-2-{2-[(2R -2-methyl-l-pyrrolidinyl]ethvU-l-benzofuran-5- carboxamide The product from Example 71D (1 1.6 g, 37.77 mmol) in acetonitrile (50 mL) was treated sequentially with a 0.12M solution of the product from Example 68B (378 mL, 45.33 mmol), Pd(OAc)2 (0.254 g, 1.13 mmol), tris(4-methylphenyl)phosphine (0.518 g, 1.699 mmol), and diisopropyl amine (39.7 mL, 283.3 mmol). After stirring at 25° C for 10 minutes, the mixture was treated with copper iodide (2.158 g, 11.33 mmol) and heated at 50°C in an inert atmosphere for 18 hours. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel using 95% DCM, 9.9% MeOH, 0.1% NH4OH to provide the title compound (1.22 g, 10.2% yield). 'HNMR (300 MHz, CD3OD) δ 1.18 (d, 3H, J=6.1 Hz), 1.47 (m, IH), L78 (m, 2H), 1.91-2.34 (m, 2H), 2.50 (m, 2H) 3.06 (m, 2H), 3.26 (m, 2H), 3.38 (s, 3H), 3.59 (s, 3H), 6.63 (s, IH), 7.51 (q, 2H), 7.84 (IH); MS (ESI) m/z 317.2 (M+H)+.
Example 7 IF (3-chlorophenyP(2-{2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl}-l-benzofuran-5-vPmethanone The product from Example 71 E (0.05 g, 0.158 mmol) in 5 mL of anhydrous THF at 0 °C was treated with 3 -chloropheny .magnesium bromide (1.58 mL, 0.79 mmol). The mixture was allowed to slowly warm to 25°C and stir under nitrogen for 18 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with DCM (50 mL x2). The organic phases were combined, dried, filtered, and the filtrate evaporated under reduced pressure. The residue was purified by preparative HPLC on a Waters Nova- Pak HR C18 column (40 mm X 100 mm, 6μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 12 minute (15 minute run time) at a flow rate of 70 mL/minute to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.50 (d, 3H), 1.72 (m, IH), 2.10 (m, 2H), 2.35 (m, IH), 3.30 (m, 4H), 3.55 (m, IH), 3.80 (m, 2H), 6.90 (s, IH), 7.50-7.80 (m, 6H), 8.02 (d, IH); MS (ESI) m/z 368 (M+H)+.
Example 72 (4-chlorophenyP(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-vPmethanone The product from Example 71E and 4-chlorophenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.18 (d, 3H, J=6.1 Hz), 1.46 (m, IH), 1.78 (m, 2H), 2.01-2.36 (m, 2H), 2.50 (m, 2H), 3.03 (m, 2H), 3.23 (m, 2H), 6.67 (s, IH), 7.57 (m, 3H), 7.78 (m, 3H), 7.97 (s, IH); MS (ESI) m/z 368.1 (M+ +l).
Example 73 (4-methoxyphenvP(2- {2-r(2R)-2-methyl- 1 -pyrrolidinyl] ethyl) - 1 -benzofuran-5 -vPmethanone
The product from Example 71E and 4-methoxyphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 'HNMR (CD3OD) 8 1.18 (d, 3H, J=6.1 Hz), 1.46 (m, IH), 2.01-2.32 (m, 2H), 2.50 (m, 2H), 3.06 (m, 2H), 3.24 (m 2H), 3.88 (s, 3H), 6.67 (s, IH), 7.05 (d, 2H, J=8.9 Hz), 7.54 (d, 2H, J=8.9 Hz), 7.68 (d, 2H, J=8.9 Hz), 7.80 (d, 2H, J=8.9 Hz), 7.92 (s, IH); MS (ESI) m/z 364.1 (M++l).
Example 74 (4-fluoro-3-methylphenvP(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPmethanone The product from Example 71E and (4-fluoro-3-methyl)phenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound. 'HNMR (300 MHz, CD3OD) 8 1.17 (d, 3H), 1.45 (m, IH), 1.80 (m, 2H), 2.0 (m, IH), 2.3 (m, 4H), 2.50 (m, 2H), 3.05 (m, 2H), 3.25 (m, 2H), 6.65 (s, IH), 7.2 (m, IH), 7.57 (d, IH), 7.63 (m, IH), 7.70 (dd, 2H), 7.95 (d, IH); MS (ESI) m/z 366 (M+H)+.
Example 75 cyclopropyl(2-{2- (2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-vPmethanone The product from Example 71E and cyclopropylmagnesium bromide were processed as described in Example 7 IF to provide the title compound. "HNMR (300 MHz, CD3OD) 8 1.10 (m, 5H), 1.28 (d, 3H), 1.78 (m, IH), 2.10 (m, 2H), 2.38 (m, lH), 2.9 (m, IH), 3.2- 3.8(m, 6H), 6.85 (s, IH), 7.58 (d, IH), 8.05 (dd, IH), 8.33 (d, IH); MS (ESI) m/z 298 (M+H)+.
Example 76 3-ethyl-l-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl}-l-benzofuran-5-yl)-l-pentanone The product from Example 71E and 2-ethylbutylmagnesium bromide were processed as described in Example 7 IF to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 0.9 (m, 6H), 1.23 (m, IH), 1.20 (m, 6H), 1.75 (m, IH), 2.1 (m, 2H), 2.35 (m, IH), 3.05 (m, IH), 3.2-3.5 (m, 7H), 3.55 (m, IH), 3.8 (m, IH), 6.85 (s, IH), 7.55 (d, IH) 7.95 (dd, IH), 8.24 (d, IH); MS (ESI) m/z 342 (M+H)+.
Example 77 (4-chloro-3-methylphenvP(2- (2-[Y2R)-2-methyl- 1 -pyrrolidinyl]ethyl) - 1 -benzofuran-5- vPmethanone The product from Example 71E and 4-chloro-3-methylphenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.47 (d, 3H), 1.75 (m, IH), 1.80 (m, 2H), 2.10 (m, 2H), 2.38 (m, IH), 2.44 (s, 3H), 3.50 (m, 2H), 3.55 (m, IH), 3.80 (m, 2H), 6.85 (s, IH), 7.5 (m, 3H), 7.7 (bs, IH), 7.79 (dd, IH), 8.01 (d, IH); MS (ESI) m/z 382 (M+H)+.
Example 78 (2-(2-r(2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-vPr4- (methylthio)phenyllmethanone The product from Example 71 E and 4-(methylthio)phenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 'HNMR (300 MHz, CD3OD) 8 1.45 (d, 3H), 1.75 (m, IH), 1.80 (m, 2H), 2.30 (m, 2H), 2.38 (m, IH), 2.54 (s, 3H), 3.50 (m, 2H), 3.55 (m, I H), 3.80 ( , 2H), 6.85 (s, IH), 7.4 (dd, 2H), 1.1 (bs, IH), 7.6 (dd, IH), 7.75 (m, 3H), 8.0 (d, IH); MS (ESI) m/z 380 (M+H)+.
Example 79 4-(dimethylamino)phenyll(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPmethanone The product from Example 71 E and 4-(dimethylamino)phenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.44 (d, 3H), 1.73 (m, IH), 1.80 (m, 2H), 2.15 (m, 2H), 2.35 (m, IH), 3.18 (s, 6H), 3.50 (m, 2H), 3.55 (m, IH), 3.80 (m, 2H), 6.80 (dd, 2H), 6.85 (s, IH), 7.56 (dd, IH), 7.65 (dd, IH), 7.75 (dd, 2H), 7.95 (d, IH); MS (ESI) m/z 377 (M+H)+.
Example 80 (4-methv.phenvD.2- l2-IY2R)-2-methyl- 1 -pyrrolidinyl]ethyl) - 1 -benzofuran-5 -vPmethanone The product from Example 71 E and 4-methylphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.48 (d, 3H), 1.75 (m, IH), 2.1 (m, 2H), 2.38 (m, IH), 2.45 (s, 3H), 3.30 (m, 4H), 3.57 (m, IH), 3.80 (m, 2H), 6.85 (s, IH), 7.38 (dd, 2H), 7.60 (dd, IH), 7.70 (dd, 2H), 7.75 (dd, IH), 8.0 (d, IH); MS (ESI) m/z 348 (M+H)+.
Example 81 (3,5-difluorophenvP(2-(2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPmethanone The product from Example 71E and 3,5-difluorophenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.45 (d, 3H), 1.75 (m, IH), 2.13 (m, 2H), 2.35 (m, IH), 3.30 (m, 4H), 3.56 (m, IH), 3.82 (m, 2H), 6.88 (s, IH), 7.38 (dd, 2H), 7.30 (m, 3H), 7.63 (dd, IH), 7.80 (dd, IH), 8.05 (d, IH); MS (ESI) m/z 370 (M+H)+.
Example 82 (2-methoxyphenvP(2-|2- (2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yPmethanone
The product from Example 71 E and 2-methoxyphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.42 (d, 3H), 1.72 (m, IH), 2.10 (m, 2H), 2.35 (m, IH), 3.30 (m, 4H), 3.55 (m, IH), 3.70 (s 3H), 3.80 (m, 2H), 6.80 (s, IH), 7.1 (m, 2H), 7.30 (dd, IH), 7.53 (m, 2H), 7.75 (dd, IH), 7.95 (d, IH); MS (ESI) m/z 364 (M+H)+.
Example 83 (3 -methoxyphenyl)(2- { 2-|Y2R)-2-methyl- 1 -pyrrolidinyl]ethyl ) - 1 -benzofuran-5-vDmethanone
The product from Example 71 E and 3-methoxyphenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound. 'HNMR (300 MHz, CD3OD) 8 1.42 (d, 3H), 1.72 (m, IH), 2.10 (m, 2H), 2.35 (m, IH), 3.30 (m, 4H), 3.55 (m, IH), 3.80 (m, 2H), 3.83 (s, 3H), 6.83 (s, IH), 7.2 (m, IH), 7.30 (m, 2H), 7.45 (m, IH), 7.60 (m, 2H), 7.80 (dd, IH), 8.02 (d, IH); MS (ESI) m/z 364 (M+H)+. Example 84 (2-(2-[(2R)-2-methyl-l -Pyrrolidinyllethyl)-l-benzofuran-5-vP(phenvPmethanone The product from Example 7 IE and phenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.15 (d, 3H), 1.45 (m, IH), 1.80 (m, 2H), 2.00 (m, IH), 2.30 (m, IH), 2.50 (m, 2H), 3.30 (m, 4H), 6.63 (s, IH), 7.55 (m, 3H), 7.65 (m, IH), 7.80 (m, 3H), 7.98 (d, IH); MS (ESI) m/z 334 (M+H)+.
Example 85 4-(2-{2-r(2R)-2-methyl-l-pyrrolidinyl1ethyl}-l-benzofuran-4-vPbenzonitrile
Example 85A 2-iodo- 1 ,3-benzenediol Resorcinol (2.75 g, 25 mmmol) in 20 mL of water and ice was treated with iodine (6.7 g, 26.4 mmol) and NaHCU3 (2.3 g, 27.4 mmol) in one portion. After stirring for 1 hour, the precipitate was separated by filtration and the filtrate was extracted twice (2x75 mL) with diethyl ether. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. The solid was triturated with 20 mL of chloroform and left at -18 °C for 24 hours. The solid was separated by filtration to provide the title compound (78% yield). 'HNMR (300 MHz, CDCI3) δ 4.85 (s, IH), 6.30 (m, 2H), 6.95 (m, IH). MS (CDI) m/z 237 (M+H)+.
Example 85B 2-(2-hvdroxyethvD-l-benzofuran-4-ol The product from Example 85A (0.2 g, 0.85 mmol) in 5 mL of DMF under nitrogen was treated with palladium bis(triphenylphosphine) dichloride (30 mg, 0.043 mmol), copper iodide (24 mg, 0.13 mmol), triethylamine (0.2 g, 2.12 mmol) and 3-butyn-l-ol (0.11 g, 1.53 mmol). The mixture was heated at 60°C for 14 hours. After filtration over celite, the mixture was diluted with 150 mL of CH2CI2 and washed with sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of CH2C.2/MeOH (95:5) to provide the title compound (62% yield). 'HNMR (300 MHz, CDC13) 8 3.05 (m, 2H), 4.0 (m, 2H), 6.60 (m, 2H), 7.03 (m, 2H). MS (CDI) m/z 179 (M+H)+.
Example 85C 2-(2-hvdroxyethvP- 1 -benzofuran-4-yl trifluoromethanesulfonate The product from Example 85B (0.1 g, 0.56 mmol) in 10 mL of CH2C12 at 0°C was treated with triethylamine (0.11 g, 1.12 mmol), DMAP (7 mg, 0.056 mmol) and N-phenyl- trifluoromethanesulfonimide (0.22 g, 0.62 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 100 mL of CH2CI2 and washed twice with water (2x100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to provide the title compound (94% yield). 'HNMR (300 MHz, CDCI3) 8 3.10 (m, 2H), 4.0 (m, 2H), 6.60 (s, IH), 7.15 (m, IH), 7.22 (m, IH), 7.45(m, IH). MS (CDI) m/z 311 (M+H)+.
Example 85D 4- 2-(2-hvdroxyethvP-l -benzofuran-4-yl1benzonitrile The product from Example 85C (0.1 g, 0.32 mmol) in 8 mL of benzene/ethanol (2:1), was treated with 4-cyanophenylboronic acid (0.052 g, 0.35 mmol), palladium diacetate (0.0032 mmol), bipheny-2yl-dicyclohexylphosphine (0.0048 mmol) and Na2CO3 (2M, 0.87 mmol) and heated at 75 °C for 14 hours. The mixture was diluted with 100 mL of CH2CI2 and washed successively with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography over silica using CH2CI2 to provide the title compound (55% yield). 'HNMR (300 MHz, CDC13) δ 3.10 (m, 2H), 4.05 (m, 2H), 6.62 (s, IH), 6.90 (m, IH), 7.25 (m, 2H), 7.52 (m, 2H), 7.73(m, 2H). MS (CDI) m/z 264 (M+H)+.
Example 85E 2-r4-(4-cyanophenvP-l -benzofuran-2 -yl]ethyl methanesulfonate The product from Example 85D (015 g, 0.57 mmol) in CH2C12 (10 mL) at 0 °C was treated with triethylamine (64 mg, 0.63 mmol) and methanesulfonyl chloride (68 mg, 0.59 mmol). After 45 minutes at room temperature the reaction was diluted with 50 mL CH2C12 and the mixture was washed with water (2x50 mL). The organic phase was dried over sodium sulfate and evaporated to provide the title compound (99% yield). 'HNMR (300 MHz, CDC13) δ 2.70 (m, 2H), 2.94 (s, 3H), 3.90 (m, 2H), 6.60 (s, IH), 6.90 (m, IH), 7.35 (m, 3H), 7.69 (m, 4H). MS (CDI) m/z 342 (M+H)+.
Example 85F 4-(2- (2-F(2R)-2-methyl- 1 -pyrrolidinyllethyl) - 1 -benzofuran-4-vDbenzonitrile The product from Example 85E (0.086 g, 0.25 mmol), (2R)-2-methylpyrrolidine-L- tartaric acid (0.12 g, 0.5 mmol) and cesium carbonate (0.41 g, 1.26 mmol) in 2 mL of MeCN were combined and heated at 45 °C for two days. The mixture was diluted with 100 mL of CH2CI2 and washed with a saturated solution of sodium bicarbonate (50 mL), water (50 mL) and brine (50 mL). The organic layer was dried, filtered, and the filtrate evaporated. The residue was purified by column chromatography over silica gel using a mixture of CH2Cl2:MeOH: NH4OH (95:5:0.5) to provide the title compound (40% yield). 'HNMR (300 MHz, CDCI3) δ 1.20 (d, 3H), 1.58 (m, 4H), 2.20-2.50 (m, 5H), 2.78 (m,2H), 6.62 (s, IH), 7.28 (m, 3H), 7.69 (m, 4H). MS (CSI) m/z 331 (M+H)+.
Example 86 4-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-6-vDbenzonitrile
Example 86A 4-iodobenzene- 1.3 -diol A solution of iodine monochloride (8.2 g, 50.5 mmol) in dry diethyl ether (100 mL) was added drop-wise over 45 minutes to a cold solution (0 °C) of resorcinol (5.5 g, 49.9 mmol) in dry ether (50 mL). After stirring at room temperature for one hour 100 mL of water and 1.0 g of sodium sulfite was added. The organic phase was separated and the aqueous phase was washed with 100 mL of ether, the combine ether phase was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified using flash chromatography over silica gel using a mixture of CH2C-2:MeOH (100:1) to provide the title compound in 50% yield. 'HNMR (300 MHz, CDC13) δ 4.95 (s, IH), 6.23 (m, IH), 6.55 (m,
IH), 7.43 (m, IH). MS (CDI) m/z 237 (M+H)+.
Example 86B 2-(2-hvdroxyethyD-l-benzofuran-6-ol The product from Example 86A was processed as described in Example 85B to provide the title compound. 'HNMR (300 MHz, CDC13) δ 3.00 (m, 2H), 3.98 (m, 2H), 6.40 (s, IH), 6.73 (m, IH), 6.90 (d, IH), 7.30 (m, IH). MS (CDI) m/z 179 (M+H)+.
Example 86C
2-(2-hvdroxyethvD-l-benzofuran-6-yl trifluoromethanesulfonate
The product from Example 86B was processed as described in Example 85C to provide the title compound. 'HNMR (300 MHz, CDC13) 8 3.00 (m, 2H), 4.2 (m, 2H), 6.65 (s,
IH), 7.20 (m, IH), 7.22 (m, IH), 7.35(m, IH). MS (CDI) m/z 311 (M+H)+.
Example 86D 4-[2-(2-hvdroxyethvD-l-benzofuran-6-yl1benzonitrile The product from Example 86C was processed as described in Example 85D to provide the title compound. 'HNMR (300 MHz, CDC13) 8 3.15 (m, 2H), 4.00 (m, 2H), 6.52 (s, IH), 6.95 (m, IH), 7.35 (m, 2H), 7.52 (m, 2H), 7.70(m, 2H); MS (CDI) m/z 264 (M+H)+.
Example 86E
2-[6-(4-cyanophenvD-l -benzofuran-2-yl]ethyl methanesulfonate
The product from Example 86D was processed as described in Example 85E to provide the title compound. 'HNMR (300 MHz, CDCI3) δ 2.65 (m, 2H), 2.99 (s, 3H), 3.95
(m, 2H), 6.45 (s, IH), 6.95 (m, IH), 7.30 (m, 3H), 7.69 (m, 4H); MS (CDI) m/z 342 (M+H)+.
Example 86F 4-(2-|2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-6-vDbenzonitrile The product from Example 86E was processed as described in Example 85F to provide the title compound. 'HNMR (300 MHz, CDC13) δ 1.20 (d, 3H), 1.58 (m, 4H), 2.20- 2.50 (m, 5H), 2.78 (m,2H), 6.52 (s, IH), 7.40 (m, IH), 7.58 (m, IH), 7.60 (s, IH), 7.73 (m, 4H); MS (CSI) m/z 331 (M+H)+.
Example 87 3-r2-(2-r(2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vD-5-rthien-2-ylmethvD- 1.2.4- oxadiazole
Example 87A 4-hvdroxy-3-iodobenzonitrile In a 2000 mL round-bottom flask containing 10.0 g (84 mmol) of 4-cyanophenol, 450 mL cone, ammonium hydroxide was added and contents were allowed to stir at 25 °C for 15 min. Next, a solution of 67.9 g (409 mmol) potassium iodide and 21.3 g (84 mmol) iodine chips, dissolved in 100 mL water, was quickly added. The reaction mixture was allowed to stir at 25 °C for 18h at which time contents were filtered. The filtrate was concentrated under reduced pressure and redissolved in 500 mL dichloromethane. The organic layer was then washed twice with 250 mL water, dried, and concentrated under reduced pressure to provide the title compound as a light yellow solid (14.3 g, 67% yield). 'HNMR (300 MHz, CDC13) δ 7.03 (d, IH), 7.66 (dd, IH), 7.98 (s, IH); MS DCI m/e, 263 (M+NH4)+.
Example 87B 2-(2-[(2R)-2-methylpyrrolidin-l-yllethvI}-l-benzofuran-5-carbonitrile The product from Example 87A (10.0 g, 40.81 mmol) was sequentially treated with 0.1M (2R)-l-(3-butynyl)-2-methylpyrrolidine in acetonitrile (490 mL, 48.9 mmol), Pd(OAc)2 (0.275 g, 1.22 mmol), Ptol3 (0.747 g, 2.44 mmol), and copper iodide (1.16 g, 6.122 mmol). After stirring at 25°C for 10 min, diisopropyl amine (43.0 mL) was added and the reaction mixture was heated at 60°C in an inert atmosphere for 16h. The reaction mixture was cooled, filtered through celite, concentrated under reduced pressure, and purified on silica gel using 95% DCM, 9.5% MeOH, 0.1% NH4OH to provide the title compound as a brown semi-solid (2.56 g, 24.6% yield). 'HNMR (300 MHz, CD3OD) δ 1.09 (d, 3H, J=6.1 Hz), 1.46 (m, IH), 1.81 (m, 2H), 2.02-2.38 (m, 2H), 2.59 (m, 2H) 3.08 (m, 2H), 3.28 (m, 2H), 6.70 (s, IH), 7.58 (s, IH), 7.97 (s, IH); MS (ESI) m/e 255 (M+H)+.
Example 87C N'-hvdroxy-2-{2- (2R)-2-methylpyrrolidin-l-yl]ethvU-l-benzofuran-5-carboximidamide The product from Example 87B (2.5 g, 9.83 mmol) in EtOH (200 mL) was stirred at 25°C for 10 minutes. The mixture was treated with hydroxylamine hydrochloride (1.71 g, 24.6 mmol) and potassium carbonate (4.49 g, 32.48 mmol) and the resulting mixture was heated at 95°C for 16h with stirring. The reaction mixture was subsequently cooled, filtered through celite, and concentrated under reduced pressure. The crude product was purified with flash chromatography to provide the title compound (1.43 g, 51% yield). MS (ESI) m/e 288 (M+H)+.
Example 87D 3-(2-{2-rf2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-5-(thien-2-ylmethvP-1.2.4- oxadiazole The product from Example 87C (0.06 g, 0.209 mmol) in acetone (10 mL) was treated with triethylamine (34.9 μL, 0.25 mmol) and stirred at 25°C for 10 minutes. The mixture was slowly treated with thien-2-ylacetyl chloride (25.7 μL, 0.25 mmol) and stirred at 25°C for 18h. The solvent was evaporated under reduced pressure, redissolved in dichloromethane (DCM) (25 mL), washed twice with water (25 mL), dried, and concentrated. The residue was dissolved in toluene (25 mL) and heated atl 10 °C in the presence of 3 A molecular sieves for 16h. The solvent was evaporated and crude product was purified on a Waters Nova-Pak HR C18 column (40 mm X 100 mm, 6 Dm particle size) using a gradient of 10%> to 100%, acetonitrile:0.1% aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL/min to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.42 (d, 3H, J=6.1 Hz), 1.78 (m, IH), 2.09 (m, 2H), 2.36 (m, IH), 3.20-3.59 (m, 5H), 3.78 (m, 2H), 4.59 (s, 2H), 6.82 (s, IH), 7.01 (t, IH). 7.09 (s, IH), 7.38 (dd, IH), 7.60 (d, IH), 8.01 (dd, IH), 8.27 (s, IH); MS (ESI) m/e 394 (M+H)+.
Example 88 4- 3-(2-(2-r(2R)-2-methylpyrrolidin-l-yl]ethyl)-l-benzofuran-5-vP-L2,4-oxadiazol-5- yllbenzonitrile 4-Cyanobenzoyl chloride was processed as described in Example 87D to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.46 (d, 3H, J=6.1 Hz), 1.78 (m, IH), 2.09 (m, 2H), 2.36 (m, IH), 3.18-3.79 (m, 7H), 6.82 (s, IH), 7.18 (m, 2H), 7.65 (d, IH), 8.03 (d, 2H), 8.16 (dd, IH), 8.41 (s, IH); MS (ESI) m/e 399 (M+H)+.
Example 89 5-(4-chlorophenvP-3-.2-(2-F(2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole 4-Chlorobenzoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 408 (M+H)+.
Example 90 5-(2-chlorophenvP-3-(2-l2-r(2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole 2-Chlorobenzoyl chloride was processed as described in Example 87D to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.46 (d, 3H, J=6.1 Hz), 1.78 (m, IH), 2.11 (m, 2H), 2.38 (m, IH), 3.21-3.90 (m, 7H), 6.88 (s, IH), 7.56-7.73 (m, 4H), 8.17 (m, 2H), 8.41 (s, IH); MS (ESI) m/e 408 (M+H)+.
Example 91 5-(4-fluorobenzvP-3-(2-{2-["(2R)-2-methylpyrrolidin-l-yl1ethyl)-l-benzofuran-5-yl)-1.2,4- oxadiazole (4-Fluorophenyl)acetyl chloride was processed as described in Example 87D to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.46 (d, 3H, J=6.1 Hz), 1.78 (m, IH), 2.1 1 (m, 2H), 2.38 (m, IH), 3.21-3.90 (m, 7H), 4.38 (s, 2H), 6.82 (s, IH), 7.10 (m, 2H), 7.42 (m, 2H), 7.59 (d, IH), 7.99 (dd, IH), 8.26 (s, IH); MS (ESI) m/e 406 (M+H)+.
Example 92 5-(4-methoxybenzvP-3-(2-(2- r2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole (4-Methoxyphenyl)acetyl chloride was processed as described in Example 87D to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.46 (d, 3H, J=6.1 Hz), 1.78 (m, IH), 2.10 (m, 2H), 2.38 (m, IH), 3.21-3.90 (m, 7H), 3.78 (s, 3H), 4.28 (s, 2H), 6.83 (s, IH), 6.92 (d, 2H), 7.32 (d, 2H), 7.59 (d, IH), 7.99 (dd, IH), 8.26 (s, IH); MS (ESI) m/e 418 (M+H)+.
Example 93 3-(r3-(2-l2-rf2R)-2-methylpyrrolidin-l-yl]ethyl)-l-benzofuran-5-vD-1.2.4-oxadiazol-5- yllmethyl ) benzonitrile 3-Cyanobenzoyl chloride was processed as described in Example 87D to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.46 (d, 3H, J=6.1 Hz), 1.78 (m, IH), 2.11 (m, 2H), 2.38 (m, IH), 3.21-3.91 (m, 7H), 6.86 (s, IH), 7.56 (m, 2H), 7.62 (d, IH), 8.09 (dd, IH), 8.21 (m, IH), 8.38 (m, 2H); MS (ESI) m/e 399 (M+H)+.
Example 94 3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl1ethvU-l-benzofuran-5-vP-5-phenyl-1.2.4-oxadiazole
Benzoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 374 (M+H)+.
Example 95 5-(4-fluorophenvP-3-(2-(2-r(2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole 4-Fluorobenzoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 392 (M+H)+.
Example 96 5-(3-chloro-4-fluorophenvP-3-(2-{2- (2R)-2-methylpyrrolidin-l-yl1ethyl)-l-benzofuran-5- vP-1 ,2,4-oxadiazole 3-Chloro-4-fluorobenzoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 426 (M+H)+.
Example 97 5-(chloromethvP-3-(2-(2-f(2R -2-methylpyrrolidin-l-yl1ethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole Chloroacetyl chloride was processed as described in Example 87D to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.46 (d, 3H, J=6.1 Hz), 1.78 (m, IH), 2.10 (m, 2H), 2.38 (m, I H), 3.21-3.90 (m, 7H), 4.96 (s, 2H), 6.83 (s, IH), 7.61 (d, IH), 8.02 (dd, IH), 8.29 (s, IH); MS (ESI) m/e 346 (M+H)+. Example 98 3-r2-(2-r(2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-5-propyl-1.2.4-oxadiazole
Butanoyl chloride was processed as described in Example 87D to provide the title compound. 'HNMR (300 MHz, CD3OD) 8 1.42-1.48 (m, 10H), 1.78 (m, IH), 2.10 (m, 2H), 2.38 (m, I H), 3.21 -3.90 (m, 7H), 4.96, 6.83 (s, IH), 7.59 (d, IH), 8.01 (dd, IH), 8.27 (s, IH); MS (ESI) m/e 340 (M+H)+.
Example 99 5-ethyl-3-(2-{2-r(2R -2-methylpyrrolidin-l-yl]ethyl)-l-benzofuran-5-vP-l,2.4-oxadiazole Propanoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 326 (M+H)+.
Example 100 5-methyl-3-(2-{2-[(2R)-2-methylpyrrolidin-l-vnethyl)-l-benzofuran-5-yP-1.2.4-oxadiazole
Acetyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 312 (M+H)+.
Example 101 4-(3-bromo-2-{2-[(2R)-2-methylpyrrolidin-l-vnethyl)-l-benzofuran-5-yPbenzonitrile The product from Example ID (2.5 g (5.2 mmol) and trifluoroacetic acid (40 mL) (TFA) were combined and stirred at 25 °C for 10 min. The mixture was slowly treated with a solution of Br2 (450 μL, 7.8 mmol) in TFA (10 mL). The mixture was allowed to stir at 25 °C for lh and then treated with saturated aqueous Na2SO3. The mixture was concentrated and redissolved in 50 mL ethyl acetate. The organic phase was washed with 1M NaOH, dried, and concentrated under reduced pressure to provide the title compound (2.1 g, 97% yield). 'HNMR (300 MHz, CD3OD) 8 1.16 (d, 3H, J=6.1 Hz), 1.42 (m, IH), 1.78 (m, 2H), 1.98 (m, I H), 2.32 (m, IH), 2.50 (m, 2H)/3.11 (m, 2H), 3.28 (m, 2H), 7.58-7.70 (m, 3H), 7.82 (m, 4H); MS (ESI) m/e 409 (M+H)+.
Example 102 4-(3-(2-fi.u-vP-2-{2-r(2R)-2-methylpyrrolidin-l-yl1ethyl}-l-benzofuran-5-vPbenzonitrile The product from Example 101 (0.100 g, 0.244 mmol) in dimethoxye thane (DME) (10 mL) was treated with Pd(PPh3)4 (0.008 g, 0.0073 mmol), 2-furylboronic acid (0.041 g, 0.317 mmol), and 1M Na2CO3 (1 mL) and the reaction mixture was refluxed in an inert atmosphere for 18h. The mixture was allowed to cool to room temperature, filtered through celite, and concentrated under reduced pressure. The crude product was purified on a Waters Nova-Pak HR CI 8 column (40 mm X 100 mm, 6 μm particle size) using a gradient of 10% to 100%, acetonitrile: 0.1% aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL/min to provide the title compound. 'HNMR (300 MHz, CD3OD) 8 1.46 (d, 3H, J=6.1 Hz), 1.78 (m, IH), 2.09 (m, 2H), 2.38 (m, IH), 3.46-3.96 (m, 7H), 6.67 (s, IH), 6.98 (s, IH), 7.64-7.77 (m, 3H). 7.81-7.92 (m, 4H), 8.16 (s, IH); MS (ESI) m/e 397 (M+H)+.
Example 103 4- 2-{2- (2R)-2-methyl-l-pyrrolidinyl1ethyl)-3-(3-pyridinvP-l-benzofuran-5-yllbenzonitrile
3-Pyridinylboronic acid was processed as described in Example 102 to provide the title compound. 'HNMR (300 MHz, CD3OD) δ 1.46 (d, 3H, J=6.1 Hz), 1.78 (m, IH), 2.06 (m, 2H), 2.37 (m, IH), 3.20-3.96 (m, 7H), 7.73-7.87 (m, 8H). 8.36 (d, IH), 8.76 (s, IH), 8.92 (s, IH); MS (ESI) m/e 408 (M+H)+.
Example 104 4-[2-(2-[(2R)-2-methyl-l-pyιτolidinyl]ethyl)-3-(3-thienvP-l-benzofuran-5-yllbenzonitrile 3-Thienylboronic acid was processed as described in Example 102 to provide the title compound. 'HNMR (300 MHz, CD3OD) 8 1.43 (d, 3H, J=6.1 Hz), 1.76 (m, IH), 2.03 (m, 2H), 2.35 (m, IH), 3.18-3.89 (m, 7H), 7.42 (dd, IH), 7.65-7.72 (m, 4H). 7.78-7.87 ( , 5H); MS (ESI) m/e 413 (M+H)+.
Example 105 4-(3-r2-formyl-3-thienvP-2--.2-r(2R)-2-methyl-l-pyrrolidinvnethyl)-l-benzofuran-5- vPbenzonitrile 2-Formyl-3-thienylboronic acid was processed as described in Example 102 to provide the title compound. MS (ESI) m/e 441 (M+H)+.
Example 106 2-methyl-4-f 2- (2-[Y 2R)-2-methyl- 1 -pyrrolidinyllethyl) - 1 -benzofuran-5-vPbenzonitrile
Example 106A 4'-methoxy-3-methyl- 1 , 1 '-biphenyl-4-carbonitrile 4-Bromo-2-methylbenzonitrile (4.9 g, 25.0 mmol), Pd(PPli3) (578 mg) in benzene (50 mL) and 2.0 M aqueous solution of Na2CO (25 mL, 50.0 mmol) was treated with 4- methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) and heated at 75 °C for 17 hours. The mixture was allowed to cool to room temperature and the phases were separated. The aqueous phase was extracted with diethyl ether (3x40 mL). The original benzene layer and the diethyl ether extracts were combined, filtered over celite, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography over silica using a mixture of hexane/CH2θ2 (3: 1) to provide the title compound as a white powder (5.73 g, 85 % yield). 'HNMR (300 MHz, CDC13) δ 2.35 (3H), 3.70 (s, 3H), 6.80-7.50 (m, 7H); MS (DCI) m/z 224 (M+H)+.
Example 106B 4'-hydroxy-3 -methyl- 1 , 1 '-biphenyl-4-carbonitrile The product from Example 106A (5.60 g, 25.4 mmol) in CH2C12 (120 mL) at 78 °C was treated with 1.0 M BBr (in CH2CI2, 76 mL, 76.0 mmol) dropwise over 1 hour. After stirring for 14 hours at room temperature, the mixture was warmed to 0 °C (ice bath) and treated with water (0.5 mL). After 10 minutes, additional water was added (2.0 mL), ice bath was removed, and 5.0 mL of water was added. The mixture was then treated with another 20 mL of water and allowed to stir for 45 minutes. The mixture was filtered and the filtrate extracted with CH2CI2. The CH2CI2 layers were combined, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to provide the title compound as an off-white powder (5.04 g, 94% yield). 'HNMR (300 MHz, CDCI3) δ 2.35 (s, 3H), 5.0 (s, IH), 6.79-7.50 (m, 7H); MS (DCI) m/z 210 (M+H)+.
Example 106C 4 ' -hydroxy-3 ' -iodo-3 -methyl- 1.1 ' -biphenyl-4-carboni trile The product from Example 106B (4.67 g, 22.3 mmol), Nal (3.343 g, 22.3 mmol), and NaOH (892 mg, 22.3 mmol) were combined in methanol (70 mL) at 0 °C and treated with bleach (5.25%, 31.6 g) dropwise over 30 minutes. After being stirred at 0 °C for 80 minutes, the mixture was quenched with 10% aqueous sodium thiosulfate (10 mL). The mixture was acidified with 1M aqueous HC1 (25 mL), neutralized with dipotassium hydrogen phosphate, recooled to 0 °C, and filtered. The solids were rinsed with water, then mostly dissolved in 50% EtOAc / hexanes and filtered. When this filtrate was mostly concentrated crystals began to form. The solids were slurried with 20% EtOAc/hexanes, collected by filtration, and washed with 10% EtOAc / hexanes followed by hexanes to provide the impure title compound as a light tan powder (52% yield). MS (ESI APCI negative ion detection) m/z 334 (M-HV; 'HNMR (300 MHz, d6-DMSO) δ 2.52 (s, 3H), 6.98 (d, 1 H), 7.58-7.63 (m, 2 H), 7.73 (s, 1 H), 7.78 (d, 1 H), 8.06 (d, 1 H), 10.66 (s, 1 H).
Example 106D 2-methyl-4-(2-|2-r(2R -2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-yPbenzonitrile The product from Example 106C (670 mg, 2.00 mmol), palladium (II) acetate (22 mg, 0.10 mmol), tri-o-tolylphosphine (61 mg, 0.20 mmol), copper (I) iodide (114 mg, 0.60 mmol), and diisopropylamine (2.8 mL, 20 mmol) were dissolved into a 0.1M MeCN solution of (R)-l-but-3-ynyl-2-methylpyrrolidine (30 mL, 3.0 mmol) and heated at 55 °C overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and chromatographed through a short column of silica with a 10 to 100% gradient of EtOAc / CH2C12 to provide the impure title compound as an orange-brown foam (55% yield), a portion of which was purified by HPLC [Waters Nova-Pak HR C18 column (40 mm X 100 mm, 6 μm particle size) using a gradient of 10% to 100%) MeCN / 0.1%> aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL / min.]. TFA salt: MS (AP) m/z 345 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.49 (d, 3 H), 1.68-1.82 (m, 1 H), 1.99-2.23 (m, 2 H), 2.30-2.44 (m, 1 H), 2.60 (s, 3 H), 3.22-3.90 (m, 7 H) 6.82 (s, 1 H), 7.55-7.87 (m, 6 H).
Example 107 3-methyl-4-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-vPbenzonitrile
Example 107 A 4'-hydroxy-3 '-iodo-2-methyl-l .1 '-biphenyl-4-carbonitrile 4'-Hydroxy-2-methyl-l, -biphenyl-4-carbonitrile was processed as described in Example 106C to provide the title compound as a light tan powder (69% yield). MS (ESI APCI negative ion detection) m/z 334 (M-H)"; 'HNMR (300 MHz, d6-DMSO) δ 2.27 (s, 3 H), 6.96 (d, 1 H), 7.23 (dd, 1 H), 7.37 (d, 1 H), 7.65-7.69 (m, 2 H), 7.77 (d, 1 H), 10.56 (s, 1 H).
Example 107B 3-methyl-4-(2-(2- (f2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile The product from Example 107 A was processed as described in Example 106D to provide the impure title compound as an orange-brown foam (42% yield), a portion of which was purified by HPLC to provide the TFA salt. 'HNMR (300 MHz, CD3OD) δ 1.49 (d, 3 H), 1.68-1.83 (m, 1 H), 1.98-2.24 (m, 2 H), 2.29 (s, 3 H), 2.29-2.43 (m, 1 H), 3.18-3.90 (m, 7 H), 6.79 (s, 1 H), 7.24 (dd, 1 H), 7.39 (d, 1 H), 7.50-7.70 (m, 4 H).
Example 108 4-(6-methyl-2-(2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-yl)benzonitrile and 4-(4-methyl-2-j2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile
4'-hydroxy-5 '-iodo-2'-methyl- 1 , 1 '-biphenyl-4-carbonitrile and
4 ' -hydroxy-3 ' -iodo-2 ' -methyl- 1.1 ' -biphenyl-4-carbonitrile 4 '-Hydroxy-2' -methyl- l,r-biphenyl-4-carbonitrile was processed as described in Example 106C, except that after neutralization with dipotassium hydrogen phosphate the mixture was extracted with 20% hexanes / EtOAc. The residue was chromatographed through silica with a 25% to 75% gradient of CH2C-2 / hexanes to provide a 7.6: 1 mixture (NMR) of the title compounds as a white microcrystalline solid (67% yield). MS (ESI APCI negative ion detection) m/z 334 (M-H)"; 'HNMR (300 MHz, CDCI3) δ 2.18 (s, 3 H), 5.29 (s, 1 H), 6.93 (s, 1 H), 7.38 (d, 2 H), 7.48 (s, 1 H), 7.69 (d, 2 H).
Example 108B 4-(6-methyl-2-{2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile and 4-(4-methyl-2-{2-[(2R -2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-vPbenzonitrile The 7.6: 1 mixture of Example 108A was processed as described Example 106D, except that after concentration the residue was partitioned between CH2CI2 and 10% aqueous ammonia. The residue was chromatographed through a short column of silica with a 0% to 2% gradient of MeOH / CH2C12 and then purified by HPLC [Waters Nova-Pak HR C18 column (40 mm X 100 mm, 6 Dm particle size) using a gradient of 10%> to 100% MeCN / 0.1%, aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL/min.] to provide the TFA salt of the title compounds as a brown-orange gum (23%> yield). MS (ESI APCI) m/z 345 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.48 (d, 3 H), 1.67-1.83 (m, 1 H), 1.98-2.23 (m, 2 H), 2.3-2.42 (m, 1 H), 2.31 (s, 3 H), 3.19-3.61 (m, 5 H), 3.70-3.88 (m, 2 H), 6.53 (s, 1 H), 7.32 (s, 1 H), 7.36 (s, 1 H), 7.52 (d, 2 H), 7.79 (d, 2 H).
Example 109 4-(7-methyl-2-|2- (2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- yPbenzonitrileExample 109 A 4'-hydroxy-5 '-iodo-3 ' -methyl- 1 , 1 '-biphenyl-4-carbonitrile 4 '-hydroxy-3' -methyl- 1, 1 '-biphenyl-4-carbonitrile (875 mg, 4.18 mmol) was dissolved into DMF (20 mL) and treated with N-iodosuccinimide (1.012 g, 4.5 mmol). The solution was stirred at room temperature for four days. Then the mixture was stirred with tetramefhylguanidine (1 mL) for ten minutes, poured into an aqueous mixture of Na2S03 and Na2C03, adjusted to pH 9 with aqueous potassium dihydrogen phosphate, and diluted with ether. The gum which separated from the biphasic mixture was dissolved into EtOAc and added to a rapidly stirred mixture of the aqueous phase and ether. The organic phase was separated, filtered, combined with the original ethereal phase, concentrated, and chromatographed through silica with a 50% to 100% gradient of CH2CI2 / hexanes to provide the title compound as an off-white powder (17% yield). MS (ESI APCI negative ion detection) m/z 334 (M-H)-; 'HNMR (300 MHz, CDCI3) δ 2.38 (s, 3 H), 7.26 (s, 1 H), 7.33 (d, 1 H), 7.60 (d, 2 H), 7.66-774 (m, 3 H).
Example 109B 4-(7-methyl-2-{2-[(2R)-2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-vPbenzonitrile The product from Example 109A was processed as described for Example 106D to provide the title compound as a brown-orange gum (44%> yield), a portion of which was purified by HPLC [Waters Nova-Pak HR C18 column (40 mm X 100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN / 0.1 %> aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL / min.] to provide the TFA salt. MS (ESI APCI) m/z 345 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.49 (s, 3 H), 1.68-1.83 (m, 1 H), 1.99-2.23 (m, 2 H), 2.30- 2.43 (m, 1 H), 2.57 (s, 3 H), 3.21-3.64 (m, 5 H), 3.71-3.91 (m, 2 H), 6.79 (s, 1 H), 7.41 (m, 1 H), 7.68 (d, 1 H), 7.75-7.84 (m, 4 H).
Example 110 4-(7-fluoro-2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-vPbenzonitrile
Example 1 10A 3 ' -fluoro-4 ' -hydroxy-5 ' -iodo- 1.1 ' -biphenyl-4-carboni trile 3 '-Fluoro-4' -hydroxy- l,l '-biphenyl-4-carbonitrile (320 mg, 1.50 mmol) was dissolved into DMF (7 mL) and treated with N-iodosuccinimide (360 mg, 1.60 mmol). The solution was stirred at room temperature overnight. Then the mixture was poured into an aqueous mixture of Na2S03 and Na2C03, adjusted to pH 9 with aqueous potassium dihydrogen phosphate, and extracted with ether. The combined organic phases were dried (Na2S0 ) and concentrated to provide the title compound as a pinkish solid (100 % yield). MS (ESI APCI negative ion detection) m/z 338 (M-H)".
Example HOB 4-(7-fluoro-2-{2-[(2R)-2-methyl-l -pyrrolidinyljethyl) -l-benzofuran-5-vPbenzonitrile The product from Example 110A was processed as described for Example 106D, except that after the solution was heated overnight, it was heated for an additional eight hours at 80 °C. The reaction mixture was cooled to room temperature and chromatographed through a short column of silica with 1 :8 hexanes / CH2CI2, followed by a 0 to 2% gradient of MeOH / CH2CI2. The appropriate fractions were concentrated and purified by HPLC [Waters Nova-Pak HR C18 column (25 mm X 100 mm, 6 μm particle size) using a gradient of 10% to 100%, MeCN / 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL / min.] to provide the title compound (2 % yield). MS (ESI) m/z 349 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.18 (d, 3 H), 1.39-1.53 (m, 1 H), 1.74-1.86 (m, 2 H), 1.95-2.09 (m, 1 H), 2.26-2.38 (m, 1 H), 2.44-2.63 (m, 2 H), 2.98-3.36 (m, 4 H), 6.72 (d, 1 H), 7.37 (dd, 1 H), 7.65 (d, 1 H), 7.77-7.87 (m, 4 H).
Example 11 1 2-fluoro-4-(2-l2-[.2R)-2-methyl-l-pyrrolidinyllethyl}-l-benzofuran-5-vPbenzonitrile
Example 1 11A 3 -fluoro-4' -methoxy- 1.1 '-biphenyl-4-carbonitrile A mixture of 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) was added to a solution of 4-bromo-2-fluorobenzonitrile (5.00 g, 25.0 mmol) and tetrakis(triphenylphosphine)palladium (578 mg, 0.50 mmol) in benzene (50 mL). The resulting mixture was treated with a 2.0 M aqueous solution of Na2CO3 (25 mL, 50 mmol) and heated briefly at reflux, then at 65 °C overnight. The mixture was cooled to room temperature and treated with 6.0 M aqueous NaOH. The aqueous phase was separated and extracted with ether. First the original organic phase and then the ethereal wash were filtered through diatomaceous earth. The collection flask was changed and the solids remaining atop the diatomaceous earth were washed through with EtOAc. The ethereal wash was concentrated and refiltered as before. The combined EtOAc rinses were combined and concentrated to provide the title compound as a yellow powder (92% yield). 'HNMR (300 MHz, d6-DMSO) δ 3.82 (s, 3 H), 7.07 (d, 2 H), 7.72 (dd, 1 H), 7.79 (d, 2 H), 7.85 (dd, 1 H), 7.95 (dd, 1 H).
Example 11 IB 3 -fluoro-4' -hydroxy- 1 , 1 '-biphenyl-4-carbonitrile The product from Example 11 1 A was processed as described in Example 106B, except that the extraction was conducted with EtOAc, to provide the title compound as a tan powder (100% yield). MS (ESI APCI negative ion detection) m/z 212 (M-H)"; "HNMR (300 MHz, CDC1 ) δ 3.82 (bs, 1 H), 6.94 (d, 2 H), 7.37 (dd, 1 H), 7.41-7.49 (m, 3 H), 7.63 (dd, 1
H).
Example 1 1 1 C 3 -fluoro-4 ' -hydroxy-3 ' -iodo- 1 , 1 '-biphenyl-4-carbonitrile The product from Example 11 IB was processed as described for Example 106C, except that the solids collected after cold-filtering were rinsed consecutively with 50% aqueous methanol and water, and dried under reduced pressure to provide the title compound as an off-white powder (86% yield). MS (ESI negative ion detection) m/z 338 (M-H)"; 'HNMR (300 MHz, CDC13 / CD3OD) δ 3.53 (bs, 1 H), 6.96 (d, 1 H), 7.34-7.49 (m, 3 H), 7.65 (dd, 1 H), 7.94 (d, 1 H).
Example 1 1 1 D 2-fluoro-4-(2-{2-[(2R)-2-methyl-l-pyrrolidinyllethyl}-l-benzofuran-5-vPbenzonitrile The product from Example 11 IC was processed as described for Example 106D, except that the solution was heated at 50 °C overnight and then at 80 °C for eight hours. The reaction mixture was cooled to room temperature and chromatographed through a short column of silica with a 0 to 2% gradient of MeOH / CH2CI2. The appropriate fractions were concentrated and then rechromatographed through a short column of silica with 1 % AcOH / CH2CI2, followed by a 0 to 2% gradient of MeOH / CH2CI2 to provide the acetic acid salt of the title compound as a brown foamy powder (28% yield). MS (ESI APCI) m/z 349 (M+H)+; 'HNMR (300 MHz, CD3OD) D 1.40 (d, 3 H), 1.60-1.77 (m, 1 H), [1.97 (s)], 1.97-2.1 1 (m, 2 H), 2.20-2.36 (m, 1 H), 2.99-3.10 (m, 1 H), 3.16-3.76 (m, 6 H), 6.79 (s, 1 H), 7.58 (d, 1 H), 7.62 (dd, 1 H), 7.64-7.70 (m, 2 H), 7.81 (dd, 1 H), 7.90 (d, 1 H).
Example 112 3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile
Example 112A 4-bromo-2-iodophenol 4-Bromophenol was processed as described in Example 106C, except that after neutralization the mixture was was partitioned between 20%> EtOAc/hexanes (250 mL) and brine (50 mL) and the aqueous phase was separated and reextracted until nearly all the product was removed (TLC). The combined organic phases were washed with brine, dried (Na2S0 ), and concentrated to provide the (90% pure) title compound (100% yield). A portion was purified by chromatography on silica using a 25 to 80% gradient of CH2CI2 / hexanes. 'HNMR (300 MHz, d6-DMSO) δ 6.83 (d, 1 H), 7.36 (dd, 1 H), 7.79 (d, 1 H), 10.59
(s, 1 H).
Example 112B 2-(5-bromo-l-benzofuran-2-vPethanol The product from Example 1 12A (26.9 g, 90% pure, 80 mmol), 3-butyn-l-ol (6.05 mL, 79.9 mmol), and copper (I) oxide (7.15 g, 50.0 mmol) were suspended in a mixture of pyridine (40 mL) and 1 -methyl-2-pyrrolidinone (160 mL) and heated at 70 °C overnight, then at 100 °C for 3.5 hours. The mixture was cooled towards room temperature, diluted with ether and filtered. The filtrate was diluted with additional ether and washed consecutively with 5% aqueous ammonia, 0.5 M aqueous NaOH, and brine. It was dried (Na2SO ), concentrated, and reconcentrated from EtOAc. 2:1 Hexanes/CH2θ2 was added to the resulting syrup and the mixture was cooled to -78 °C. Upon warming towards room temperature, the pure title compound crystallized as an off-white microcrystalline solid. It was collected by filtration and washed with 4: 1 hexanes / CH2CI2, then hexanes (8%> yield). 'HNMR (300 MHz, d6-DMSO) 8 2.92 (t, 2 H), 3.75 (dt, 2 H), 4.82 (t, 1 H), 6.63 (s, 1 H), 7.35 (dd, 1 H), 7.48 (d, 1 H), 7.75 (d, 1 H).
Example 112C 3-[2-(2-hydroxyethvP- 1 -benzofuran-5-yllbenzonitrile The product from Example 112B(193 mg, 0.80 mmol), 3-cyanophenylboronic acid (147 mg, 1.00 mmol), and tetrakis(triphenylphosphine)palladium (35 mg, 0.030 mmol) were suspended into dioxane (3 mL) and then treated with 1.0 M aqueous Na2C03 (2.1 mL, 2.1 mmol). The mixture was heated at 90 °C for 3.5 hours, then cooled to room temperature, partitioned between EtOAc and water, worked up as usual, dried (Na2SO ), and concentrated. The residue was chromatographed through a short column of silica with a 0 to 2%> gradient of EtOAc / CH2CI2 to provide the title compound as a tea-colored syrup (82% yield). 'HNMR (300 MHz, d6-DMSO) δ 2.95 (t, 2 H), 3.78 (dt, 2 H), 4.83 (t, 1 H), 6.70 (s, 1 H), 7.59-7.61 (m, 2 H), 7.66 (dd, 1 H), 7.80 (ddd, 1 H), 7.91 (dd, 1 H), 8.04 (ddd, 1 H), 8.15 (dd, 1 H).
Example 1 12D 2-[5-(3-cvanophenyl)-l-benzofuran-2-yl]ethyl methanesulfonate The product from Example 112C (170 mg, 0.65 mmol) and triethylamine (100 μL, 0.72 mmol) were dissolved into CH2CI2 (3 mL) and cooled to 0°C. The solution was treated with methanesulfonyl chloride (55 μL, 0.71 mmol), and after 10 minutes it was permitted to slowly warm to room temperature. More methanesulfonyl chloride (10 μL, 0.13 mmol) and triethylamine (10 μL, 0.072 mmol) were added. The mixture was stirred until the reaction was nearly complete and then washed consecutively with water and brine, dried (Na2S04), concentrated, and used without further purification in the next step.
Example 1 12E 3-(2- (2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-5-yDbenzonitrile The crude product from Example 1 12D, the mono-(L)-tartaric acid salt of (2R)-2- methylpyrrolidine (306 mg, 1.3 mmol), and CS2CO3 (652 mg, 2.0 mmol) were stirred in an approximately 0.2 M MeCN solution of (2R)-2-methylpyrrolidine (1.6 mL, 0.3 mmol). The mixture was heated at 40 °C overnight. More CS2CO3 (326 mg, 1.0 mmol) and acetonitrile (0.5 mL) were added and the reaction was stirred at 40 °C for four days. The mixture was cooled to room temperature, diluted with CH2CI2, filtered, and concentrated. The residue was chromatographed twice through a short column of silica with a 0 to 5% gradient of MeOH/CH2Cl2 to provide the title compound as an orange-tan gum (28% yield). 'HNMR (300 MHz, CD3OD) δ 1.18 (d, 3 H), 1.39-1.54 (m, 1 H), 1.75-1.87 (m, 2 H), 1.96-2.09 (m, 1 H), 2.27-2.39 (m, 1 H), 2.46-2.63 (m, 2 H), 2.95-3.15 (m, 2 H), 3.20-3.35 (m, 2 H), 6.63 (s, 1 H), 7.49-7.52 (m, 2 H), 7.62 (dd, 1 H), 7.67 (ddd, 1 H), 7.78 (dd, 1 H), 7.90 (ddd, 1 H), 7.98 (dd, 1 H).
Example 113 (2R)- 1 - {2-[5-(4-fluorophenyP- 1 -benzofuran-2-yllethyl) -2-methylpyrrolidine
Example 1 13 A 2-r5-(4-fluorophenvD-benzofuran-2-yll-ethanol 4-Fluorophenylboronic acid was processed as described in Example 1 12C to provide the title compound as a white microcrystalline solid (19% yield). 'HNMR (300 MHz, d6- DMSO) δ 2.94 (t, 2 H), 3.77 (dt, 2 H), 4.84 (t, 1 H), 6.67 (s, 1 H), 7.28 (dd, 2 H), 7.48 (dd, 1 H), 7.56 (d, 1 H), 7.70 (dd, 2 H), 7.78 (d, 1 H). Example 1 13B (2R)-1 - (2-r5-C4-fluorophenvP- 1 -benzofuran-2 -yllethyl) -2-methylpyrrolidine The product from Example 1 13A was processed as described in Example 112D and Example 112E to provide the title compound as an orange-tan syrup (60% yield). 'HNMR (300 MHz, CD3OD) δ 1.17 (d, 3 H), 1.38-1.52 (m, 1 H), 1.72-1.86 (m, 2 H), 1.94-2.08 (m, 1 H), 2.23-2.34 (m, 1 H), 2.41-2.59 (m, 2 H), 2.92-3.13 (m, 2 H), 3.19-3.3 (m, 2 H), 6.59 (s, 1 H), 7.15 (m, 2 H), 7.43 (dd, 1 H), 7.46 (d, 1 H), 7.61 (dd, 2 H), 7.68 (d, 1 H).
Example 114 (2R)-l-{2-[5-(3.4-dichlorophenyP-l-benzofuran-2-yl]ethyl) -2-methylpyrrolidine 3,4-Dichlorophenylboronic acid was processed as described Examples 1 12C, 112D, and 112E except that in the procedure in Example 1 12E the reaction was conducted at 60 °C overnight, and after the ethereal extracts were filtered through diatomaceous earth the filtrate was concentrated and semi-purified by HPLC [Waters Nova-Pak HR C 18 column (40 mm X 100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL / min.] to provide the title compound (62% yield) as a TFA salt. MS (ESI APCI) m/z 374 / 376 / 378 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.49 (d, 3 H), 1.68-1.82 (m, 1 H), 1.99-2.23 (m, 2 H), 2.30-2.43 (m, 1 H), 3.20- 3.63 (m, 5 H), 3.70-3.90 (m, 2 H), 6.80 (s, 1 H), 7.53-7.59 (m, 4 H), 7.78-7.82 (m, 2 H).
Example 115 (2R)-2-methyl-l-{2-[5-(2-methylphenvP-l-benzofuran-2-yl]ethyl)pyrrolidine
Example 115 A (2R)-l-[2-(5-bromo-l -benzofuran-2 -vPethyl]-2-methylpyrrolidine 4-Bromo-2-iodophenol (2.99 g, 90 % pure, 9 mmol), palladium (II) acetate (112 mg, 0.50 mmol), triphenylphosphine (262 mg, 1.0 mmol), copper (I) iodide (571 mg, 3.0 mmol), and diisopropylamine (14 mL, 100 mmol) were dissolved into a 0.09 M MeCN solution of (R)-l-but-3-ynyl-2-methylpyrrόlidine (120 mL, 10.8 mmol) and stirred at room temperature three days, then at 80 °C overnight. The reaction mixture was cooled to room temperature, concentrated, and chromatographed through a short column of silica with 2: 1 hexanes / CH2CI2 followed by a 0 to 1% gradient of MeOH / CH2CI2. The appropriate fractions were concentrated, and the residue extracted with MeOH. The extracts were concentrated and partitioned between CH2Cl2 and 1 M aqueous Na2C03, worked up as usual, dried (Na2S04), and concentrated to provide the title compound as a dark red syrup (26 % yield).
Example 115B (2R)-2-methyl- 1 - {2-[5-(2-methylphenvP- 1 -benzofuran-2-yllethyl}pyrrolidine A portion (-330 μL) of a solution of the product from Example 115A (650 mg, 2.1 mmol) and tetrakis(triphenylphosphine)palladium (125 mg, 0.1 1 mmol) in benzene (6.2 mL) was added to a mixture of (2-methylphenyl)boronic acid (~24 mg, -0.18 mmol) in ethanol (150 μL). The mixture was treated with 2.0 M aqueous Na2CU3 (200 μL, 0.4 mmol), and the reaction vial was sealed, placed on a heater-stirrer apparatus, and heated at 75 °C for four days. The mixture was cooled to room temperature, diluted with 1 :1 MeOH / DMSO (1 mL), filtered, and purified by HPLC [Waters Nova-Pak HR C18 column (25 mm X 100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL / min.] to provide the title compound. MS (APCI) m/z 320 (M+H)+.
Example 1 16 (2R)-2-methyl-l-{2-[5-(3-methylphenvP-l-benzofuran-2-yl]ethyl}pyrrolidine (3-Methylphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 320 (M+H)+.
Example 117 (2R)-2 -methyl- 1 - {2-[5-(4-methylphenvP- 1 -benzofuran-2-yllethyl}pyrrolidine (4-Methylphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (APCI) m/z 320 (M+H)+.
Example 118 methyl 4-(2- (2-r(2R)-2-methyl- 1 -pyrrolidinyl]ethyl } - 1 -benzofuran-5-vPbenzoate (4-Methoxycarbonylphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 364 (M+H)+. Example 119 (2R)- 1 - (2-[5-f 2-methoxyphenvP- 1 -benzofuran-2-yl]efhyl} -2-methylpyrrolidine (2-Methoxyphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (ESI) m/z 336 (M+H)+.
Example 120 (2R)- 1 - j2-[5-(3-methoxyphenvD- 1 -benzofuran-2 -yllethyl) -2-methylpyrrolidine (3-Methoxyphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 336 (M+H)+.
Example 121 (2R)-l-{2-r5-(4-methoxyphenyP-l-benzofuran-2-vnethy ) -2-methylpyrrolidine (4-Methoxyphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (ESI) m/z 364 (M+H)+.
Example 122 (2R)-l-(2-[5-(3-fluorophenvP-l-benzofuran-2-yl]ethyl) -2-methylpyrrolidine (3-Fluorophenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (ESI) m/z 324 (M+H)+.
Example 123 (2R)-l-(2-[5-(2-chlorophenyP-l-benzofuran-2-yl1ethyl) -2-methylpyrrolidine (2-Chlorophenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 340 (M+H)+.
Example 124 (2R)-l-(2-[5-(3-chlorophenvP-l-benzofuran-2-yl]ethyl)-2-methylpyrrolidine (3-Chlorophenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 340 / 342 (M+H)+.
Example 125 l-{2-[5-.4-chlorophenyP-benzofuran-2-yll-ethyl) -2-methylpyrrolidine (4-Chlorophenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (ESI) m/z 340 / 342 (M+H)+.
Example 126 (2R)-2-methyl- 1 -(2- (5-[3-(trifluoromethvDphenyl]- 1 -benzofuran-2 -yl) ethvPpyrrolidine (3-Trifluoromethylphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (APCI) m/z 374 (M+H)+.
Example 127 (2R)-2-methyl-l-(2-(5-[4-(trifluoromethvPphenyll-l-benzofuran-2-yl)ethvDpyrrolidine (4-Trifluoromethylphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 374 (M+H)+.
Example 128 (2R -2-mefhyl-l -(2- {5-[3-(trifluoromethoxy)phenyl]- 1 -benzofuran-2-yl) ethvDpyrrolidine (3-Trifluoromethoxyphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 390 (M+H)+.
Example 129 ("2R -2-methyl-l -(2- {5-[4-(trifluoromethoxy)phenyl]-l-benzofuran-2-yl) ethvPpyrrolidine (4-Trifluoromethoxyphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (APCI) m/z 390 (M+H)+.
Example 130 ("2R 1 - (2-T5-(3 ,4-dimethylphenvD- 1 -benzoiuran-2-yllethyl) -2-methylpyrrolidine (3,4-Dimethylphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (ESI) m/z 334 (M+H)+.
Example 131 C2R -l-(2-[5-(3.5-dichlorophenvP-l-benzofuran-2-ynethyl)-2-methylpyrrolidine (3,5-Dichlorophenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (APCI) m/z 374 / 376 (M+H)+.
Example 132 (2R)-l-(2-[5-(3.5-dimethylphenyP-l-benzofuran-2-yl]ethyl)-2-methylpyrrolidine (3,5-Dimethylphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 334 (M+H)+.
Example 133 [4-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yPphenyl1methanol A solution (1.2 mL) of the product from Example 115A (350 mg, 1.1 mmol) in benzene (3.6 mL) was added to a mixture of palladium (II) acetate (11 mg, 0.05 mmol), and biphen-2-yl-dicyclohexylphosphine (28 mg, 0.08 mmol). The reaction mixture was then treated with 4-(hydroxymethyl)phenylboronic acid (87 mg, 0.57 mmol) in ethanol (500 μL) followed by 2M aqueous Na2Cθ3 (500 μL). The mixture was stirred thoroughly overnight. Additional ethanol (500 μL) was added and the mixture was stirred for four days, diluted with EtOAc, filtered, chromatographed through a short column of silica with a gradient of 0 to 2% MeOH / EtOAc, purified by HPLC [Waters Nova-Pak HR CI 8 column (25 mm X 100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL / min.], and then rechromatographed through a short column of silica with MeOH / CH2CI2 to provide the title compound (12% yield). MS (ESI APCI) m/z 336 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.21 (d, 3 H), 1.42-1.58 (m, 1 H), 1.77-1.91 (m, 2 H), 1.99-2.13 (m, 1 H), 2.35-2.77 (m, 3 H), 2.97-3.18 (m, 2 H), 3.2-3.4 (m, 2 H), 4.64 (s, 2 H), 6.61 (s, 1 H), 7.42 (d, 2 H), 7.45-7.48 (m, 2 H), 7.60 (d, 2 H), 7.72 (dd, 1 H).
Example 134 3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yPpyridine 3-(l,3,2-Dioxaborinan-2-yl)pyridine was processed as described in Example 133 to provide the title compound (1% yield). MS (ESI APCI) m/z 307 (M+H)+; 'HNMR (300 MHz, CD3OD) 8 1.20 (d, 3 H), 1.41-1.56 (m, 1 H), 1.76-1.89 (m, 2 H), 1.97-2.12 (m, 1 H), 2.32-2.70 (m, 3 H), 2.98-3.19 (m, 2 H), 3.2-3.4 (m, 2 H), 6.66 (d, 1 H), 7.47-7.57 (m, 3 H), 7.80 (dd, 1 H), 8.10 (ddd, 1 H), 8.49 (m, 1 H), 8.81 (m, 1 H).
Example 135 (2R)-1 -(2-15-1 2-("4-fluorophenvPvinyl]-l-benzofuran-2-yl)ethvP-2-methylpyrrolidine trans-2-(4-Fluorophenyl)vinylboronic acid was processed as described in Example 133 to provide the title compound (4% yield). MS (ESI APCI) m/z 350 (M+H)+.
Example 136 l-[3-(2-{2-[(2R)-2-methyl-l -pyrrolidinyl1ethyl)-l-benzofuran-5-vPphenyl]ethanone
Example 136A 1 -(4'-hydroxy- 1 , 1 '-biphenyl-3 -vPethanone 4-Iodophenol (5.39 g, 24.5 mmol) and 3-acetylphenylboronic acid (4.42 g, 26.95 mmol) were mixed in N,N-dimethylformamide (15 mL) and treated with 1.0 M aqueous Na2C03 (75 mL) and palladium (II) acetate (110 mg, 0.49 mmol). The suspension was heated at 55°C for one hour and then brought to room temperature. CH2C12 (100 mL) was added to the mixture which was then filtered. The aqueous layer of the filtrate was extracted with CH2CI2 and the combined organic phases were washed consecutively with pH 6 potassium phosphate buffer and brine, then dried (Na2S0 ), concentrated, and chromatographed through silica with a 33 to 100%) gradient of hexanes / CH2CI2 followed by a gradient of 0 to 3%> EtOAc / CH2CI2. Impure fractions were combined, concentrated, and rechromatographed as before, twice, to provide the title compound as an oil which slowly crystallized to a white solid upon standing (-95% yield). MS (ESI APCI negative ion detection) m/z 211 (M-H)"; 'HNMR (300 MHz, CDCI3) 8 2.65 (s, 3 H), 6.97 (d, 2 H), 7.47- 7.53 (m, 3 H), 7.74 (ddd, 1 H), 7.88 (ddd, 1 H), 8.13 (dd, 1 H).
Example 136B 1 -(4'-hydroxy-3 '-iodo- 1 , 1 '-biphenyl-3 -vPethanone The product from Example 136A (5.76 g, 27 mmol) was suspended in concentrated aqueous ammonia (400 mL) and treated with a solution of potassium iodide (23.3 g, 140 mmol) and iodine (7.24 g, 28.5 mmol) in water (100 mL). As the reaction did not go to completion, the mixture was treated with a second solution of potassium iodide (15.8 g, 95 mmol) and iodine (4.83 g, 19 mmol) in water (50 mL). After an hour the ammonia was removed under reduced pressure on a rotary evaporator. The mixture was extracted with EtOAc, and the combined organic phases were washed consecutively with pH 6 potassium phosphate buffer and brine, then dried (Na2SO4), concentrated, and chromatographed through silica with 1% acetic acid in a gradient of 0 to 5% EtOAc / CH2C1 to provide the title compound as a beige powder (21%) yield). MS (ESI APCI negative ion detection) m/z 337 (M-H)"; 'HNMR (300 MHz, CDC13) δ 2.65 (s, 3 H), 5.37 (bs, 1 H), 7.08 (d, 1 H), 7.48-7.55 (m, 2 H),7.71 (ddd, 1 H), 7.88-7.93 (m, 2 H), 8.09 (dd, 1 H).
Example 136C l-[3-(2-{2-[(2R -2-methyl-l-pyrrolidinyl1ethyl}-l-benzofuran-5-vPphenyl]ethanone The product from Example 136B (1.15 g, 3.40 mmol), palladium (II) acetate (38 mg, 0.17 mmol), biphen-2-yl-dicyclohexylphosphine (119 mg, 0.34 mmol), diisopropylamine (4.8 mL, 34 mmol), and copper (I) iodide (76 mg, 0.40 mmol) were suspended in a 0.09 M MeCN solution of (R)-l-but-3-ynyl-2-methylpyrrolidine (45 mL, 4.0 mmol). N,N- dimethylformamide (10 mL) was added, and the mixture was heated at 45 °C overnight, cooled to room temperature, partitioned between CH2CI2 (100 mL) and 5% aqueous ammonia (100 mL), worked up as usual but with 5% aqueous ammonia, filtered, and concentrated. The residue was dissolved into CH2CI2 and washed consecutively with water and brine, dried (Na2S04), concentrated, and chromatographed through silica with a gradient of 0 to 4% MeOH / CH2CI2. The appropriate fractions were combined and rechromatographed with 50%) CH2CI2 / hexanes followed by a gradient of 0 to 4% MeOH / CH2C12 to provide the title compound as a dark brown gum (30% yield). MS (APCI) m/z 348 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.17 (d, 3 H), 1.38-1.52 (m, 1 H), 1.73-1.86 (m, 2 H), 1.94-2.07 ( , 1 H), 2.23-2.34 (m, 1 H), 2.40-2.58 (m, 2 H), 2.67 (s, 3 H), 2.95-3.14 (m, 2 H), 3.19-3.32 (m, 2 H), 6.62 (s, 1 H), 7.49-7.52 (m, 2 H), 7.57 (dd, 1 H), 7.78 (dd, 1 H), 7.88 (ddd, 1 H), 7.96 (ddd, 1 H), 8.22 (dd, 1 H).]
Example 137 l-[3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl}-l-benzofuran-5-yPphenyl1ethanol The product from Example 136C (46 mg, 0.12 mmol) in ethanol (2 mL) and tetrahydrofuran (0.5 mL) was treated with sodium borohydride. The mixture was concentrated and passed through a short column of silica with a gradient of 2 to 10% MeOH / CH2CI2. The resulting residue rinsed with ether, dissolved into methanol (1 mL), treated with 0.1 M aqueous hydrochloric acid (0.2 mL) heated at 60 °C for three hours, treated with more 0.1 M aqueous hydrochloric acid (0.05 mL), heated at 60 °C for one hour, concentrated, and chromatographed through a short column of silica with a gradient of 2 to 10% 2 M NH3 in MeOH / CH2CI2 to provide the title compound as a white powder (11% yield). 'HNMR (300 MHz, CD3OD) δ 1.17 (d, 3 H), 1.4-1.54 (m, 1 H), 1.49 (d, 3 H), 1.73-1.86 (m, 2 H), 1.95- 2.08 (m, 1 H), 2.24-2.36 (m, 1 H), 2.43-2.60 (m, 2 H), 2.93-3.14 (m, 2 H), 3.19-3.33 (m, 2 H), 4.89 (q, 1 H), 6.59 (s, 1 H), 7.32 (ddd, 1 H), 7.39 (dd, 1 H), 7.45-7.47 (m, 2 H), 7.49 (ddd, 1 H), 7.62 (m, 1 H), 7.71 (dd, 1 H).
Example 138 2-[3-(2-{2-r(2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-yDphenyl1-2-propanol The product from Example 136C (87 mg, 0.25 mmol) was dissolved into tetrahydrofuran (5 mL), treated with 3 M methylmagnesium bromide in ether (0.3 mL, 0.9 mmol), stirred overnight, quenched with 0.5 M aqueous dipotassium hydrogen phosphate, and diluted with EtOAc and a little CH2CI2. The resulting emulsion was sonicated, and the aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na2S04), concentrated, and chromatographed on silica with a gradient of 2 to 10% MeOH / 20% MeCN / CH2C12 followed by 10% MeOH / CH2C12 to provide the title compound as an orange resin (-33% yield). 'HNMR (300 MHz, CD3OD) δ 1.20 (d, 3 H), 1.42-1.58 (m, 1 H), 1.58 (s, 6 H), 1.76-1.90 (m, 2 H), 1.96-2.12 (m, 1 H), 2.3-2.7 (m, 3 H), 2.97-3.13 (m, 2 H), 3.22-3.4 (m, 2 H), 6.62 (s, 1 H), 7.38 (dd, 1 H), 7.40-7.46 (m, 2 H), 7.46-7.48 (m, 2 H), 7.72 (dd, 1 H), 7.76 (dd, 1 H).
Example 139 1 -D-(2- (2-[(2R -2-methyl- 1 -pyrrol idinyll ethyl) - 1 -benzofuran-5-vPphenyllethanone oxime The product from Example 136C (240 mg, 0.5 mmol) and hydroxylamine hydrochloride (139 mg, 2.00 mmol) were dissolved into methanol (2 mL) and treated with Na2C03 (318 mg, 3.0 mmol). The suspension was stirred at room temperature overnight and then heated at 70 °C three days. The mixture was cooled to room temperature and filtered, the solids being rinsed with 50%, MeOH / CH2CI2. The filtrate was concentrated, then partitioned between water and MeOH / CH2CI2; some clean product remained undissolved and was separated. The organic phase was concentrated, dissolved in a little methanol, and seeded with the previously collected product. After this material had crystallized, both crops of product were rinsed with methanol and permitted to dry to provide the title compound as a white microcrystalline solid (49% yield). 'HNMR (300 MHz, CDC13) δ 1.18 (d, 3 H), 1.4-2.1 (m, 4 H), 2.2-2.6 (m, 3 H), 2.34 (s, 3 H), 3.00-3.12 (m, 2 H), 3.20-3.34 (m, 2 H), 6.49 (s, 1 H), 7.41 -7.48 (m, 3 H), 7.56-7.63 (m, 2 H), 7.68 (dd, 1 H), 7.70 (bs,l H), 7.88 (dd, 1 H).
Example 140 1 -[3-(2- |2-[(2R)-2-methyl-l -pyrrolidinyl]ethyl)-l -benzofuran-5-vPphenyl]ethanone O- methyloxime 0-Methylhydroxylamine was processed as described in Example 139, except that after the reaction was complete it was diluted with CH2CI2, filtered, concentrated, and chromatographed through a short column of silica with a gradient of 1 to 4% MeOH / CH2CI2 to provide the title compound as an orange gum (53%, yield). MS (ESI APCI) m/z 377 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.17 (d, 3 H), 1.41-1.51 (m, 1 H), 1.75-1.84 (m, 2 H), 1.96-2.05 (m, 1 H), 2.26 (s, 3 H), 2.27-2.33 (m, 1 H), 2.44-2.59 (m, 2 H), 2.96-3.11 (m, 2 H), 3.20-3.3 (m, 2 H), 3.98 (s, 3 H), 6.60 (s, 1 H), 7.45 (dd, 1 H), 7.52-7.54 (m, 2 H), 7.58- 7.65 (m, 2 H), 7.74 (s, 1 H), 7.89 (dd, 1 H).
Example 141 l-[3-(2-(2-[(2R -2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)phenyl1ethanone O- ethyloxime O-Ethylhydroxylamine was processed as described in Example 139 to provide the title compound as an orange gum (56% yield). MS (ESI APCI) m/z 391 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.17 (d, 3 H), 1.33 (t, 3 H), 1.41-1.51 (m, 1 H), 1.75-1.85 (m, 2 H), 1.97-2.06 (m, 1 H), 2.27 (s, 3 H), 2.27-2.34 (m, 1 H), 2.45-2.60 (m, 2 H), 2.96-3.12 (m, 2 H), 3.20-3.3 (m, 2 H), 4.23 (q, 2 H), 6.60 (s, 1 H), 7.44 (dd, 1 H), 7.48 (s, 2 H), 7.58-7.64 (m, 2 H), 7.73 (s, 1 H), 7.89 (dd, 1 H). Example 142 1 -[3-(2- |2-r(2R)-2-methyl- 1 -pyrrolidinyllethyl) - 1 -benzofuran-5-vPphenyllethanone 0-(tert- butyPoxime 0-tert-Butylhydroxylamine was processed as described in Example 139 to provide the title compound as an orange gum (56% yield). MS (ESI APCI) m/z 419 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.17 (d, 3 H), 1.37 (s, 9 H), 1.41-1.51 (m, 1 H), 1.75-1.84 (m, 2 H), 1.97-2.06 (m, 1 H), 2.24 (s, 3 H), 2.27-2.34 (m, 1 H), 2.45-2.59 (m, 2 H), 2.96-3.1 1 (m, 2 H), 3.20-3.3 (m, 2 H), 6.61 (s, 1 H), 7.43 (dd, 1 H), 7.47 (s, 2 H), 7.57-7.64 (m, 2 H), 7.72 (s, 1 H), 7.89 (dd, 1 H).
Example 143 ethyl 3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzoate
Example 143 A ethyl 4'-hydroxy- 1 , 1 '-biphenyl-3-carboxylate 4-Iodophenol and 3-ethoxycarbonylphenylboronic acid were processed as described in Example 136A, except that the reaction was done overnight at room temperature and the chromatography was conducted twice with 50% CH2CI2 / hexanes followed by a gradient of 0 to 1% MeOH / CH2CI2 to provide the title compound as a white powder (71% yield). 'HNMR (300 MHz, d6-DMSO) δ 1.34 (t, 3 H), 4.34 (q, 2 H), 6.89 (d, 2 H), 7.50-7.59 (m, 3 H), 7.83-7.89 (m, 2 H), 8.11 (dd, 1 H), 9.62 (s, 1 H).
Example 143B ethyl 4'-hydroxy-3'-iodo- 1 , 1 '-biphenyl-3-carboxylate The product from Example 143A (7.71 g, 31.8 mmol) was dissolved into N,N- dimethylformamide (30 mL), diluted with concentrated aqueous ammonia (320 mL), and treated with a solution of potassium iodide (27.72 g, 167 mmol) and iodine (8.48 g, 33.4 mmol) in water (100 mL) all at once. After the mixture was stirred for one hour, the ammonia was removed under reduced pressure on a rotary evaporator. The remaining solution was neutralized to pH 7 with aqueous hydrochloric acid, diluted with EtOAc (200 mL), worked up as usual, dried (Na2S04), concentrated, and chromatographed on silica with a 33 to 100%, gradient of CH2CLJ hexanes to provide the title compound as a white microcrystalline solid (37% yield). 'HNMR (300 MHz, d6-DMSO) δ 1.35 (t, 3 H), 4.35 (q, 2 H), 7.00 (d, 1 H), 7.53-7.60 (m, 2 H), 7.84-7.91 (m, 2 H), 7.97 (d, 1 H), 8.08 (dd, 1 H), 10.55 (bs, 1 H).
Example 143C ethyl 3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yPbenzoate The product from Example 143B was treated as described for Example 136C, except that the reaction was conducted at 65 °C to provide the title compound as a viscous dark brown oil (52% yield). MS (ESI APCI) m/z 378 (M+H)+.
Example 144 3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yPbenzoic acid The product from Example 143C (755 mg, 2 mmol) was dissolved into ethanol (20 mL) and treated with 2 M aqueous NaOH (2 mL). The mixture was heated at 55 °C for 40 minutes, cooled to room temperature, concentrated, and partitioned between isopropanol and a mixture of 1 M aqueous potassium dihydrogen phosphate and brine. The aqueous phase was separated and extracted with isopropanol, and the combined organic phases were washed with a mixture of pH 6 potassium phosphate buffer and brine. The aqueous phase was separated and extracted with isopropanol, and the combined organic phases were washed with brine. Again, the aqueous phase was separated and extracted with isopropanol, and the combined organic phases were diluted with EtOAc, and filtered. The filtrate was dried (Na2S0 ) and concentrated. The residue was chromatographed on silica with 50%, EtOAc / CH2CI2, followed by 10% MeOH / 45% EtOAc / CH2C12, followed by 30% MeOH / CH2C12. The appropriate fractions were concentrated and the residue dissolved into EtOAc / CH2CI2, and the solids which precipitated were washed with additional EtOAc / CH2CI2 to provide the title compound as a white powder. MS (ESI APCI) m/z 350 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.39 (s, 3 H), 1.58-1.76 (m, 1 H), 1.91-2.10 (m, 2 H), 2.16-2.31 (m, 1 H), 2.89- 3.04 (m, 1 H), 3.08-3.3 (m, 4 H), 3.50-3.71 (m, 2 H), 6.70 (s, 1 H), 7.39-7.59 (m, 3 H), 7.69 (d, 1 H), 7.79 (s, 1 H), 7.92 (d, 1 H), 8.23 (s, 1 H).]
Example 145 N-methoxy-N-me thyl-3 -(2- (2-[(2R)-2-methyl- 1 -pyrrolidinyllethyl) - 1 -benzofuran-5 - yPbenzamide The product from Example 144 was suspended in CH2C12 (25 mL) and treated with 2 M oxalyl chloride in CH2C12 (3.0 mL, 6.0 mmol). After the bubbling had subsided, N,N- dimethylformamide (300 μL) was added slowly over 15 minutes. After an additional hour, more N,N-dimethylformamide (100 μL) was added. After another 30 minutes, the mixture was concentrated and dissolved into CH2C12 (5 mL). N,O-Dimethylhydroxylamine hydrochloride (488 mg, 5.0 mmol) and pyridine (1 mL) were added, the reaction flask was placed in a water bath, and the mixture was stirred overnight, concentrated, diluted with 1 ,2- dichloroethane (5 mL), heated at 85 °C for four hours, concentrated, and partitioned between CH2CI2 and water. Saturated aqueous NaHC03 was added until the pH of the aqueous phase exceeded seven. Then the aqueous phase was separated and extracted with CH2CI2. The combined organic phases were washed consecutively with water and brine, dried (Na2S04), and chromatographed on silica with a gradient of 0 to 4% MeOH / CH2CI2 to provide the title compound as a viscous brown syrup (60% yield from ester). 'HNMR (300 MHz, CD3OD) δ 1.19 (s, 3 H), 1.37-1.54 (m, 1 H), 1.73-1.88 (m, 2 H), 1.95-2.09 (m, 1 H), 2.27-2.39 (m, 1 H), 2.45-2.64 (m, 2 H), 2.95-3.17 (m, 2 H), 3.20-3.3 (m, 2 H), 3.39 (s, 3 H), 3.63 (s, 3 H), 6.62 (s, 1 H), 7.46-7.83 (m, 4 H), 7.73-7.81 ( , 2 H), 7.86 (s, 1 H).
Example 146 1 -[3 -(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyllethyl) - 1 -benzofuran-5-vPphenyl]- 1 -propanone The product from Example 145 (20 mg, 0.05 mmol) was dissolved into tetrahydrofuran (900 μL), cooled to 0 °C, and treated with 1.0 M ethylmagnesium bromide in tetrahydrofuran (150 μL, 150 μmol). The reaction mixture was then stirred at room temperature overnight, quenched by the addition of saturated aqueous NH4C1, and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc, and the combined organic phases were washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, concentrated, and purified by HPLC [Waters Nova-Pak HR CI 8 column (25 mm X 100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL / min.] to provide the title compound (44% yield). MS (ESI APCI) m/z 362 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.18 (d, 3 H), 1.21 (t, 3 H), 1.39-1.53 (m, 1 H), 1.74-1.87 (m, 2 H), 1.95-2.09 (m, 1 H), 2.24- 2.37 (m, 1 H), 2.42-2.61 (m, 2 H), 2.94-3.18 (m, 4 H), 3.20-3.35 (m, 2 H), 6.63 (s, 1 H), 7.50- 7.52 (m, 2 H), 7.58 (dd, 1 H), 7.77-7.79 (m, 1 H), 7.87 (ddd, 1 H), 7.96 (ddd, 1 H), 8.22 (dd, I H).
Example 147 cvclopropyl[3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPphenyl]methanone The product from Example 145 and cyclopropylmagnesium bromide were processed as described in Example 146 to provide the title compound (48% yield). MS (ESI APCI) m/z 374 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.08-1.22 (m, 7 H), 1.39-1.53 (m, 1 H), 1.73- 1.86 (m, 2 H), 1.95-2.08 (m, 1 H), 2.23-2.35 (m, 1 H), 2.41-2.60 (m, 2 H), 2.87-3.15 (m, 3 H), 3.19-3.35 (m, 2 H), 6.63 (s, 1 H), 7.48-7.55 (m, 2 H), 7.60 (dd, 1 H), 7.78-7.81 (m, 1 H), 7.89 (ddd, 1 H), 8.02 (ddd, 1 H), 8.25 (dd, 1 H).
Example 148 3-methyl-l-[3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPphenyl]-l- butanone The product from Example 145 and isobutylmagnesium chloride were processed as described in Example 146, except that after reacting overnight additional isobutylmagnesium chloride (400 mol%>) was added and the reaction mixture was stirred for four more hours, to provide the title compound (19% yield). MS (ESI APCI) m/z 390 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.01 (d, 6 H), 1.17 (d, 3 H), 1.37-1.53 (m, 1 H), 1.73-1.86 (m, 2 H), 1.94- 2.07 (m, 1 H), 2.20-2.35 (m, 2 H), 2.41-2.59 (m, 2 H), 2.95 (d, 2 H), 2.95-3.14 (m, 2 H), 3.19-3.34 (m, 2 H), 6.62 (s, 1 H), 7.49-7.52 (m, 2 H), 7.57 (dd, 1 H), 7.77 (dd, 1 H), 7.86 (ddd, 1 H), 7.93 (ddd, 1 H), 8.19 (dd, 1 H).
Example 149 3-(2-j2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzaldehvde The product from Example 145 and cyclopentylmagnesium bromide were processed as described in Example 146, except that additional cyclopentylmagnesium bromide was added after the reaction had stirred overnight (400 mol%) and after another four hours (600 mol%>). The reaction mixture was allowed to stir for three additional days (16% yield). MS (ESI APCI) m/z 334 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.17 (d, 3 H), 1.38-1.53 (m, 1 H), 1.77-1.86 (m, 2 H), 1.94-2.08 (m, 1 H), 2.23-2.34 (m, 1 H), 2.40-2.59 (m, 2 H), 2.94-3.15 (m, 2 H), 3.19-3.34 (m, 2 H), 6.63 (d, 1 H), 7.51-7.54 (m, 2 H), 7.65 (dd, 1 H), 7.80 (dd, 1 H), 7.87 (ddd, 1 H), 7.96 (ddd, 1 H), 8.16 (dd, 1 H), 10.07 (s, 1 H).
Example 150 r3-(2-(2-r(2R)-2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-vDphenyllC2- thienvDmethanone The product from Example 145 and 2-thienyllithium were processed as described in Example 146 to provide the title compound (53% yield). MS (ESI APCI) m/z 416 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.18 (d, 3 H), 1.38-1.53 (m, 1 H), 1.73-1.86 (m, 2 H), 1.95- 2.08 (m, 1 H), 2.24-2.36 (m, 1 H), 2.42-2.61 (m, 2 H), 2.95-3.15 (m, 2 H), 3.19-3.34 (m, 2 H), 6.63 (d, 1 H), 7.27 (d, 1 H), 7.48-7.57 (m, 2 H), 7.63 (dd, 1 H), 7.76-7.84 (m, 3 H), 7.90- 7.98 (m, 2 H), 8.07 (dd, 1 H).
Example 151 (3-fluorophenyD[3-(2-|2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- yDphenyl]methanone The product from Example 145 and 3-fluorophenylmagnesium bromide were processed as described in Example 146 to provide the title compound (46% yield). MS (ESI APCI) m/z 428 (M+H)+; 'HNMR (300 MHz, CD3OD) 8 1.17 (d, 3 H), 1.36-1.53 (m, 1 H), 1.72-1.86 (m, 2 H), 1.94-2.07 (m, 1 H), 2.22-2.33 (m, 1 H), 2.39-2.58 (m, 2 H), 2.93-3.14 (m, 2 H), 3.18-3.3 (m, 2 H), 6.62 (s, 1 H), 7.37-7.45 (m, 1' H), 7.49-7.52 (m, 2 H), 7.52-7.66 (m, 4 H), 7.72 (ddd, 1 H), 7.77 (dd, 1 H), 7.94 (ddd, 1 H), 8.02 (dd, 1 H).
Example 152 [3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-vPphenyl]methanol The product from Example 144 (167 mg, 0.48 mmol) was dissolved into 1 M BH3 in tetrahydrofuran (2 mL, 2 mmol), stirred at room temperature overnight, quenched with 0.5 M aqueous dipotassium hydrogen phosphate, and diluted with EtOAc. The organic phase was separated and washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na2SO ), concentrated, and chromatographed through a short column of silica with a gradient of 0 to 5% MeOH / CH2C12, and through a second short column of silica with a gradient of 0 to 5% MeCN / CH2CI2, collecting and concentrating the material with a mass ion corresponding to a borane complex. This residue was dissolved in methanol (1.5 mL), treated with 0.1 M aqueous hydrochloric acid (0.3 mL), heated at 60 °C for three hours, treated with more 0.1 M aqueous hydrochloric acid (0.1 mL), heated at 60 °C for one hour, concentrated, and chromatographed through a short column of silica with a gradient of 2 to 10%) 2 M NH3 in MeOH / CH2C12 to provide the title compound as a white powder (13% yield). MS (ESI APCI) m/z 336 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.18 (s, 3 H), 1.38- 1.53 (m, 1 H), 1.73-1.87 (m, 2 H), 1.94-2.08 (m, 1 H), 2.24-2.36 (m, 1 H), 2.41-2.60 (m, 2 H), 2.94-3.14 (m, 2 H), 3.19-3.34 (m, 2 H), 4.68 (s, 2 H), 6.60 (s, 1 H), 7.28-7.34 (m, 1 H), 7.40 (dd, 1 H), 7.46-7.49 (m, 2 H), 7.52 (ddd, 1 H), 7.62 (s, 1 H), 7.73 (dd, 1 H).
Example 153 (2R)-l-[2-(5-benzyl-l-benzofuran-2-yPethyll-2-methylpyrrolidine
Example 153 A 4-benzyl-2-iodophenol 4-Benzylphenol was processed as described in Example 143B, except that neutralization after the reaction was complete was not conducted and the chromatography was conducted with a gradient of 25 to 33% CH2CI2 / hexanes to provide the title compound (42% yield). 'HNMR (300 MHz, CDC13) 8 3.88 (s, 2 H), 5.13 (s, 1 H), 6.90 (d, 1 H), 7.05 (dd, 1 H), 7.13-7.33 (m, 5 H), 7.47 (d, 1 H).
Example 153B (2R)-l -r2-(5-benzyl-l-benzofuran-2-vPethyl]-2-methylpyrrolidine The product from Example 153 A was treated as described in Example 136C, except that the reaction was conducted at room temperature for one day, then at 65 °C overnight, and worked up as follows: The reaction mixture was brought to room temperature, concentrated, suspended in CH2CI2 and mixed with 10% aqueous ammonia, and filtered through diatomaceous earth. The filtrate was diluted with water and the aqueous phase was separated and extracted with CH2CI2. The combined organic phases were washed with 5% aqueous ammonia and then worked up as usual, dried (Na2S0 ), concentrated, and chromatographed three times on silica with MeOH / CH2CI2. The appropriate fractions were concentrated and the resulting residue dissolved in methanol and filtered. The filtrate was concentrated to provide the title compound as a brown gum (3% yield). MS (ESI APCI) m/z 320 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.18 (d, 3 H), 1.38-1.53 (m, 1 H), 1.73-1.87 (m, 2 H), 1.95-
2.09 (m, 1 H), 2.26-2.39 (m, 1 H), 2.45-2.61 (m, 2 H), 2.90-3.1 1 (m, 2 H), 3.18-3.3 (m, 2 H), 4.01 (s, 2 H), 6.47 (d, 1 H), 7.05 (dd, 1 H), 7.11-7.33 (m, 7 H).
Example 154 1 -(2- |2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl) - 1 -benzofuran-5-vP- 1 H-imidazole
Example 154A 4-( 1 H-imidazol- 1 -vP-2-iodophenol 4-Imidazol-l-ylphenol was processed as described in Example 143B, except that after removal of the ammonia under reduced pressure, the mixture was diluted with brine and extracted with 33% isopropanol / EtOAc. The organic extracts were combined and partially concentrated before being washed with brine. The brine phase was separated and extracted as before. The combined organic phases were then concentrated until only some unseparated N,N-dimethylformamide and water remained, and set aside overnight. The crystals which formed were collected by filtration and washed with 2: 1 EtOAc / ether. The filtrate was concentrated and diluted with brine. After a microcrystalline solid had finished precipitating, it too was collected and washed as before, then mostly dissolved in MeOH / CH2CI2, filtered, and concentrated. The resulting second batch was combined with the first to provide the title compound as an off-white powder (64% yield). 'HNMR (300 MHz, CD3OD) 8 6.93 (d, 1 H),
7.10 (d, 1 H), 7.37 (dd, 1 H), 7.43 (dd, 1 H), 7.86 (d, 1 H), 7.97 (d, 1 H).
Example 154B 1 -(2- {2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vP-l H-imidazole The product from Example 154 A was processed as described in Example 136C except that the reaction was carried out at 80 °C for six hours, additional alkyne solution (10 moP/o) was added, and after an additional 2.3 hours the reaction was brought to room temperature, concentrated, and chromatographed through a short column of silica covered with a layer of diatomaceous earth with a gradient of 0 to 10% 2 M NH3 in MeOH / CH2C12. The appropriate fractions were twice combined, concentrated, and chromatographed through silica with 67% CH2C12 / hexanes followed by a gradient of 0 to 10% MeOH / CH2C12. The appropriate fractions were combined, dissolved into CH2CI2, washed with 10% aqueous NaOH, dried (Na2SO ), concentrated, rechromatographed again through a short column of silica with a gradient of 0 to 20% MeOH / CH2CI2, and concentrated to provide the title compound (58% yield). MS (ESI APCI) m/z 296 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.17 (d, 3 H), 1.37-1.52 (m, 1 H), 1.72-1.86 (m, 2 H), 1.92-2.08 (m, 1 H), 2.22-2.34 (m, 1 H), 2.40-2.59 (m, 2 H), 2.95-3.16 (m, 2 H), 3.18-3.34 (m, 2 H), 6.65 (s, 1 H), 7.14 (s, 1 H), 7.39 (dd, 1 H), 7.51-7.58 (m, 2 H), 7.68 (d, 1 H), 8.06 (s, 1 H).
Example 155 4-(3-bromo-2-{2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-vP-2- methylbenzonitrile The product of Example 106D was processed as described in Example 101 to provide the title compound as a brownish-orange gum (18% yield). MS (ESI) m/z 423 / 425 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.39 (d, 3 H), 1.60-1.77 (m, 1 H), 1.96-2.12 (m, 2 H), 2.20- 2.33 (m, 1 H), 2.61 (s, 3 H), 2.9-3.5 (m, 5 H), 3.52-3.76 (m, 2 H), 7.60-7.77 (m, 6 H).
Example 156A 4-(3-chloro-2-{2-r(2R)-2-methyl-l-pyrrolidinyllethyl}-l-benzofuran-5-yl)benzonitrile and Example 156B 4-(3.6-dichloro-2-{2-[(2R)-2 -methyl- l -pyrrolidinyl]ethyl)-l-benzofuran-5-vDbenzonitrile The mono-(L)-tartaric acid salt of the product of Example ID (120 mg, 0.25 mmol) was suspended in trifluoroacetic acid and treated with N-chlorosuccinimide (53 mg, 0.40 mmol) and stirred for two days. The reaction mixture was poured into aqueous Na2S03, made alkaline with aqueous Na2CU3, and extracted with CH2CI2. The combined organic phases were washed with brine, dried (Na2SO4), concentrated, and purified by HPLC [Waters Nova-Pak HR C 18 column (40 mm X 100 mm, 6 μm particle size) using a gradient of 10% to 100%) MeCN / 0.1% aqueous TFA over 12 min (15 min run time) at a flow rate of 70 L / min.] to provide the title chloro (57% yield) and dichloro (12% yield) compounds as brown gums. 156A MS (ESI) m/z 365 / 367 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.48 (d, 3 H), 1.67-1.83 (m, 1 H), 1.99-2.24 (m, 2 H), 2.30-2.44 (m, 1 H), 3.21-3.63 (m, 5 H), 3.72-3.92 (m, 2 H), 7.65 (d, 1 H), 7.73 (dd, 1 H), 7.80-7.89 (m, 5 H). 156B MS (ESI) m/z 399 / 401 / 403 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.48 (d, 3 H), 1.67-1.83 (m, 1 H), 2.00-2.25 (m, 2 H), 2.27-2.45 (m, 1 H), 3.21-3.64 (m, 5 H), 3.72-3.92 (m, 2 H), 7.57 (s, 1 H), 7.63 (d, 2 H), 7.80 (s, 1 H), 7.84 (d, 2 H).
Example 157 4-(3-iodo-2-{2-f(2R)-2-methyl-l-pyrrolidinyllethyl}-l-benzofuran-5-yPbenzonitrile The mono-(L)-tartaric acid salt of the product of Example ID and N-iodosuccinimide were processed as in Example 156, except that a large excess of N-iodosuccinimide (2.4 molar equivalents) was utilized, to provide the title compound as a tan gum (18% yield). MS (ESI) m/z 457 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.49 (d, 3 H), 1.67-1.84 (m, 1 H), 2.00-2.25 (m, 2 H), 2.29-2.44 (m, 1 H), 3.22-3.63 (m, 5 H), 3.72-3.91 (m, 2 H), 7.59-7.64 (m, 2 H), 7.72 (dd, 1 H), 7.80-7.89 (m, 4 H).
Example 158 4-(2-{2-[(2R)-2-methyl-5-oxo-l-pyrrolidinyllethyl}-l-benzofuran-5-yl)benzonitrile The mono-(L)-tartaric acid salt of the product of Example ID (96 mg, 0.20 mmol) was suspended in acetone (10 mL) and treated with a solution of KMnO (158 mg, 1.0 mmol) and MgSO4 (120 mg, 1.0 mmol) in water (5 mL) over 30 minutes. After the puφle color had disappeared, the solids were filtered off. The filtrate was diluted with EtOAc, washed with aqueous potassium dihydrogen phosphate, concentrated, and purified by HPLC [Waters Nova-Pak HR C18 column (25 mm X 100 mm, 6 μm particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL / min.] to provide the title compound (2 % yield). MS (ESI APCI) m/z 345 (M+H)+; ]HNMR (300 MHz, CD3OD) δ 1.22 (d, 3 H), 1.55-1.64 (m, 1 H), 2.15-2.32 (m, 2 H), 2.34-2.42 (m, 1 H), 2.99-3.13 (m, 2 H), 3.39-3.46 (m, 1 H), 3.68-3.76 (m, 1 H), 3.89-3.97 (m, 1 H), 6.65 (s, 1 H), 7.51-7.56 (m, 2 H), 7.76-7.84 (m, 5 H).
Example 159 4-(3-acetyl-2-{2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile The product of Example ID (330 mg, 1.0 mmol) was dissolved into CH2C1 (500 μL) and cooled to 0 °C. Acetyl chloride (140 μL, 2.0 mmol) and 1 M SnCl4 in CH2C12 (1.5 mL, 1.5 mmol) were added, the reaction was permitted to warm to room temperature and it was stirred overnight. The mixture was partitioned between 20%> EtOAc / CH2CI2 and 0.5 M aqueous dipotassium hydrogen phosphate. The aqueous phase and solids were separated and extracted with CH2CI2, and the organic phases were combined and worked up as usual but with an aqueous dipotassium hydrogen phosphate wash, dried (Na2S04), and concentrated. The residue was then resubjected to the same reaction conditions used previously except with additional CH2CI2 (7 mL), stirred for five days, and worked up as before. The concentrated residue was chromatographed through silica (MeOH / EtOAc / CH2C1 ) to afford an inseparable mixture of product and starting material.
The mixture (260 mg) and (4-tert-butylphenyl)-hydrazine hydrochloride (201 mg, 1.0 mmol) were dissolved into methanol (2 mL) and treated with 88% aqueous formic acid. The mixture was stirred overnight, concentrated, partitioned between 0.5 M dipotassium hydrogen phosphate and CH2C12, worked up as usual, dried (Na2S04), concentrated, and chromatographed through silica with a gradient of 0.5 to 4%, MeOH in 20%> MeCN / CH2C12. The appropriate fractions were concentrated, and after a few days appeared to have decomposed, partially to the desired ketone. The residue was rechromatographed through a short column of silica with a gradient of 0 to 4% MeOH / CH2CI2, and then purified by HPLC [Waters Nova-Pak HR C18 column (40 mm X 100 mm, 6 μm particle size) using a gradient of 10% to 100%) MeCN / 0.1%, aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL / min.] to provide the title compound (4% yield). MS (ESI APCI) m/z 373 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.49 (d, 3 H), 1.68-1.84 (m, 1 H), 2.01 -2.25 (m, 2 H), 2.31- 2.46 (m, 1 H), 2.80 (s, 3 H), 3.3-3.71 (m, 5 H), 3.76-3.92 (m, 2 H), 7.69-7.76 (m, 2 H), 7.84 (d, 2 H), 7.89 (d, 2 H), 8.20-8.22 (m, 1 H).
Example 160 cyclopropyl[4-(2-(2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPphenyllmethanone The product from Example ID (330 mg, 1.0 mmol) was dissolved into tetrahydrofuran (1 mL), treated with -0.7 M cyclopropylmagnesium bromide in tetrahydrofuran (2 mL, -1.4 mmol) and copper (I) iodide (a few milligrams), and heated at 45 °C for one day and at 60 °C for two days. The reaction was brought to room temperature, quenched with 0.4 M aqueous hydrochloric acid (5 mL), and extracted with EtOAc. The organic phase was washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na2S04), concentrated, and purified by HPLC [Waters Nova-Pak HR C18 column (40 mm X 100 mm, 6 μm particle size) using a gradient of 10%, to 100%, MeCN / 0.1%, aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL / min.] to provide the title compound as a powder (44% yield). MS (ESI APCI) m/z 374 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 1.06-1.21 (m, 7 H), 1.38-1.53 (m, 1 H), 1.73-1.86 (m, 2 H), 1.94-2.08 (m, 1 H), 2.23-2.34 (m, 1 H), 2.40-2.59 (m, 2 H), 2.83-3.15 (m, 3 H), 3.19-3.34 (m, 2 H), 6.62 (s, 1 H), 7.51 (d, 1 H), 7.56 (dd, 1 H), 7.76-7.85 (m, 3 H), 8.12 (d, 2 H).
Example 161 3,5-dimethyl-4-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yDisoxazole
Example 161 A 2-[5-(3.5-Dimethyl-isoxazol-4-vD-benzofuran-2-yl]-ethanol To a well stirred suspension of the product from Example 112B (1.446 g, 6.00 mmol), 3,5-dimethylisoxazole-4-boronic acid (2.09 g, 6.6 mmol) (Frontier Scientific, chemical abstracts number 16114-47-9), palladium (II) acetate (0.07 g, 0.3 mmol), and biphen-2-yl- dicyclohexylphosphine (0.15 g, 0.6 mmol) in toluene (20 mL) was added 10 mL of isopropanol and 10 mL of water. The reaction was heated at 60° C for 36 hours, then cooled, poured into ethyl acetate (50 mL), and washed with water (100 mL). After drying over sodium sulfate, the organic layer was concentrated in vacuo and purified by flash chromatography, eluting with 1 : 1 :4 of ethyl acetate/hexane/dichloromethane to provide the title compound as a tan oil, (97% yield). MS (DCI) m/z 258.2 (M+H)+; 'HNMR (300 MHz, CDC13) δ 1.74 (s, IH), 2.24 (s, 3H), 2.40 (s, 3H), 3.05 (t, 2H, J=6.0 Hz), 4.02 (t, 2H, J=6.0 Hz), 7.08 (dd, IH, J=9.0, 2.1 Hz), 7.34 (d, IH, J=2.1 Hz), 6.54 (s, IH), 7.46 (d, IH, 9.0 Hz).
Example 161B 2-[5-(3.5-dimethyl-4-isoxazolyl)-l -benzofuran-2 -yllethyl methanesulfonate To a well stirred solution of the product from Example 161A (643 mg, 2.5 mmol) and methanesulfonic anhydride (522 mg, 3 mmol), in 3 mL of dichloromethane at 0 °C was added 0.53 mL (3.75 mmol) of triethylamine slowly. The reaction was allowed to warm to 23 °C and poured into dichloromethane, then washed with aqueous sodium phosphate (buffered to pH 8), dried over sodium sulfate, then concentrated in vacuo to provide the title compound as an oil.
Example 161C 3.5-dimethyl-4-(2-(2-[(2R)-2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-vDisoxazole A 3.3 mL (1 mmol) aliquot of the product from Example 161B in 8.33 mL of acetonitrile was transferred to a separate flask. Mono-(L)-tartaric acid salt of (R)-2- methylpyrrolidine (0.82 g, 3.5 mmol) was converted to the free base by shaking with 1 mL of toluene, 0.5 L of 50%, wt/vol sodium hydroxide, and 2 mL of brine. After separating, the toluene layer was decanted by pipette and added to the 3.3 mL aliquot of the product from Example 16 IB. After stirring for one week at room temperature, the reaction was poured into dichloromethane and washed with aqueous ammonia, dried over sodium sulfate, and purified by flash chromatography, eluting with 97:3 dichloromethane/methanol/0.1% NH3, to give 225 mg (69%) of the title compound as a clear oil. MS (DCI) m/z 325.2 (M+H)+; 'HNMR (300 MHz, CDCI3) δ 1.18 (d, IH, J=6.3Hz), 2.24 (s, 3H), 2.40 (s, 3H), 1.5-2.0 (m, 6H), 2.5 (m, IH), 3.02 (t, 2H, J=7.5 Hz), 3.23 (m, 2H), 6.48 (s, IH), 7.08 (dd, IH, J=9.0, 2.1 Hz), 7.34 (d, IH, J=2.1 Hz), 7.44 (d, IH, 9.0 Hz).
Example 162 4-[2-(2-aminoethyl)-l-benzofuran-5-yl]benzonitrile
Example 162A 4-[2-(2-azidoe thy!)- 1 -benzofuran-5-yl]benzonitrile Methanesulfonic acid (109 mg, 0.32 mmol), the product from Example IC and sodium azide (83 mg, 1.28 mmol) was stirred in DMF for 4 days, then poured into dichloromethane and washed with water. The crude product was purified by flash chromatography, eluting with 2: 1 dichloromefhane/hexane to provide the title compound as a clear syrup (65 mg, 71%,).
Example 162B 4-[2-(2-aminoethvD-l-benzofuran-5-yllbenzonitrile The product from Example 162A was dissolved in 3 mL of tetrahydrofuran, and treated with triphenylphosphine (262 mg, 1 mmol) was added, along with 0.5 mL water. After 3 days, the reaction was poured into dichloromethane and washed with aqueous ammonia. The organic layer was purified by flash chromatography, eluting with 10-20%) methanol/dichloromethane, (0.1 % NH3) to give the title compound as a white powder, mp 1 18-120 °C; MS (DCI) m/z 263.0 (M+H)+; 'HNMR (300 MHz, CD3OD) δ 3.00 (m, 2H), 3.08 (m, 2H), 6.64 (s, IH), 7.56 (m, 2H), 7.82 (m, 5H).
Example 163 4-(2-{2-[(2R)-2-ethyl-l-pyrrolidinyl1ethyl}-l -benzofuran-5-vPbenzonitrile The product from Example IC and (2R)-ethylpyrrolidine (Andres, Jose M.; Herraiz- Sierra, Ignacio; Pedrosa, Rafael; Perez-Encabo, Alfonso; Eur.J.Org.Chem.; vol. 9; 2000; ppl 719 - 1726; chemical abstracts number 123168-37-6 hydrochloride salt)were processed as described in Example ID to provide the titled compound, except that potassium carbonate was substituted for sodium carbonate, and the reaction was run at 60°C, then worked up by pouring into toluene. The organic phase was extracted with 7:2: 1 of water/N- methylpyrrolidinone/10% aqueous methanesulfonic acid, and the aqueous phase then covered with isopropyl acetate and adjusted to pH 1 1 with 50% aqueous NaOH. After shaking and separation of the layers, the isopropanol extract was saved, then combined with a second isopropanol extract of the aqueous layer. The combined isopropanol extract was washed three times with 5% aqueous NaHCO3, water, dried over magnesium sulfate, filtered, and concentrated in vacuo to provide a brown oil. The free base was converted to the mono-L- tartrate salt by addition of 1 equivalent of L-tartaric acid to the free base in ethanol. The mixture was heated to 70 °C, and on allowing to cool, deposited an off-white solid. This was slurried with isopropyl acetate, and the solid collected by filtrate as the tartrate salt of the title compound, mp 147 °C; MS m/z (M+H)+ 345.
Example 164 4-(2-(2-[(2S)-2-(fluoromethvP-l-pyrrolidinyl1ethyl)-l-benzofuran-5-vPbenzonitrile
Example 164A tert-butyl C2S -2-(r(methylsulfonvPoχv]methyl)-l-pyrrolidinecarboxylate N-Boc-(2S)-prolinol (6.04 g) in 100 mL of dichloromethane was treated with 4.04 g of triethylamine, cooled to 0 °C, and treated with methanesulfonyl chloride (4.0 g) slowly. After stirring at 0 °C for 30 minutes, the reaction was allowed to warm to room temperature, washed with 5% aqueous NaHC03 solution, dried over sodium sulfate, and concentrated to dryness to give the title compound as an off-white oil (8.47 g).
Example 164B tert-butyl (2S)-2-(fluoromethvP-l-pyrrolidinecarboxylate The product from Example 164 A (7 g) in 100 mL of THF and tetrabutylammonium fluoride (42 mL of a 1M solution in THF) was heated at reflux for 17 hours, cooled, concentrated to dryness, diluted with 125 mL of ethyl acetate, washed with 5% aqueous NaHC03, brine, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to provide an oil. The oil was distilled in vacuo (50 °C, 1.2 torr) to give 4.9 g of the title compound as a colorless oil.
Example 164C (2S)-2-(fluoromethvPpyrrolidine The product of Example 164B (4.4 g) in 100 mL of ethyl acetate was treated with 10 mL of 4N HCl in 1 ,4-dioxane. The solution was stirred overnight, an additional 5 mL 4N HCl in 1,4-dioxane was added, and the slurry was stirred for another 24 hours. The off-white solid was collected by filtration, washed with acetonitrile, and dried at 50 °C under vacuum to give the title compound as a sticky solid (1.40 g). 13C NMR (DMSO) δ 81.6 (JCF=167 Hz), 58.1 (JCF=18 Hz), 45.0, 25.2 (JCF=6 Hz), 23.3.
Example 164D 4-(2-{2-[(2S)-2-(fluoromethvP-l-pyrrolidinyl]ethyl}-l-benzofuran-5-vPbenzonitrile The product from Example IC and the product from Example 164C were processed as described in Example ID to provide the titled compound, except that potassium carbonate was substituted for sodium carbonate, and the reaction was run at 60 °C for 3 days, then worked up by pouring into toluene. The organic phase was extracted with 7:2:1 of water N- methylpyrrolidinone/10% aqueous methanesulfonic acid, and the aqueous phase then covered with isopropyl acetate and adjusted to pH 11 with 50%> aqueous NaOH. After shaking and separation of the layers, the isopropanol extract was saved, then combined with a second isopropanol extract of the aqueous layer. The combined isopropanol extract was washed three times with 5% aqueous NaHCθ3, water, dried over magnesium sulfate, filtered, and concentrated in vacuo to a brown oil. The free base was converted to the mono-L-tartrate salt by addition of 1 equivalent of L-tartaric acid to the free base in ethanol. Two hours after removal of some of the ethanol under vacuum, the mixture deposited an off-white solid. The solid was collected by filtrate and dried in vacuo overnight to give the title product as the tartrate salt of 4- {2-[2-(2(R)-fluoromethyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - benzonitrile, mp 156.3 °C, MS m/z (M+H)+ 349; 13C NMR (DMSO) 8 158.6, 154.2, 145.2, 133.2, 132,7, 129.4, 127.7, 122.8, 119.2, 118.9, 1 11.2, 109.4, 103.0, 85.6 and 84.3, 72.1 , 62.8, 53.5, 52.3, 27.2, 26.4, 22.7.
Example 165 4-(2- (2-[(2R -2-methyl- 1 -pyrrolidinyl]ethyl) - 1 -benzothien-5-vPbenzonitrile
Example 165A l-Bromo-4-["(2,2-diethoxyethyl)thio]benzene 1 -Bromo-4-[(2,2-diethoxyethyl)thio]benzene (Chemical Abstracts number 96804-05- 6) was prepared as described in Banfield et al.; J.Chem.Soc; 1956; 2603-2607, and in Amin, et al.; J.Chem.Soc.Perkin Trans.2; 1982; 1489-1492. 4-Bromothiophenol (20 g, 95%) in ethanol (80 mL) was treated with 21 wt%> of sodium ethoxide in ethanol (36 g, 1.05 eq). The solution was heated at 55 °C for 30 minutes and bromoacetaldehyde diethylacetal (22.56 g, 1.05 eq) was added. The mixture was heated at reflux for 10 hours, ethanol was removed and the residue was diluted with 80 mL of water. The product was extracted with 2x120 mL of ethyl acetate. The combined ethyl acetate layer was washed with 2x40 mL of 15 % NaCl and concentrated under vacuum to a brown oil (32.0 g, 92.5 % potency, 96.5 %> yield). The product can be further purified by column chromatography (silica gel, 5:95 EtOAc :hexane).
Example 165B 5-bromo-l-benzothiophene 5-Bromobenzo[b]thiophene (Chemical Abstracts number 4923-87-9) was prepared as described in Banfield et al.; J.Chem.Soc; 1956; 2603-2607, and in Seed, Alexander J.; et al. J.Mater.Chem.; vol 10; 2000; 2069 - 2080. A mixture of phosphoric acid (218 g) and chlorobenzene (2 L) was heated at 130 °C and then treated with the product from Example 165A (107.0 g) over 2 hours using a syringe pump. The mixture was heated at 130 °C for 15 hours. Dean-Stark trap was used at the beginning of the reflux to remove water from the mixture. The mixture was allowed to cool to room temperature and quenched with 400 mL of water. The bottom aqueous layer was extracted with 200 mL of methylene chloride. The combined organic layer was washed with 200 mL of 10 % Na2CU3, and concentrated to brown oil (129.4 g). The crude oil was dissolved in IL of 10:90 EtOAC:hexane, filtered through a short pad of silica gel and concentrated to a yellow oil (85.54 g, 95.8 % yield). Further purification was done by column chromatography (silica gel, 5:95 EtOAc :hexane).
Example 165C 2-(5-bromo- 1 -benzothien-2-yl)ethanol The product from Example 165B (0.93 g) in THF (10 mL) at -55 °C was treated with lithium diisopropylamide (2.4 mL, 2M, 1.1 eq) precooled to -50 to -55 °C forming a red brown solution. The mixture was warmed to -25 °C and treated with a solution of ethylene oxide (0.96 g, 5 eq) in THF (13 mL) keeping the temperature at -20 to -25 °C. The mixture was warmed to -15 °C and stirred for 3 hours. The mixture was acidified with 2N HCl, washed with 2x20 mL water and concentrated to crude solid (1.16 g). The crude product was purified by column chromatography (silica gel, 1 :1 EtOAc:hexane) to give the title compound (0.62 g). Η NMR(CDCl3j δ) 1.6 (broad s, IH), 3.17 (t, 2H), 3.93 (m, 2H),7.02 (s, IH), 7.35 (d of d, IH), 7.61 (d, IH), 7.80 (s, IH). MS (m/z): 274, 276 (M+NH4).
Example 165D 2-(5 -bromo- 1 -benzothien-2-vPethyl 4-methylbenzenesulfonate The product from Example 165C (0.5 g) in methylene chloride (10 mL) was added triethylamine (0.3 g, 1.5 eq) followed by tosyl chloride (0.37 g, 1.0 ea). The solution was stirred at RT overnight and washed with 3x20 mL of water. The methylene chloride layer was concentrated to viscous oil (0.98 g, 68.1 %> potency, 83.5 % yield). The crude product can be purified by crystallization from 20:80 EtOAc:hexane to give crystalline solid (0.48 g). Η NMR(CDC13, 8) 2.38 (s, 3H), 3.21 (t, 2H), 4.30 (t, 2H), 6.87 (s, IH), 7.18 (d, 2H), 7.36 (d of d, IH), 7.55 (d, IH), 7.63 (d, 2H), 7.75 (d, IH). MS(m/z): 428, 430 (M+NH4).
Example 165E (2RVl-[2-("5-bromo-l-benzothien-2-vPethyl1-2-methylpyrrolidine Toluene-4-sulfonic acid, the product from Example 165D (0.45 g), and K2CO3 (0.23 g, 1.5 eq) was treated with a solution of (2R)-2-methylpyrrolidine solution in acetonitrile (11.1 g, 12.6 mg/g of solution, 1.5 eq). The mixture was heated at 55 °C for 24 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was dissolved in 30 mL EtOAc, washed with 2x10 mL water, concentrated, and the residue was purified by column chromatography (silica gel, 10:90 MeOH:CHC-3) to provide the title compound as an oil (0.26 g, 73.3 %). 'H NMR(CDCl3, δ) 1.10 (d, 3H), 1.4-2.0 (m, 4H), 2.20 (q, IH), 2.30-2.50 (m, 2H), 3.00-3.23(m, 4H), 6.97 (s, IH), 7.33 (d of d, IH), 7.60 (d, IH), 7.78 (d, IH). MS (m/z): 324, 326 (M+H)+.
Example 165F 4-(2- |2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl) - 1 -benzothien-5-yl)benzonitrile The product from Example 165E (0.4 g), 4-cyanophenylboronic acid(0.45 g, 2.5 eq), triphenylphosphine (65 mg, 0.2 eq), and bistriphenylphosphine palladium dichloride (87 mg, 0.1 eq) in isopropanol (8 mL) was treated with potassium phosphate (0.52 g, 2 eq) in 8 mL of water. The mixture was heated at 65 °C under nitrogen for 25 hours, allowed to cool to room temperature, and treated with H20:NMP:MeSO3H (70:20: 10, 10 mL). The mixture was extracted with toluene (2x10 mL) and the acidic aqueous phase was basified to pH 10 using 50 % NaOH. The basified solution was extracted with methylene chloride (10 mL), washed with water (2x 10 mL), and concentrated to a brown oil. The brown oil was dissolved in EtOAc (20 mL), washed with water (2x10 mL), and concentrated. The residue was purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to provide the title compound (0.37 g). MS m/z 347(M+H)+. The free base was dissolved in 5 mL of MeOH and added to L-tartaric acid (0.16 g, 1 eq) in 5 mL of MeOH. The mixture was concentrated to dryness, and crystallized from EtOAc/EtOH to give the tartrate salt (0.33 g). Η NMR(DMSO-d6) δ 1.17 (doublet), 1.41-1.49(multiplet), 1.74-1.82(multiplet), 1.97-2.03(multiplet), 2.55- 2.59(multiplet), 2.80 (multiple-), 3.12-3.37(multiplet), 4.11 (singlet), 7.33 (singlet), 7.66 (doublet), 7.93(singlet), 8.02(doublet), 8.13 (doublet).
Example 166 4-(2- (2-[(2S -2-methylpyrrolidinyl]ethyl) - 1 -benzofuran-5-vDbenzonitrile
Example 166A (2S)-2-methylpyrrolidine (2S)-2-methylpyrrolidine hydrobromide can be prepared using the procedure described in Nijhuis, Walter H.N., et al., J.Org.Chem.; vol. 54; 1 ; (1989) pp. 209-216; or Kim, Mahn-Joo, et al., Bioorg.Med.Chem.Lett.; vol. 6; 1; (1996) pp. 71-76).
Example 166B 4-(2-{2-[(2S)-2-methylpyrrolidinyl]ethyl)-l -benzofuran-5-vPbenzonitrile (2S)-2-Methylpyrrolidine hydrobromide and the product from Example IC can be processed as described in Example ID to provide the title compound.
Example 167 (2R)-2-methylpyrrolidine (2R)-2-Methyl pyrrolidine tartrate was prepared using the procedure described in Elworthy, Todd R.; Meyers, A. I., Tetrahedron, vol. 50, 20, (1994) pp 6089-6096, or (2R)-2- methyl pyrrolidine hydrobromide was prepared using the procedure described in Karrer, Ehrhardt, Helv.Chim.Acta, vol. 34, (1951) pp. 2202,2208; Gaffield, William, Lundin, Robert E., Keefer, Larry K., Tetrahedron, 37; 1981; 1861-1869; Yamada et al., Tetrahedron Lett. (1973) p. 381 ; or Andres, Jose M., Herraiz-Sierra, Ignacio, Pedrosa, Rafael, Perez-Encabo, Alfonso, Eur.J.Org.Chem., 9; (2000) pp 1719-1726.
Example 168 (2R)-2-methyl-l-[2-(5-phenoxy-l-benzofuran-2-yl)ethyl]pyrrolidine
2-Iodo-4-phenoxy-phenol The title compound is prepared by treating 4-phenoxy phenol (Aldrich, CA no. 831 - 82-3) as described in Example 143A.
(2R)-2-methyl-l-[2-(5-phenoxy-l -benzofuran-2 -vPethyllpyrrolidine The product from Example 168A and (R)-l-but-3-ynyl-2-methylpyrrolidine is treated as described in Example 136C to provide the title compound.
Example 169 (2R)-1 -(2- {5-[(3-fluorophenyl)thio]- 1 -benzofuran-2-yl) ethyP-2-methylpyrrolidine (2R)-l-[2-(5-Bromo-l-benzofuran-2-yl)ethyl]-2-methylpyrrolidine is treated with 2 molar equivalents of tert-butyl lithium and bis(3-fluorophenyl)disulfide (Lancaster synthesis Ltd., Chemical Abstracts number 63930-17-6) in tetrahydrofuran at -78 °C to provide the title compound.
Example 170 3-(2-{3-[(2R)-2-methyl-l-pyrrolidinyl1propyl)-l -benzofuran-5-yPbenzonitrile
Example 170A 3-(5-bromo-l-benzofuran-2-yP-l-propanol The product from Example 112 A and 4-pentyn-l-ol is processed as described in Example 1 12B to provide the title compound.
Example 170B 3-[2-(3-hvdroxypropyP-l-benzofuran-5-yl]benzonitrile The product from Example 170A(193 mg, 0.80 mmol) and 3-cyanophenylboronic acid is processed as described in Example 1 12C to provide the title compound.
Example 170C 3 -[5 -(3 -cyanophenyP- 1 -benzofuran-2-yl1propyl methanesulfonate The product from Example 170B and methanesulfonyl chloride is processed as described in Example 1 12D to provide the title compound. Example 170D 3-(2-(3-[(2R)-2-methyl-l-pyrrolidinyl1propyl)-l-benzofuran-5-vPbenzonitrile The product from Example 170 and (2R)-2-methylpyrrolidine is processed as described in Example 1 12E to provide the title compound.
Example 171 3-(2-{[(2R)-2-methyl-l-pyrrolidinyl1methyl)-l-benzofuran-5-vPbenzonitrile 2-Propyn-l-ol and the product from Example 1 12A is processed as described in Examples 1 12B-E to provide the title compound.
Example 172 3-(2- (4-[(2R)-2-methyl- 1 -pyrrolidinyl]butyl) - 1 -benzofuran-5-yl)benzonitrile 5-Hexyn-l-ol and the product from Example 112A are processed as described in Examples 112B-E to provide the title compound.
Example 173 4-(4-{2-r2-(2S)-methyl-l-pyrrolidinvPethvn-l-benzofuran-5-yl)benzovPmoφholine (2 S)-2-Methy .pyrrolidine hydrobromide and the product from Example 23D (2-{5-[4- (4-moφholinylcarbonyl)phenyl]-l-benzofuran-2-yl} ethyl methanesulfonate) are processed as described in Example ID to provide the titled compound.
Example 174 4- (4-methyl-2-oxo-3-[2-(2S)-methyl-l -pyrrolidinyl ethyl]-2H-chromen-6-yl)benzonitrile (2S)-2-Methylpyrrolidine hydrobromide and the product from Example 41C (2-{5-[4- (4-moφholinylcarbonyl)phenyl]-l -benzofuran-2 -yl} ethyl methanesulfonate) are processed as described in Example ID to provide the titled compound.
Example 175 4-l4-methyl-2-oxo-3-r2-(2R)-methyl-l-pyrrolidinyl ethyl1-2H-chromen-6-yl)benzonitrile (2R)-2-Methylpyrrolidine hydrobromide and the product from Example 41C (2-{5-[4- (4-moφholinylcarbonyl)phenyl]-l-benzofuran-2-yl} ethyl methanesulfonate) are processed as described in Example 1 D to provide the titled compound.
Example 176
4-{r6-(2-{2-r(2S)-methylpyrrolidinyllethyl)-l-benzofuran-5-vD-3- pyridinyll c arbonyl ) moφholine
(2S)-2-Methylpyrrolidine hydrobromide and the product from Example 44E (2-{5-[4-
(4-moφholinylcarbonyl)phenyl]-l-benzofuran-2-yl}ethyl methanesulfonate) are processed as described in Example 1 D to provide the titled compound.
• Example 177 4-(2-|2-[(2R)-2-methylpyrrolidinyl]ethyl)-2,3-dihydro-l-benzofuran-5-yl)benzonitrile (2S)-2-Methylpyrrolidine hydrobromide and the product from Example 67D are processed as described in Example ID to provide the titled compound.
Example 178 4-(2-{2-[(2S -2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-4-vDbenzonitrile (2S)-2-Methylpyrrolidine hydrobromide and the product from Example 85E are processed as described in Example 1 D to provide the titled compound.
Example 179 4- (2-[2-(2S -methyl-pyrrolidin-l-vD-ethyll-benzofuran-6-yl) -benzonitrile (2S)-Methylpyrrolidine hydrobromide and the product from Example 86E are processed as described in Example ID to provide the titled compound.
Example 180 3-(2-{2-[(2S)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile (2S)-2-Methylpyrrolidine hydrobromide and the product from Example 1 12D are processed as described in Example ID to provide the titled compound.
Examples 181-202 Compounds of Formula (50) Examples 181-202 are compounds of formula (50), wherein Re is aryl or heterocycle. Such compounds can be prepared according to the procedures shown in Schemes 13 and 14 below:
Scheme 13
* (50)
R6 = aryl, heterocycle
As shown in Scheme 13, (2R)-l-[2-(5-bromo-l-benzofuran-2-yl)ethyl]-2- methylpyrrolidine is treated with tert-butyl lithium and tributylstannyl chloride at -78 °C to provide (2R)-2-methyl-l -{2-[5-(tributylstannyl)-l-benzofuran-2-yl]ethyl}pyrrolidine. (2R)- 2-Methyl-l-{2-[5-(tributylstannyl)-l-benzofuran-2-yl]ethyl}pyrrolidine is treated with a suitable starting material, for example, aryl halides, aryl triflates, or heterocyclic halides in the presence of a palladium catalyst, like palladium (II) acetate, and a trivalent phosphine, like tri(2-furyl)phosphine, in an organic solvent such as dimethylformamide at 25 °C to 120 °C to provide compounds of formula (50). Compounds of formula (50) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (50) can be partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.
Scheme 14
R6 = aryl, heterocycle
As shown in Scheme 14, (2R)-l-[2-(5-bromo-l-benzofuran-2-yl)ethyl]-2- methylpyrrolidine is treated with tert-butyl lithium and a borate ester, such as tri- isopropoxyborane, in tetrahydrofuran at -78 °C to provide diisopropyl 2-{2-[(2R)-2-methyl- l-pyrrolidinyl]ethyl}-l-benzofuran-5-ylboronate. Diisopropyl 2-{2-[(2R)-2-methyl-l- pyrτolidinyl]ethyl}-l-benzofuran-5-ylboronate is treated with water to provide the boronic acid or the boronate ester is used directly in the Suzuki coupling reaction. The boronic acid or the boronate ester is treated with a suitable starting material, for example, aryl halides, aryl triflates, or heterocyclic halides, a palladium catalyst such as palladium (II) acetate, a trivalent phosphine such as biphen-2-yl-dicyclohexylphosphine, and aqueous sodium carbonate or potassium phosphate in an organic solvent, such as ethanol or tetrahydrofuran, at 25 °C to 120 °C to provide compounds of formula (50). Compounds of formula (50) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (50) can be partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.
Examples of compounds that can be prepared according to procedures described in Schemes 13 and 14 and starting materials suitable for preparing such compounds are provided below in Table 2.
Table 2
Examples 203-224 Compounds of Formula (51) Examples 203-224 are compounds of formula (51), wherein 1^ is aryl or heterocycle. Such compounds can be prepared according to the procedure shown in Scheme 15 below: Scheme 15
(51) R4 = aryl or heterocycle
As shown in Scheme 15, 2-(2-Hydroxyethyl)-l-benzofuran-4-yl trifluoromethanesulfonate, prepared as described in Examples 85A-85C herein, is treated with methanesulfonyl chloride and triethylamine in CH2CI2 at 0 °C to provide 2-{2- [(methylsulfonyl)oxy]ethyl}-l-benzofuran-4-yl trifluoromethanesulfonate. 2-{2- [(Methylsulfonyl)oxy]ethyl}-l-benzofuran-4-yl trifluoromethanesulfonate is treated with (2R)-methy .pyrrolidine mono-(L)-tartaric acid salt and Cs2C0 in MeCN at approximately 35 °C for 1 to 4 days to provide 2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-4-yl trifluoromethanesulfonate. 2- {2-[(2R)-2-Methyl-l -pyrrolidinyl] ethyl} - 1 -benzofuran-4-yl trifluoromethanesulfonate is processed as described in Murata, et al., Journal of Organic Chemistry (2000) 65, 164-168 to provide (2R)-2-methyl-l-{2-[4-(4,4,5,5-tetτamethyl-l ,3,2- dioxaborolan-2-yl)-l-benzofuran-2-yl]ethyl}pyrrolidine. For example, one equivalent of 2- {2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -l-benzofuran-4-yl trifluoromethanesulfonate is treated with palladium acetate or [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium (PdChdppf), 3 equivalents of triethylamine, and 1.5 equivalents of pinacolborane in 1 ,4- dioxane at 25 ° C for several hours or until the reaction is complete as judged by TLC. (2R)- 2-Methyl-l-{2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-benzofuran-2- yl]ethyl}pyrrolidine is treated with a suitable starting material, for example, aryl halides, aryl triflates, or heterocyclic halides, a palladium catalyst, such as palladium (II) acetate, a trivalent phosphine such as biphen-2-yl-dicyclohexylphosphine, and aqueous sodium carbonate or potassium phosphate in an organic solvent such as ethanol or tetrahydrofuran at 25 °C to 120 °C to provide compounds of formula (51). Compounds of formula (51) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (51) is partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.
Examples of compounds that can be prepared according to procedures described in Scheme 15 and starting materials suitable for preparing such compounds are provided below in Table 3.
Table 3
Examples 225-246 Compounds of Formula (52) Examples 225-246 are compounds of formula (52), wherein R is aryl or heterocycle. Such compounds can be prepared according to the procedure shown in Scheme 16 below:
Scheme 16
R7 = aryl or heterocycle As shown in Scheme 16, 2-(2-hydroxyethyl)-l -benzofuran-6-yl trifluoromethanesulfonate, prepared as described in Examples 86A to 86C, is processed according to procedures described for Examples 203-224 as shown in Scheme 15 to provide compounds of formula (52). Compounds of formula (52) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (52) can be partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.
Examples of compounds that can be prepared according to procedures described in Scheme 16 and starting materials suitable for preparing such compounds are provided below in Table 4.
Table 4
Examples 247-268 Compounds of Formula (53) Examples 247-268 are compounds of formula (53), wherein R5 is aryl or heterocycle. Such compounds can be prepared according to the procedures shown in Scheme 17 below:
Scheme 17
Scheme 15
As shown in Scheme 17, 3-bromo-l,2-benzenediol is treated with bis- triphenylphosphine palladium dichloride, copper iodide, triethylamine, and 3-butyn-l-ol and heated at between 40 °C and 80 °C for several hours or until TLC (thin layer chromatography) indicates the reaction is complete to provide 2-(2-hydroxyethyl)-l- benzofuran-7-ol. 2-(2-Hydroxyethyl)-l-benzofuran-7-ol is then processed according to procedures described for Examples 203-224 as shown as in Scheme 15 to provide 2-{2-[(2R)- 2-methyl-l -pyrrolidinyljethyl} -l-benzofuran-7-yl trifluoromethanesulfonate, which is processed as described in Murata, et al., Journal of Organic Chemistry (2000) 65, 164-168 and followed by treatment with a suitable starting material, for example, aryl halides, aryl triflates, or heterocyclic halides, a palladium catalyst, such as palladium (II) acetate, a trivalent phosphine such as biphen-2-yl-dicyclohexylphosphine, and aqueous sodium carbonate or potassium phosphate in an organic solvent such as ethanol or tetrahydrofuran at 25 °C to 120 °C to provide compounds formula (53). Compounds of formula (53) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (53) can be partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.
Examples of compounds that can be prepared according to procedures described in Scheme 17 and starting materials suitable for preparing such compounds are provided below in Table 5.
Table 5
Examples 269-283 Compounds of Formula (54) Examples 269-283 are compounds of formula (54), wherein Re is a heterocycle selected from imidazolyl, benzimidazolyl, 3H-imidazo[4,5-c]pyridinyl, pyrrolyl, and pyrazolyl, and wherein the heterocycle can be substituted with 1 , 2, or 3 substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, arylalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, haloalkylcarbonyl, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NRARB, (NRARβ)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl; and RA and RB are as defined in formula (I). Such compounds can be prepared according to the procedures shown in Scheme 18 below:
(54) As shown in Scheme 18, (2R)-l-[2-(5-bromo-l-benzofuran-2-yl)ethyl]-2- methylpyrrolidine is treated with a palladium source such as palladium (II) acetate, a trivalent phosphine such as 1,1 '-bis(diphenylphosphino)ferrocene, a base such as Cs2C03, a metal alkoxide such as sodium tert-butoxide, and a suitable starting material such as imidazolyl, benzimidazolyl, 3H-imidazo[4,5-c]pyridinyl, pyrrolyl, and pyrazolyl in an organic solvent such as toluene at 60 °C to 140 °C to provide compounds of formula (54). Compounds of formula (54) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (54) can be partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel. Compounds of formula (54) also are prepared by treating (2R)-l-[2-(5-bromo-l- benzofuran-2-yl)ethyl]-2-methylpyrrolidine with a copper source such as the benzene complex of copper (I) trifluoromethanesulfonate, a ligand such as 1,10-phenanthroline, trans,trans-dibenzylideneacetone, a base such as CS2CO3 and a suitable starting material such as imidazolyl, benzimidazolyl, 3H-imidazo[4,5-c]pyridinyl, pyrrolyl, and pyrazolyl in an organic solvent such as xylenes at 100 °C to 150 °C to provide compounds of formula (54). Examples of compounds that can be prepared according to procedures described in Scheme 18 and starting materials suitable for preparing such compounds are provided below in Table 6. Table 6
Examples 284-287 Compounds of Formula (55) Examples 284-287 are compounds of formula (55) wherein RA and R20 are as defined in formula (I). Such compounds can be prepared according to procedures shown in Scheme 19.
Scheme 19
(55) As shown in Scheme 19, (2R)-l-[2-(5-bromo-l -benzofuran-2 -yl)ethyl]-2- methylpyrrolidine is treated with a palladium source such as palladium (II) acetate, a palladium activating ligand such as l, -bis(diphenylphosphino)ferrocene, tri- tertbutylphosphine, BINAP, or 2-(di-tert-butylphosphino)-o-biphenyl, or l,3-bis(2,6- diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene, a base such as CS2CO3, a metal alkoxide such as sodium tert-butoxide, and a suitable starting material, for example, a heterocycle, or an aryl group, or a cycloalkyl group, wheren the heterocycle, aryl or cycloalkyl group has a -NHRA substituent in an organic solvent such as toluene at 60 °C to 140 °C to provide compounds of formula (55). Compounds of formula (55) can be isolated and purified by methods known to those skilled in the art. For example, compounds of formula (55) can be partitioned between dichloromethane and water, the organic phase concentrated, and the residue purified by chromatography on silica gel.
Examples of compounds that can be prepared according to procedures described in Scheme 19 and starting materials suitable for preparing such compounds are provided below in Table 7.
Table 7
Compounds of the present invention may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are "R" or "S" depending on the configuration of substituents around the chiral carbon atom. The terms "R" and "S" used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present invention contemplates various stereoisomers and mixtures thereof and are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
The term "pharmaceutically acceptable carrier," as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of one skilled in the art of formulations.
The present invention provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
Further included within the scope of the present invention are pharmaceutical compositions comprising one or more of the compounds of formula I-VII prepared and formulated in combination with one or more non-toxic pharmaceutically acceptable compositions. The pharmaceutical compositions can be formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally , intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the such as), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative agents, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the such as. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the such as. Prolonged absoφtion of the injectable pharmaceutical form may be brought about by the use of agents delaying absoφtion, for example, aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is often desirable to slow the absoφtion of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amoφhous material with poor water solubility. The rate of absoφtion of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absoφtion of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Suspensions, in addition to the active compounds, may contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.
If desired, and for more effective distribution, the compounds of the present invention can be incoφorated into slow-release or targeted-delivery systems such as polymer matrices, liposomes, and microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incoφoration of sterilizing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of such composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incoφorating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic, parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this puφose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absoφtion accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the such as.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
Compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the such as. The preferred lipids are the natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), p 33 et seq.
The terms "pharmaceutically acceptable salts, esters and amides," as used herein, refer to carboxylate salts, amino acid addition salts, zwitterions, esters and amides of compounds of formula I-VII which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the such as, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. By "pharmaceutically acceptable salt" is meant those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the such as and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the such as and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the such as. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the such as. Preferred salts of the compounds of the invention include phosphate, tris and acetate.
The term "pharmaceutically acceptable ester," as used herein, refers to esters of compounds of the present invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Examples of pharmaceutically acceptable, non-toxic esters of the present invention include Ci-to-Cβ alkyl esters and Cs-to-C-? cycloalkyl esters, although Cι-to-C4 alkyl esters are preferred. Esters of the compounds of formula I-VII may be prepared according to conventional methods.
The term "pharmaceutically acceptable amide," as used herein, refers to non-toxic amides of the present invention derived from ammonia, primary Ci-to-Cδ alkyl amines and secondary Ci-to-Cβ dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-.0-C3 alkyl primary amides and C1-.0-C2 dialkyl secondary amides are preferred. Amides of the compounds of formula I-VII may be prepared according to conventional methods.
The term "pharmaceutically acceptable prodrug" or "prodrug," as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the such as, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. Prodrugs of the present invention may be rapidly transformed in vivo to a parent compound of formula I-VII, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), hereby incoφorated by reference.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The present invention contemplates pharmaceutically active compounds either chemically synthesized or formed by in vivo biotransformation to compounds of formula I- VII.
The compounds of the present invention, including but not limited to those specified in the examples, possess an affinity for the histamine-3 receptors. As histamine-3 receptor ligands, the compounds of the present invention may be useful for the treatment and prevention of diseases or conditions such as acute myocardial infarction, Alzheimer's disease, attention-deficit hyperactivity disorder, bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric disorder, drug abuse, deficits of memory and learning, jet lag, Parkinson's disease, epilepsy, schizophrenia, dementia, depression, cutaneous carcinoma, mild cognitive impairment, medullary thyroid carcinoma, melanoma, allergic rhinitis, asthma, narcolepsy, mood and attention alteration, Meniere's disease, gastrointestinal disorders, inflammation, migraine, motion sickness, neurogenic inflammation, obsessive compulsive disorder, Tourette's syndrome, obesity, pain, seizures, septic shock, vertigo, and wakefulness.
The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat septic shock and cardiovascular disorders, in particular, acute myocardial infarction may be demonstrated by Imamura et al., Circ.Res., (1996) 78, 475-481; Imamura et. al., Circ.Res., (1996) 78, 863-869; R. Levi and N.C.E. Smith, "Histamine H3-receptors: A new frontier in myocardial ischemia", J. Pharm. Exp. Ther., 292: 825-830, (2000); and Hatta, E., K Yasuda and R. Levi, "Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocradial ischemia", J. Pharm. Exp. Ther., 283: 494-500, (1997).
The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat sleep disorders, in particular, narcolepsy may be demonstrated by Lin et al., Brain Res. (1990) 523, 325-330; Monti et al., Neuropsychopharmacology (1996) 15, 31-35; Sakai, et al., Life Sci. (1991) 48, 2397-2404; Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75-78; Panula, P. et al., Neuroscience (1998) 44, 465-481); Wada et al., Trends in Neuroscience (1991) 14, 415; and Monti et al., Eur. J. Pharmacol. (1991) 205, 283.
The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat cognition and memory process disorders may be demonstrated by Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75-78; Panula, P. et al., Neuroscience (1997) vol. 82, 993-997; Haas et al., Behav. Brain Res. (1995) 66, 41-44; De Almeida and Izquierdo, Arch. Int. Pharmacodyn. (1986) 283, 193- 198; Kamei et al., Psychopharmacology (1990) 102, 312-318; and Kamei and Sakata, Jpn. J. Pharmacol. (1991) 57, 437-482; Schwartz et al., Psychopharmacology; The fourth Generation of Progress. Bloom and Kupfer (eds). Raven Press, New York, (1995) 397; and Wada et al., Trends in Neurosci., (1991) 14, 415.
The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat attention-deficit hyperactivity disorder (ADHD) may be demonstrated by Shaywitz et al., Psychopharmacology (1984) 82, 73-77; Dumery and Blozovski, Exp. Brain Res. (1987) 67, 61-69; Tedford et al., J. Pharmacol. Exp. Ther. (1995) 275, 598-604; and Tedford et al., Soc. Neurosci. Abstr. (1996) 22, 22.
The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat seizures, in particular, epilepsy may be demonstrated by Yokoyama et al., Eur. J. Pharmacol. (1993) 234, 129; Yokoyama and Iinuma, CNS Dmgs (1996) 5, 321 ; Onodera et al., Prog. Neurobiol. (1994) 42, 685; R. Leurs, R.C. Vollinga and H. Timmerman, "The medicinal chemistry and therapeutic potentials of ligand of the histamine H3 receptor", Progress in Dmg Research 45: 170-165, (1995); Leurs and Timmerman, Prog. Dmg Res. (1992) 39, 127; The Histamine H3 Receptor, Leurs and Timmerman (eds), Elsevier Science, Amsterdam, The Netherlands (1998); H. Yokoyama and K. Iinuma, "Histamine and Seizures: Implications for the treatment of epilepsy", CNS Dmgs, 5(5); 321-330, (1995); and K. Humkami, H. Yokoyama, K. Onodera, K. Iinuma and T. Watanabe, AQ-0145, "A newly developed histamine H3 antagonist, decreased seizure susceptibility of electrically induced convulsions in mice", Meth. Find. Exp. Clin. Pharmacol, 17(C): 70-73, (1995).
The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat motion sickness, Alzheimer's disease, and Parkinson's disease may be demonstrated by Onodera et al. Prog. Neurobiol. (1994) 42, 685; Leurs and Timmerman, Prog. Dmg Res. (1992) 39, 127; and The Histamine H3 Receptor, Leurs and Timmerman (eds), Elsevier Science, Amsterdam, The Netherlands (1998).
The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat narcolepsy, schizophrenia, depression, and dementia may be demonstrated by R. Leurs, R.C. Vollinga and H. Timmerman, "The medicinal chemistry and therapeutic potentials of ligand of the histamine H receptor", Progress in Dmg Research 45: 170-165, (1995); The Histamine H3 Receptor, Leurs and Timmerman (eds), Elsevier Science, Amsterdam, The Netherlands (1998); and Perez-Garcia C, et. al. Laboratory of Pharmacology, University of San Pablo CEU, Madrid, Spain, Psychopharmacology (Berl) (1999) Feb., 142(2): 215-20).
The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat wakefulness, cognitive enhancement, mood and attention alteration, vertigo and motion sickness, and treatment of cognitive deficits in psychiatric disorder may be demonstrated by (Schwartz, Physiol. Review (1991) 71, p. 1-51). The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat mild cognitive impairment, deficits of memory, deficits of learning and dementia may be demonstrated by (C. E. Tedford, in "The Histamine H3 Receptor: a target for new dmgs", the Pharmacochemistry Library, vol. 30 (1998) edited by R. Leurs and H. Timmerman, Elsevier (New York), p. 269 and references also contained therein.)
The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat obesity may be demonstrated by Leurs et al. Trends in Pharm. Sci. (1998) 19, 177-183; Itoh. E, Fujimiay, M, and Inui, A, Thioperamide, A histamine H3 receptor antagonist, powerfully suppresses peptide YY-induced fodd intake in rats, Biol. Psych. 45(4): 475-481 , (1999); Yates S.I, Pawlowski, G.P, Antal, J.M, Ali, S.M, Jiang, J, and Bmnden, K.R, Effects of a novel histamine H3 receptor antagonist, GT-2394, on food intake and weight gain in Sprague-Dawley rats, Abstracts, Society for Neuroscience, 102.10, p. 219, November, (2000); and Bjenning, C, Johannesson, U, Juul, A-G, Lange, K.Z, and Rimvall, K, Peripherally administered ciproxifan elevates hypothalamic histamine levels and potently reduces food intake in the Sprague Dawley rat. Abstracts, International Sendai Histamine Symposium, Sendai, Japan, November, 2000, #P 39.
The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat inflammation and pain may be demonstrated by Phillips et al. Annual Reports in Medicinal Chemistry (1998) 33, 31-40.
The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat migraine may be demonstrated by R. Leurs, R.C. Vollinga and H. Timmerman, "The medicinal chemistry and therapeutic potentials of ligands of the histamine H receptor", Progress in Dmg Research 45: 170-165, (1995); and Matsubara et al, Eur. J. Pharmacol. (1992) 224, 145; and Rouleau et al, J. Pharmacol. Exp. Ther. (1997) 281, 1085.
The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat cancer, in particular, melanoma, cutaneous carcinoma and medullary thyroid carcinoma may be demonstrated by Polish Med. Sci. Mon, (1998) vol. 4, issue 5, 747; Adam Szelag, "Role of histamine H3-receptors in the proliferation of neoplastic cells in vitro", Med. Sci. Monit, 4(5): 747-755, (1998); and Fitzsimons, C, H. Duran, F. Labombarda, B. Molinari and E. Rivera, "Histamine receptors signalling in epidermal tumor cell lines with H-ras gene alterations", Inflammation Res, 47 (Suppl 1): S50-S51 , (1998).
The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat vestibular dysfunctions, in particular, Meniere's disease may be demonstrated by R. Leurs, R.C. Vollinga and H. Timmerman, "The medicinal chemistry and therapeutic potentials of ligands of the histamine H receptor", Progress in Dmg Research 45: 170-165, (1995).
The ability of the compounds of the present invention, including but not limited to those specified in the examples, to treat asthma may be demonstrated by Delaunois A, Gustin P, Garbarg M, and Ansay M, "Modulation of acetylcholine, capsaicin and substance P effects by histamine H3 receptors in isolated perfused rabbit lungs", European Journal of Pharmacology 277(2-3):243-50, (1995); and Dimitriadou, et al, "Functional relationship between mast cells and C-sensitive nerve fibres evidenced by histamine H3-receptor modulation in rat lung and spleen", Clinical Science. 87(2): 151-63, (1994).
The ability of the compounds of the present invention, including but not limited to those specified in the examples, to allergic rhinitis may be demonstrated by McLeod et al. Progress in Resp. Research 31, 133 (2001).
Aqueous liquid compositions of the present invention are particularly useful for the treatment and prevention of asthma, epilepsy, Raynaud's syndrome, male sexual dysfunction, female sexual dysfunction, migraine, pain, eating disorders, urinary incontinence, functional bowel disorders, neurodegeneration and stroke.
When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester, amide or prodmg form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; dmgs used in combination or coincidental with the specific compound employed; and such as factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.003 to about 30 mg/kg/day. For puφoses of oral administration, more preferable doses can be in the range of from about 0.1 to about 15 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for puφoses of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof. All references cited herein are incoφorated by referance. In the case of inconsistencies, the instant disclosure, including definitions, will prevail.

Claims

What is claimed is:
1. A compound of formula (I)
(I), or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein
A is selected from the group consisting of carbonyl and a covalent bond;
D is selected from the group consisting of O and S;
L is selected from the group consisting of lower alkylene, fluoroalkylene, and hydroxyalkylene;
P and Q taken together form a covalent bond or are both hydrogen;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, alkenyl, and alkynyl; or
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle;
R3 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARβ)alkyl, (NRARβ)carbonyl, and (NRARB)sulfonyl;
R^ R5, Re and R are each independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, - NRARB, (NRARB)alkyl, (NRARB)carbonyl, (NRARB)sulfonyl, -L2R2o, and -R20L3R22;
L2 is selected from the group consisting of alkylene, alkenylene, O, S, S(O), S(O)2, C(=0), C=(NOR2,), and N(RA);
L3 is selected from the group consisting of a covalent bond, alkylene, alkenylene, O, S, C(=0), N(=OR21), and N(RA); R20 is selected from the group consisting of aryl, heterocycle, and cycloalkyl;
R21 is selected from the group consisting of hydrogen and alkyl;
R22 is selected from the group consisting of aryl, heterocycle, and cycloalkyl;
RA and RB are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl and formyl; provided that at least one of R-i, R5, Re, or R7 is aryl, heterocycle, cycloalkyl, -L2R20 or -R2oL3R22.
2. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl;
R , R , R5 and R7 are hydrogen;
R6 is L2R20;
L2 is C(=0); and
R20 is aryl.
3. A compound according to claim 1 wherein A is a covalent bond;
D is O;
P and Q taken together form a covalent bond;
R) and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-mefhyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2 S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R4, R5 and R7 are hydrogen;
R6 is L2R20;
L2 is C(=0); and
R20 is aryl.
4. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2 -methyl- 1 -pyrrolidinyl;
R3, R4, R5 and R7 are hydrogen;
R6 is L2R20;
L2 is C(=0); and
R20 is phenyl substituted with 0, 1 , 2 or 3 substitutents selected from the group consisting of hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NRARB)carbonyl, and-NRARB.
5. A compound according to claim 4 selected from the group consisting of (4-fluorophenyl)(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)methanone; (3-fluorophenyl)(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)methanone;
(2-fluorophenyl)(2-{2-[(2R)-2 -methyl- 1 -pyrrolidinyljethyl} -l-benzofuran-5- yl)methanone;
(3-chlorophenyl)(2-{2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -1 -benzofuran- 5- yl)methanone;
(4-chlorophenyl)(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)methanone;
(4-methoxyphenyl)(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-5- yl)methanone;
(4-fluoro-3-methylphenyl)(2-{2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -1 -benzofuran- 5-yl)methanone;
(4-chloro-3-methylphenyl)(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran- 5-yl)methanone;
(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)[4- (methylthio)phenyljmethanone;
[4-(dimethylamino)phenyl](2-{2-[(2R)-2 -methyl- 1 -pyrrolidinyljethyl} -1-benzofuran- 5-yl)methanone;
(4-methylphenyl)(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)methanone;
(3,5-difluorophenyl)(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)methanone;
(2-methoxyphenyl)(2-{2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -l-benzofuran-5- yl)methanone;
(3-methoxyphenyl)(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)methanone; and
(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)(phenyl)methanone.
6. A compound according to claim 1 wherein
A is a covalent bond; D is O; P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1- dioxidothiomoφholinyl;
R , R-t, R5 and R7 are hydrogen; is L2R20;
L2 is C(=0); and
R20 is cycloalkyl.
7. A compound according to claim 1 wherein
A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1 -yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2 S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1Jhept-5-yl, and l ,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R4, R5 and R7 are hydrogen;
L2 is C(=0); and R20 is cycloalkyl.
8. A compound according to claim 1 wherein A is a covalent bond;
D is O;
P and Q taken together form a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2 -methyl- 1 -pyrrolidinyl; R3, R-t, R5 and R7 are hydrogen; Re is L2R20; L2 is C(=0); and R20 is cycloalkyl.
9. A compound according to claim 8 that is cyclopropyl(2- {2-[(2R)-2 -methyl- 1- pyrrolidinyljethyl} -1 -benzofuran-5-yl)methanone.
10. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1- dioxidothiomoφholinyl;
R3, R-t, R5 and R are hydrogen;
R6 is L2R2o;
L2 is selected from the group consisting of alkylene and alkenylene; and
R20 is aryl.
11. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy- 1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2 S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-mefhyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl- 1 -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R-i, R5 and R7 are hydrogen;
R6 is L2R2o;
L2 is selected from the group consisting of alkylene and alkenylene; and
R20 is aryl.
12. A compound according to claim 1 wherein A is a covalent bond;
D is O;
P and Q taken together form a covalent bond;
Ri and R taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R3, j, R5 and R are hydrogen; and Re is L2R20; L2 is selected from the group consisting of alkylene and alkenylene; and R20 is phenyl substituted with 0, 1 , 2, or 3 substituents selected from the group consisting of hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NRARB)carbonyl, and -NRARB.
13. A compound according to claim 12 selected from the group consisting of (2R)-l-(2-{5-[ 2-(4-fluorophenyl)vinyl]-l-benzofuran-2-yl}ethyl)-2- methylpyrrolidine; and
(2R)-l-[2-(5-benzyl-l-benzofuran-2-yl)ethyl]-2-methylpyrrolidine.
14. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl;
R3, R4, R5 and R7 are hydrogen; and
R is alkylcarbonyl.
15. A compound according to claim 1 wherein A is a covalent bond;
D is O;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-mefhyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l-pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l ,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R;, R5 and R7 are hydrogen; and
Re is alkylcarbonyl.
16. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2 -methyl- 1 -pyrrolidinyl; R3, R-t, R5 and R are hydrogen; and R6 is alkylcarbonyl.
17. A compound according to claim 16 that is 3-efhyl-l-(2-{2-[(2R)-2-methyl-l- pyrrolidinyl]ethyl}-l-benzofuran-5-yl)-l-pentanone.
18. A compound according to claim 1 wherein A is a covalent bond;
D is O;
P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl;
R3, R , R5 and R are hydrogen; and
Re is heterocycle.
19. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-mefhyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R4, R5 and R are hydrogen; and
Re is heterocycle.
20. A compound according to claim 1 wherein A is a covalent bond;
D is O; L is -CH2CH2-;
P and Q taken together form a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1 - dioxidothiomoφholinyl; R3, R-;, R5 and R7 are hydrogen;
R3, R4, R5 and R7 are hydrogen; and
Re is heterocycle selected from the group consisting of furyl, imidazolyl, isothiazolyl, isothiazolinyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzo thiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, quinolinyl, quinolizinyl, quinoxalinyl, or quinazolinyl wherein the heterocycle is substituted with 0, 1, 2, or 3 substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, arylalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, haloalkylcarbonyl, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl.
21. A compound according to claim 21 selected from the group consisting of
5-(chloromethyl)-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)- 1 ,2,4-oxadiazole;
3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)-5-propyl-l,2,4- oxadiazole;
5-ethyl-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)-l ,2,4- oxadiazole;
5-methyl-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)- 1 ,2,4- oxadiazole;
3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)pyridine;
1 -(2- {2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -l-benzofuran-5-yl)-l H-imidazole; and 3,5-dimethyl-4-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)isoxazole;
3,5-dimethyl-4-{2-[2-(2R)-methyl-pyrrolidin-l-yl-ethyl]-benzofuran-5-yl} -isoxazole;
5-{2-[2-(2R)-methyl-pyrrolidin-l-yl-ethyl]-benzofuran-5-yl}-2-phenyl-oxazole;
2- {2-[2-(2R)-methyl-pyrrolidin-l-yl-ethyl]-benzofuran-5-yl} -thiazole;
4-{2-[2-(2R)-methyl-pyrrolidin-l-yl-ethyl]-benzofuran-5-yl}-lH-pyrazole;
4-{2-[2-(2R)-methyl-pyrrolidin-l-yl-ethyl]-benzofuran-5-yl}-l-phenyl-lH-pyrazole;
1 -methyl-4- {2-[(2R)-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H- imidazole;
4- {2-[2-(2R)-methyl-pyrrolidin-l-yl-ethyl]-benzofuran-5-yl} -thiazole;
2- {2-[2-(2R)-methyl-pyrrolidin-l-yl-ethyl]-benzofuran-5-yl}-l H-imidazole;
4- {2-[2-(2R)-methyl-pyrrolidin-l-yl-ethyl]-benzofuran-5-yl}-l H-benzoimidazole;
3-methyl-6-{(2R)-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-pyridazine;
2- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl-ethyl]-benzofuran-5-yl} -pyrazine;
5- {2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl} -pyrimidine;
5-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-pyridazin-4-ylamine;
5-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-nicotinonitrile;
4- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H-indole;
4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-phthalonitrile;
5-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-indan-l -one; l-{2-[5-(5,6-dihydro-2H-pyran-3-yl)-benzofuran-2-yl]-ethyl}-(2R)-methyl- pyrrolidine; l -[2-(5-cyclohept-l-enyl-benzofuran-2-yl)-ethyl]-2R)-methyl-pyrrolidine;
(2R)-methyl-l-(2-{5-[2-(l lH-10-thia-dibenzo[a,d]cyclohepten-5-ylidene)-ethyl]- benzofuran2-yl}-ethyl)-pyrrolidine;
4- {2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl} -pyridine;
4- {2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5-yl} -pyridine; l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-lH-imidazole-4,5- dicarbonitrile;
4,5-dichloro-l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-lH- imidazole;
1 - {2-[2-(2(R)-methylpyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H-benzoimidazole; 3-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-3H-imidazo[4,5- c]pyridine;
(5-hydroxymethyl-3- {2-[2-(2(R)-methylpyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} -3H- imidazol-4-yl)-methanol; l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-l H-pyrrole; l-(l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-lH-pyrrol-3-yl)- ethanone;
3-methyl-l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-lH-pyrrole;
1 - {2-[2-(2(R)-methylpyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} -3 ,4-bis- trifluoromethyl- 1 H-pyrrole;
1 - {2-[2-(2(R)-methylpyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H-pyrazole;
4-methyl-l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-l H-pyrazole; l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-lH-pyrazole-4- carboxylic acid ethyl ester;
1 - {2-[2-(2(R)-methylpyrrolidin- 1 -yl)-ethyl]-benzofuran-5-yl} - 1 H-pyrazole-4- carbonitrile;
4-chloro-l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-l H-pyrazole; and
3,5-dimethyl-l-{2-[2-(2(R)-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-lH- pyrazole.
22. A compound according to claim 1 wherein
A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2 -methyl- 1 -pyrrolidinyl;
R3, R-ι, R5 and R7 are hydrogen; and
R<5 is heterocycle selected from the group consisting of l,2,4-oxadiazol-3-yl, 3- pyridinyl, 4-isoxazolyl, and lH-imidazol-1-yl wherein the heterocycle is substituted with 0, 1, or 2 substituents selected from the group consisting of hydrogen, alkyl, haloalkyl, and hydroxyalkyl.
23. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond; and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1 - dioxidothiomoφholinyl;
R3, R4, R5 and R7 are hydrogen;
R6 is -R20L3R22;
R20 is heterocycle;
L3 is selected from the group consisting of a covalent bond and alkylene; and
R22 is aryl.
24. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy- 1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2 -ethyl- 1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R , R5 and R7 are hydrogen;
JAe is -R20L3R22;
R20 is heterocycle;
L3 is selected from the group consisting of a covalent bond and alkylene; and
R22 is aryl.
25. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2 -methyl- 1 -pyrrolidinyl;
R3, R-t, R5 and R7 are hydrogen;
R20 is l,2,4-oxadiazol-3-yl;
L3 is selected from the group consisting of a covalent bond and alkylene; and
R22 is phenyl substituted with 0, 1, 2, or 3 substitutents selected from the group consisting of hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NRARB)carbonyl, and -NRARB.
26. A compound according to claim 25 selected from the group consisting of
4- [3 -(2- {2-[(2R)-2-methylpyrrolidin- 1 -yl]ethyl } - 1 -benzofuran-5 -yl)- 1 ,2 ,4-oxadiazol- 5-yl]benzonitrile; 5-(4-chlorophenyl)-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)- 1 ,2,4-oxadiazole;
5-(2-chlorophenyl)-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)- 1,2,4-oxadiazole;
5-(4-fluorobenzyl)-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)- 1,2,4-oxadiazole;
5-(4-methoxybenzyl)-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5- yl)- 1 ,2,4-oxadiazole;
3-{[3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)-l ,2,4- oxadiazol-5-yl]methyl}benzonitrile;
3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)-5-phenyl-l ,2,4- oxadiazole;
5-(4-fluorophenyl)-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5-yl)- 1,2,4-oxadiazole; and
5-(3-chloro-4-fluorophenyl)-3-(2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l- benzofuran-5-yl)-l,2,4-oxadiazole.
27. A compound according to claim 1 wherein
A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl;
R3, R-i, R5 and R7 are hydrogen;
R20 is l,2,4-oxadiazol-3-yl;
L3 is selected from the group consisting of a covalent bond and alkylene; and
R22 is heterocycle.
28. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l ,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R4, R5 and R7 are hydrogen;
R20 is l ,2,4-oxadiazol-3-yl;
L3 is selected from the group consisting of a covalent bond and alkylene; and
R22 is heterocycle.
29. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2 -methyl- 1 -pyrrolidinyl; R3, R , R5 and R7 are hydrogen;
Re is -R2oL3R22;
R20 is l,2,4-oxadiazol-3-yl;
L3 is selected from the group consisting of a covalent bond and alkylene; and
R22 is 2-thienyl.
30. A compound according to claim 29 that is 3-(2-{2-[(2R)-2 -methylpyrrolidin- 1 - yl]ethyl}-l-benzofuran-5-yl)-5-(thien-2-ylmethyl)-l,2,4-oxadiazole.
31. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl;
R3, R-j, R5 and R7 are hydrogen;
Re is -R20L3R22;
R20 is aryl;
L3 is C(=0); and
R22 is cycloalkyl.
32. A compound according to claim 1 wherein A is a covalent bond;
D is O;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R , R5 and R7 are hydrogen;
Re is -R20L3R22;
R20 is aryl;
L3 is C(=0); and
R22 is cycloalkyl.
33. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond; and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl- 1 -pyrrolidinyl; R3, R , R5 and R7 are hydrogen; Re is -R20L3R22; R20 is phenyl; L3 is C(=O); and R22 is cycloalkyl.
34. A compound according to claim 33 selected from the group consisting of cyclopropyl[3 -(2- {2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -l-benzofuran-5- yl)phenyl]methanone; and cyclopropyl[4-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)phenyl] methanone .
35. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxido thiomoφholinyl ;
R3, R4, R5 and R7 are hydrogen;
Re is -R20L3R22;
R20 is aryl;
L3 is C(=0); and
R22 is aryl.
36. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R , 5 and R7 are hydrogen;
R20 is aryl;
L3 is C(=0); and
R22 is aryl.
37. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2 -methyl- 1 -pyrrolidinyl;
R3, R4, R5 and R7 are hydrogen;
R6 is -R20L3R22;
R20 is phenyl;
L3 is C(=0); and
R22 is phenyl substituted with 0, 1, 2, or 3 substituents selected from the group consisting of hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NRARB)carbonyl, and-NRARB.
38. A compound according to claim 37 that is (3-fluorophenyl)[3-(2-{2-[(2R)-2-methyl- 1 -pyrrol idinyl] ethyl } - 1 -benzofuran- 5 -y l)phenyl ] methanone .
39. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
R] and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl;
R3, R-j, R5 and R7 are hydrogen;
Re is -R20L3R22;
R20 is aryl;
L3 is C(=0); and
R22 is heterocycle.
40. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l-pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l ,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R4, R5 and R7 are hydrogen;
Re is -R20L3R22;
R20 is aryl;
L3 is C(=0); and
R22 is heterocycle.
41. A compound according to claim 1 wherein A is a covalent bond;
D is O;
L is -CH2CH2-;
P and Q taken together form a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2 -methyl- 1 -pyrrolidinyl; R3, R4, R5 and R are hydrogen; Re is -R20L3R22; R20 is phenyl; L3 is C(=O); and R22 is 2-thienyl.
42. A compound according to claim 41 that is [3-(2-{2-[(2R)-2-methyl-l- pyrrol idinyl] ethyl } - 1 -benzofuran- 5 -yl)phenyl] (2-thienyl)mefhanone .
43. A compound according to claim 1 of formula (II)
(II), or a pharmaceutical acceptable salt, ester, amide, or prodmg thereof, wherein R7 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl;
R8 is selected from the group consisting of hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl and (NRARB)carbonyl;
R9 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl;
X is selected from the group consisting of CH, CRx and N;
Y is selected from the group consisting of CH, CRY and N;
Z is selected from the group consisting of CH, CRz and N; and
Rx, Ry and Rz are each independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl.
44. A compound according to claim 43 wherein A is a covalent bond.
45. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and R8 is cyano.
46. A compound according to claim 43 wherein A is a covalent bond; Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; R3, R4, R5, R7 and R are hydrogen; R8 is cyano; X is CH;
Y is CH; and Z is CH.
47. A compound according to claim 46 selected from the group consisting of: 4- {2-[2-(diethylamino)ethyl]-l -benzofuran-5-yl}benzonitrile; 4-(2-{2-[tert-butyl(methyl)amino]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-(2-{2-[isopropyl(methyl)amino]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-(2- {2-[isobutyl(methyl)amino]ethyl} - 1 -benzofuran-5-yl)benzonitrile; 4-(2-{2-[ethyl(isopropyl)amino]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-(2-{2-[ethyl(propyl)amino]ethyl}-l-benzofuran-5-yl)benzonitrile; and 4- [2 -(2-aminoethyl)- 1 -benzofuran- 5 -yl]benzonitrile .
48. A compound according to claim 43 wherein A is a covalent bond ;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; R8 is cyano; X is N;
Y is CH; and Z is CH.
49. A compound according to claim 43 wherein A is' a covalent bond;
R\ and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and R8 is heterocyclecarbonyl.
50. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and
R8 is heterocyclecarbonyl wherein the heterocycle is selected from the group consisting of azetidinyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5- dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl.
51. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and
R8 is heterocyclecarbonyl wherein the heterocycle is selected from the group consisting of 1 -azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 - pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl.
52. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and
R8 is heterocyclecarbonyl wherein the heterocycle of heterocarbonyl is 4-moφholinyl.
53. A compound according to claim 43 wherein L is -CH2CH2-;
A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl;
R3, R-i, R5, R7 and R9 are hydrogen;
R8 is heterocyclecarbonyl wherein the heterocycle of heterocarbonyl is 4- moφholinyl; X is CH;
Y is CH; and Z is CH.
54. A compound according to claim 53 selected from the group consisting of: N,N-diethyl-N-(2- {5-[4-(4-moφholinylcarbonyl)phenyl]- 1 -benzofuran-2- yl}ethyl)amine;
N-(tert-butyl)-N-methyl-N-(2- {5-[4-(4-moφholinylcarbonyl)phenyl]- 1 -benzofuran-2- yl}ethyl)amine;
N-isopropyl-N-methyl-N-(2-{5-[4-(4-moφholinylcarbonyl)phenyl]-l-benzofuran-2- yl}ethyl)amine;
N-isobutyl-N-methyl-N-(2-{5-[4-(4-moφholinylcarbonyl)phenyl]-l-benzofuran-2- yl}ethyl)amine;
N-ethyl-N-isopropyl-N-(2-{5-[4-(4-moφholinylcarbonyl)phenyl]-l-benzofuran-2- yl}ethyl)amine;
N,N-dimethyl-N-(2-{5-[4-(4-moφholinylcarbonyl)phenyl]-l-benzofuran-2- yl}ethyl)amine; and
N-ethyl-N-(2- {5-[4-(4-moφholinylcarbonyl)phenyl]- 1 -benzofuran-2-yl} ethyl)-N- propylamine.
55. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; R8 is heterocyclecarbonyl; X is N;
Y is CH; and Z is CH.
56. A compound according to claim 43 wherein A is a covalent bond; Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl;
R8 is heterocyclecarbonyl wherein the heterocycle of heterocarbonyl is selected from the group consisting of azetidinyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl.;
X is N;
Y is CH; and Z is CH.
57. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl;
R8 is heterocyclecarbonyl wherein the heterocycle of heterocarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomoφholinyl, and 1 , 1 -dioxidothiomoφholin-4-yl;
X is N;
Y is CH; and Z is CH.
58. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl;
R8 is heterocyclecarbonyl wherein the heterocycle of heterocarbonyl is 4- moφholinyl;
X is N;
Y is CH; and Z is CH.
59. A compound according to claim 43 wherein L is -CH2CH2-;
A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl;
R , R , R5, R7 and R9 are hydrogen;
R8 is heterocyclecarbonyl wherein the heterocycle of heterocarbonyl is 4- moφholinyl;
X is N;
Y is CH; and
Z is CH.
60. A compound according to claim 59 selected from the group consisting of:
4-[(6- {2-[2-(N,N-diethyl)ethyl]- 1 -benzofuran-5-yl} -3-pyridinyl)carbonyl]moφholine;
N-(tert-butyl)-N-methyl-N-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l- benzofuran-2-yl}ethyl)amine;
N-isobutyl-N-methyl-N-(2- {5-[5-(4-moφholinylcarbonyl)-2 -pyridinyl]- 1 -benzofuran- 2-yl}ethyl)amine;
N-isopropyl-N-methyl-N-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l- benzofuran-2 -yl } ethyl)amine ;
N-ethyl-N-isopropyl-N-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran- 2-yl } ethyl)amine ;
N,N-dimethyl-N-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran-2- yl}ethyl)amine;
N-ethyl-N-propyl-N-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran-2- yl}ethyl)amine;
N-allyl-N-(2- {5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]- 1 -benzofuran-2- yl}ethyl)amine;
3-[(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran-2-yl}ethyl)amino]-l- propanol; and
N-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran-2-yl}ethyl)-N- propylamine.
61. A compound according to claim 43 wherein A is a covalent bond; and
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle.
62. A compound according to claim 43 wherein A is a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; and
R8 is cyano.
63. A compound according to claim 43 wherein A is a covalent bond;
R) and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1-azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l-pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl; and
R8 is cyano.
64. A compound according to claim 43 wherein L is alkyl;
A is a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl;
R3, (, R5, and R are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and halogen;
R8 and R9 are independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, and oximyl;
X is selected from the group consisting of CH and CRx;
Y is selected from the group consisting of CH and CRy;
Z is selected from the group consisting of CH and CRz; and
Rx, Ry, and Rz are independently selected from the group consisting of alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, and oximyl.
65. A compound according to claim 43 wherein L is alkyl;
A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy- 1 -pyrrolidinyl, (3S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl- 1 -pyrrolidinyl, (2 S)-2-me thyl- 1 -pyrrolidinyl, (2R)-2-methyl-5 -oxo- 1 -pyrrolidinyl, (2 S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2 S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2 -ethyl- 1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2 -ethyl- 1 -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R , R5, and R7 are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and halogen;
R8 and R9 are independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, and oximyl;
X is selected from the group consisting of CH and CRx;
Y is selected from the group consisting of CH and CRy;
Z is selected from the group consisting of CH and CRz; and
Rx, RY, and Rz are independently selected from the group consisting of alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, and oximyl.
66. A compound according to claim 65 selected from the group consisting of: 4- {2-[2-(l-pyrrolidinyl)ethyl]-l-benzofuran-5-yl} benzonitrile; 4-{2-[2-(l-piperidinyl)ethyl]-l-benzofuran-5-yl}benzonitrile; 4- {2-[2-(2-methyl-l -piperidinyl)ethyl]- 1 -benzofuran- 5 -yl} benzonitrile; 4-(2-{2-[(3R)-3-hydroxypyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-{2-[2-(lH-imidazol-l-yl)ethyl]-l-benzofuran-5-yl}benzonitrile; 4-(2- {2-[(3S)-3-(dimethylamino)pyrrolidinyl]ethyl} - 1 -benzofuran-5-yl)benzonitrile; 4-(2-{2-[(2S)-2-(hydroxymethyl)pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-(2-{2-[(cis)-2,6-dimethylpiperidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 4- {2-[2-( 1 -azepanyl)ethyl]- 1 -benzofuran-5-yl}benzonitrile; 4- {2-[2-(4-methyl-l -piperidinyl)ethyl]- 1 -benzofuran-5-yl}benzonitrile; 4-(2-{2-[2-pyrrolidine methyl carboxylate]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-{2-[2-(3,6-dihydro-l(2H)-pyridinyl)ethyl]-l-benzofuran-5-yl}benzonitrile; 4-(2-{2-[(2R)-2-(hydroxymethyl)pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-(2-{2-[(3R)-(dimethylamino)pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-(2-{2-[l-(2S)-2-methylpyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-(2-{2-[l-(2-methylpyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile;
4-(3-bromo-2-{2-[(2R)-2-methylpyrrolidin- 1 -yl]ethyl} -1 -benzofuran-5 - yPbenzonitrile;
2-methyl-4-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yPbenzonitrile;
3-methyl-4-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yPbenzonitrile;
4-(6-methyl-2- {2-[(2R)-2-methyl-l -pyrrolidinyljethyl}- 1 -benzofuran-5- yPbenzonitrile;
4-(4-methyl-2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)benzonitrile;
4-(7-methyl-2-{2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -l-benzofuran-5- yPbenzonitrile;
4-(7-fluoro-2- {2-[(2R)-2-methyl- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5- yl)benzonitrile;
2-fluoro-4-(2- {2-[(2R)-2 -methyl- 1 -pyrrolidinyljethyl} -l-benzofuran-5- yl)benzonitrile;
3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile;
(2R)-l-{2-[5-(4-fluorophenyl)-l -benzofuran-2 -yljethyl} -2-methylpyrrolidine;
(2R)-l-{2-[5-(3,4-dichlorophenyl)-l-benzofuran-2-yl]ethyl}-2-methylpyrrolidine;
(2R)-2-methyl-l-{2-[5-(2-methylphenyl)-l -benzofuran-2 -yl]ethyl}pyrrolidine;
(2R)-2-methyl-l-{2-[5-(3-methylphenyl)-l -benzofuran-2 -yl]ethyl}pyrrolidine;
(2R)-2-methyl-l-{2-[5-(4-methylphenyl)-l-benzofuran-2-yl]ethyl}pyrrolidine;
4-{2-[2-(2-methylpyrrolidin-l-yl)-ethyl]-benzofuran-5-yl}-benzoic acid methyl ester;
(2R)-l-{2-[5-(2-methoxyphenyl)-l -benzofuran-2 -yljethyl} -2-methylpyrrolidine;
(2R)-l-{2-[5-(3-methoxyphenyl)-l-benzofuran-2-yl]ethyl} -2-methylpyrrolidine;
(2R)- 1 - {2-[5-(4-methoxyphenyl)- 1 -benzofuran-2 -yljethyl} -2-methylpyrrolidine;
(2R)-l-{2-[5-(3-fluorophenyl)-l -benzofuran-2 -yl]ethyl} -2-methylpyrrolidine;
(2R)-l-{2-[5-(2-chlorophenyl)-l -benzofuran-2 -yljethyl} -2-methylpyrrolidine;
(2R)-l-{2-[5-(3-chlorophenyl)-l-benzofuran-2-yl]ethyl}-2-methylpyrrolidine;
1 - {2-[5-(4-chlorophenyl)-benzofuran-2-yl]-ethyl} -2-methylpyrrolidine; (2R)-2-methyl-l-(2-{5-[3-(trifluoromethyl)phenyl]-l-benzofuran-2- yl } ethyPpyrrolidine ;
(2R)-2-methyl-l-(2-{5-[4-(trifluoromethyl)phenyl]-l-benzofuran-2- y 1 } ethyPpyrrolidine ;
(2R)-2-methyl-l-(2-{5-[3-(trifluoromethoxy)phenyl]-l-benzofuran-2- yl} ethyPpyrrolidine;
(2R)-2-methyl- 1 -(2- {5-[4-(trifluoromethoxy)phenylJ- 1 -benzofuran-2- y 1 } ethy l)pyrrol idine;
(2R)-l-{2-[5-(3,4-dimethylphenyl)-l-benzofuran-2-yl]ethyl}-2-methylpyrrolidine;
(2R)-l-{2-[5-(3,5-dichlorophenyl)-l-benzofuran-2-yl]ethyl}-2-methylpyrrolidine;
(2R)- 1 - {2-[5-(3 ,5-dimethylphenyl)- 1 -benzofuran-2-ylJethyl} -2-methylpyrrolidine;
[4-(2-{2-[(2R)-2-methyl-l -pyrrolidinyl]ethyl}-l-benzofuran-5-yl)phenyl]methanol; l-[3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)phenyl]ethanone; l-[3-(2-{2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -l-benzofuran-5-yl)phenyl]ethanol;
2-[3 -(2- {2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -1 -benzofuran-5-yl)phenyl]-2- propanol; l-[3-(2-{2-[(2R)-2-methyl-l -pyrrolidinyljethyl} -l-benzofuran-5-yl)phenyl]ethanone oxime; l-[3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)phenyl]ethanone O-methyloxime; l-[3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)phenyl]ethanone O-ethyloxime; l-[3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)phenyl]ethanone 0-(tert-butyl)oxime; ethyl 3-(2- {2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-5-yl)benzoate;
3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzoic acid;
N-methoxy-N-methyl-3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)benzamide; l-[3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)phenyl]-l- propanone;
3-methyl-l-[3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)phenyl]- 1-butanone; 3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzaldehyde;
[3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)phenyl]methanol;
4-(3-bromo-2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)-2- methylbenzonitrile;
4-(3-chloro-2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)benzonitrile;
4-(3,6-dichloro-2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yPbenzonitrile;
4-(3-iodo-2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile;
4-(2- {2-[(2R)-2-methyl-5-oxo- 1 -pyrrolidinyljethyl} - 1 -benzofuran-5-yl)benzonitrile;
4-(3-acetyl-2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yPbenzonitrile;
4-(2-{2-[(2R)-2-ethyl-l -pyrrolidinyljethyl} -l-benzofuran-5-yl)benzonitrile;
4-(2-{2-[(2S)-2-(fluoromethyl)-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile;
4-(2-{2-[(2R)-2 -methyl- 1 -pyrrolidinyljethyl} -l-benzothien-5-yl)benzonitrile;
3-(2-{3-[(2R)-2-methyl-l-pyrrolidinyl]propyl}-l-benzofuran-5-yl)benzonitrile;
3-(2-{[(2R)-2-methyl-l-pyrrolidinyl]methyl}-l-benzofuran-5-yl)benzonitrile; and
3-(2-{4-[(2R)-2-methyl-l-pyrrolidinyl]butyl}-l-benzofuran-5-yl)benzonitrile;
67. A compound according to claim 43 wherein A is a covalent bond;
L is -CH2CH2-;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle substituted with 0, 1 or 2 substituents selected from alkyl; R3, R , R5, R7, and R9 are hydrogen; R8 is cyano; X is CH; Y is CH; and Z is CH.
68. A compound according to claim 67 selected from the group consisting of 4-(2-{2-[(2S)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-(2-{2-[2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-(2- {2-[(2S)-2-ethyl-l -pyrrolidinyl]ethyl}-l -benzofuran-5-yl)benzonitrile; 4-(2-{2-[(2R)-2-ethyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-(2-{2-[2-ethyl-l -pyrrolidinyljethyl} -l-benzofuran-5-yl)benzonitrile; 4-(2-{2-[(2R,5R)-2,5-dimethylpyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-(2-{2-[(2S,5S)-2,5-dimethylpyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; 4-(2-{2-[(trans)-2,5-dimethylpyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile; and 3-(2-{2-[(2S)-2 -methyl- l-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzonitrile.
69. A compound according to claim 67 that is 4-(2-{2-[(2R)-2-methyl-l- pyrrolidinyljethyl} -1 -benzofuran-5-yl)benzonitrile.
70. A compound according to claim 43 wherein L is -CH2CH2-;
A is a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl;
R3 is heterocycle;
R-i, R5, R7 and R9 are hydrogen;
R8 is cyano;
X is CH;
Y is CH; and
Z is CH.
71. A compound according to claim 43 wherein L is -CH2CH2-;
A is a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromefhyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyp-1 -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3 is heterocycle;
R-t, R5, R7 and R9 are hydrogen;
R is cyano;
X is CH;
Y is CH; and Z is CH.
72. A compound according to claim 43 wherein
L is -CH2CH2-;
A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl;
R3 is a heterocycle selected from the group consisting of 2-furyl, 3-pyridinyl, and 2- thienyl wherein the heterocycle is substituted with 0, 1 , or 2 substituents selected from the group consisting of hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, and oximyl;
I }, R5, R and R9 are hydrogen;
R8 is cyano;
X is CH;
Y is CH; and Z is CH.
73. A compound according to claim 72 selected from the group consisting of 4-(3-(2-furyl)-2-{2-[(2R)-2-methylpyrrolidin-l-yl]ethyl}-l-benzofuran-5- yPbenzonitrile;
4-[2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-3-(3-pyridinyl)-l-benzofuran-5- yl]benzonitrile;
4-[2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-3-(3-thienyl)-l-benzofuran-5- yl]benzonitrile; and
4-(3-(2-formyl-3-thienyl)-2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yPbenzonitrile.
74. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; Rg is cyano; X is N;
Y is CH; and Z is CH.
75. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl;
Rg is cyano;
X is N;
Y is CH; and Z is CH.
76. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1-azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy- 1 -pyrrolidinyl, (3 S)-3-hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2 S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl;
Rg is cyano;
X is N;
Y is CH; and
Z is CH.
77. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; and
Rg is heterocyclecarbonyl.
78. A compound according to claim 43 wherein A is a covalent bond ;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1- dioxidothiomoφholinyl; and
Rg is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl.
79. A compound according to claim 43 wherein A is a covalent bond ;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; and
Rg is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and l ,l-dioxidothiomoφholin-4-yl.
80. A compound according to claim 43 wherein A is a covalent bond ;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1 -yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l-pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromefhyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2 -ethyl -1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl- 1 -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl; and
Rg is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1 -dioxidothiomoφholinyl.
81. A compound according to claim 43 wherein A is a covalent bond ;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy- 1 -pyrrolidinyl, (3 S)-3-hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-mefhyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoro methyl)- 1 -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l ,4-dioxa-8- azaspiro[4.5]dec-8-yl; and
Rg is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl.
82. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; and
Rg is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is 4- moφholinyl.
83. A compound according to claim 43 wherein A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l-pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl- 1 -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl; and
R8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is 4- moφholinyl.
84. A compound according to claim 43 wherein L is -CH2CH2-;
A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1- dioxidothiomoφholinyl;
R3, R4, R5, R7 and R9 are hydrogen; R8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is 4- moφholinyl;
X is CH;
Y is CH; and Z is CH.
85. A compound according to claim 43 wherein L is -CH2CH2-;
A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy- 1 -pyrrolidinyl, (3S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2 -methyl-5 -oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromefhyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l ,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R4, R5, R7 and R9 are hydrogen;
R8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is 4- moφholinyl;
X is CH;
Y is CH; and Z is CH.
86. A compound according to claim 85 selected from the group consisting of: 4-(4-{2-[2-(2-methyl-l-pyrrolidinyl)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine; 4-(4-{2-[2-(l-piperidinyl)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine; 4-(4-{2-[2-(2-methyl-l-piperidinyl)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine;
(3R)- 1 -(2- {5-[4-(4-moφholinylcarbonyl)phenyl]- 1 -benzofuran-2-yl} ethyl)-3- pyrrolidinol;
4-[4-(2-{2-[(2R,5R)-2,5-dimethylpyrrolidinyl]ethyl}-l-benzofuran-5- yl)benzoyl]moφholine;
4-[4-(2-{2-[(cis)-2,6-dimethylpiperidinyl]ethyl}-l-benzofuran-5- yl)benzoyl]moφholine;
4-(4-{2-[2-(azepinyl)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine;
4-(4-{2-[2-(4-methyl-l-piperidinyl)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine;
4-(4-{2-[2-(4-moφholine)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine;
4-(4-{2-[2-(3,6-dihydro-l(2H)-pyridinyl)ethyl]-l-benzofuran-5- yl}benzoyl)moφholine; and
4-(4-{2-[2-(2S)-pyrrolidinylmethanol)ethyl]-l-benzofuran-5-yl}benzoyl)moφholine.
87. A compound according to claim 43 wherein A is a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle;
R8 is heterocyclecarbonyl;
X is N;
Y is CH; and
Z is CH.
88. A compound according to claim 43 wherein L is -CH2CH2-;
A is a covalent bond ;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; R8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl;
X is N;
Y is CH; and Z is CH.
89. A compound according to claim 43 wherein L is -CH2CH2-;
A is a covalent bond ;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1- dioxidothiomoφholinyl;
R8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl;
X is N;
Y is CH; and Z is CH.
90. A compound according to claim 43 wherein L is -CH2CH2-;
A is a covalent bond ;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-mefhyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l-pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2 -ethyl- 1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl;
Rg is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl.;
X is N;
Y is CH; and Z is CH.
91. A compound according to claim 43 wherein L is -CH2CH2-;
A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl;
R8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is 4- moφholinyl;
X is N;
Y is CH; and Z is CH.
92. A compound according to claim 43 wherein L is -CH2CH2-; A is a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2 S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl- 1 -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l ,4-dioxa-8- azaspiro[4.5]dec-8-yl;
Rg is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is 4- moφholinyl;
X is N;
Y is CH; and
Z is CH.
93. A compound according to claim 43 wherein
L is -CH2CH2-;
A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl ;
R3, R , R5, R7 and R are hydrogen;
R8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is 4- moφholinyl;
X is N; Y is CH; and Z is CH.
94. A compound according to claim 43 wherein
A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyπolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-mefhyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromefhyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R-j, R5, R7 and R9 are hydrogen;
R8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is 4- moφholinyl;
X is N;
Y is CH; and Z is CH.
95. A compound according to claim 94 selected from the group consisting of: 4-[(6-{2-[2-(l-pyrrolidinyl)ethyl]-l-benzofuran-5-yl}-3- pyridinyl)carbonyl]moφholine;
4-{[6-(2-{2-[(2R)-methylpyrrolidinyl]ethyl}-l-benzofuran-5-yl)-3- pyridinyl] carbonyl } moφholine ; 4-[(6-{2-[2-(l-piperidinyl)ethyl]-l-benzofuran-5-yl}-3- pyridinyl)carbonyl]moφholine;
(3R)-l-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran-2-yl}ethyl)-3- pyrrolidinol;
4- { [6-(2- {2-[(2R,5R)-2,5-dimethylpyrrolidinyl]ethyl} - 1 -benzofuran-5 -yl)-3- pyridinyl]carbonyl} moφholine;
4-{[6-(2-{2-[(cis)-2,6-dimethylpiperidinyl]ethyl}-l-benzofuran-5-yl)-3- pyridinyl]carbonyl}moφholine;
4-{[6-(2-{2-[l -azepanyl]ethyl}-l-benzofuran-5-yl)-3-pyridinyl]carbonyl}moφholine;
4-[(6- {2-[2-(4-methyl-l-piperidinyl)ethyl]-l-benzofuran-5-yl}-3- pyridinyl)carbonyl]moφholine;
4-[(6-{2-[2-(4-moφholinyl)ethyl]-l-benzofuran-5-yl}-3- pyridinyl)carbonyl]moφholine;
8-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran-2-yl}ethyl)-l ,4-dioxa- 8-azaspiro[4.5]decane;
5-(2-{5-[5-(4-moφholinylcarbonyl)-2-pyridinyl]-l-benzofuran-2-yl}ethyl)-2-oxa-5- azabicyclo[2.2.1]heptane; and
(2S)-1 -(2- {5-[5-(4-moφholinylcarbonyl)-2 -pyridinyl]- l-benzofuran-2-yl}ethyl)-2- pyrrolidinol.
96. A compound according to claim 43 wherein A is carbonyl;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and
R8 is selected from the group consisting of cyano and heterocyclecarbonyl.
97. A compound according to claim 43 wherein A is carbonyl;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and
R8 is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl.
98. A compound according to claim 43 wherein A is carbonyl;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and
Rg is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH- pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1,1- dioxidothiomoφholin-4-y 1.
99. A compound according to claim 43 wherein A is carbonyl;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; and
R is selected from the group consisting of cyano and heterocyclecarbonyl.
100. A compound according to claim 43 wherein A is carbonyl;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1 - dioxidothiomoφholinyl; and
Rg is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl.
101. A compound according to claim 43 wherein A is carbonyl;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; and
Rg is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH- pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1,1- dioxidothiomoφholin-4-yl.
102. A compound according to claim 43 wherein
A is carbonyl; and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2 S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl; and
R8 is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH- pyrrolyl, 1 -pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1,1- dioxidothiomoφholin-4-yl.
103. A compound according to claim 1 of formula (III)
(HI), or a pharmaceautical acceptable salt, ester, amide, or prodmg thereof, wherein
Re is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARβ, (NRARβ)alkyl, (NRARβ)carbonyl and (NRARB)sulfonyl;
Rg is selected from the group consisting of hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl and (NRARB)carbonyl;
R9 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARβ, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl;
X is selected from the group consisting of CH, CRx and N;
Y is selected from the group consisting of CH, CRy and N;
Z is selected from the group consisting of CH, CRz and N; and
Rx, Ry and Rz are each independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARβ)carbonyl and (NRARB)sulfonyl.
104. A compound according to claim 103 wherein A is a covalent bond.
105. A compound according to claim 103 wherein A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and
R8 is selected from the group consisting of cyano and heterocyclecarbonyl.
106. A compound according to claim 103 wherein A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and
R8 is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1- pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1 -dioxidothiomoφholinyl.
107. A compound according to claim 103 wherein A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and
Rg is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH- pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1,1- dioxidothiomoφholin-4-yl.
108. A compound according to claim 103 wherein A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; and
R8 is selected from the group consisting of cyano and heterocyclecarbonyl.
109. A compound according to claim 103 wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1- dioxidothiomoφholinyl; and
R8 is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH- pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1,1- dioxidothiomoφholin-4-yl.
110. A compound according to claim 103 wherein
A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-mefhyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2 S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l ,4-dioxa-8- azaspiro[4.5]dec-8-yl; and
R8 is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH- pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1,1- dioxidothiomoφholin-4-yl.
1 11. A compound according to claim 110 that is 4-(2- {2-[(2R)-2-methyl- 1 - pyrrolidinyl] ethyl } - 1 -benzofuran-6-yl)benzonitrile .
112. A compound according to claim 103 wherein A is carbonyl.
113. A compound according to claim 103 wherein A is carbonyl; and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and R8 is cyano.
114. A compound according to claim 103 wherein L is -CH2CH2-;
A is carbonyl;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; R3 is methyl;
R4, R5, Re and R9 are hydrogen; R8 is cyano; X is CH; Y is CH; and Z is CH.
1 15. A compound according to claim 114 that is 4-{3-[2-(diethylamino)ethyl]-4-methyl-2- oxo-2H-chromen-7-yl}benzonitrile.
1 16. A compound according to claim 103 wherein A is carbonyl;
R\ and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and R is heterocyclecarbonyl.
1 17. A compound according to claim 103 wherein A is carbonyl; and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and
R8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4-thiomoφholinyl, and 1 , 1 -dioxidothiomoφholin-4-yl.
1 18. A compound according to claim 103 wherein A is carbonyl;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; and R8 is cyano.
1 19. A compound according to claim 103 wherein A is carbonyl;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; and
R8 is cyano.
120. A compound according to claim 103 wherein A is carbonyl;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy- 1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl- 1 -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl; and Rg is cyano.
121. A compound according to claim 103 wherein
A is carbonyl;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl;
R3 is methyl;
R4, R5, Re and R9 are hydrogen;
R8 is cyano;
X is CH;
Y is CH; and
Z is CH.
122. A compound according to claim 103 wherein L is -CH2CH2-;
A is carbonyl;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-m ethyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l-pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l ,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R is methyl;
R , R5, Re and R are hydrogen;
R8 is cyano;
X is CH;
Y is CH; and
Z is CH.
123. A compound according to claim 122 selected from the group consisting of 4-{4-methyl-2-oxo-3-[2-(l-pyrrolidinyl)ethyl]-2H-chromen-7-yl}benzonitrile; 4-{4-methyl-2-oxo-3-[2-(l-piperidinyl)ethyl]-2H-chromen-7-yl}benzonitrile; 4- {4-methyl-2-oxo-3-[2-(2S)-mefhyl-l -pyrrolidinyl ethyl]-2H-chromen-6- yl} benzonitrile; and
4- {4-methyl-2-oxo-3-[2-(2R)-methyl- 1 -pyrrolidinyl ethyl]-2H-chromen-6- yl}benzonitrile.
124. A compound according to claim 103 wherein A is carbonyl;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; and
R8 is heterocyclecarbonyl.
125. A compound according to claim 103 wherein A is carbonyl; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1 ,1- dioxidothiomoφholinyl; and
R8 is heterocyclecarbonyl wherein the heterocycle of heterocarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl.
126. A compound according to claim 103 wherein
A is carbonyl;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy- 1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- ( fluoromethyl)- 1 -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl; and
R8 is heterocyclecarbonyl wherein the heterocycle of heterocarbonyl is selected from the group consisting of 1-azetidinyl, 4-moφholinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomoφholinyl, and l,l-dioxidothiomoφholin-4-yl.
127. A compound according to claim 1 of formula (IV)
(IV), or a pharmaceutical acceptable salt, ester, amide, or prodmg thereof, wherein
R7 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARβ)alkyl, (NRARβ)carbonyl and (NRARB)sulfonyl;
R8 is selected from the group consisting of hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl and (NRARB)carbonyl;
R9 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl;
X is selected from the group consisting of CH, CRx and N;
Y is selected from the group consisting of CH, CRy and N;
Z is selected from the group consisting of CH, CRz and N; and
Rx, Ry and Rz are each independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl.
128. A compound according to claim 127 wherein A is a covalent bond.
129. A compound according to claim 127 wherein A is a covalent bond;
R\ and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and R8 is cyano.
130. A compound according to claim 127 wherein L is -CH2CH2-;
A is a covalent bond ;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; R3, R4, R5, R7 and R are hydrogen; R8 is cyano; X is CH; Y is CH; and Z is CH.
131. A compound according to claim 130 that is 4-(2- {2-[(2R)-2- methylpyrrolidinyl]ethyl}-2,3-dihydro-l-benzofuran-5-yl)benzonitrile.
132. A compound according to claim 1 of formula (V)
(V), or a pharmaceutical acceptable salt, ester, amide, or prodmg thereof, wherein
Re is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl; R8 is selected from the group consisting of hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl and (NRARB)carbonyl;
R9 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl;
X is selected from the group consisting of CH, CRx and N;
Y is selected from the group consisting of CH, CRy and N;
Z is selected from the group consisting of CH, CRz and N; and
Rx, Ry and Rz are each independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl.
133. A compound according to claim 132 wherein A is a covalent bond.
134. A compound according to claim 132 wherein A is a covalent bond;
Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and R8 is cyano.
135. A compound according to claim 132 wherein L is -CH2CH2-;
A is a covalent bond ;
R] and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; R3, R4, R5, R and R9 are hydrogen; R is cyano; X is CH; Y is CH; and Z is CH.
136. A compound according to claim 1 of formula (VI)
(VI), or a pharmaceutical acceptable salt, ester, amide, or prodmg thereof, wherein
R5, Re, and R7 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl;
R8 is selected from the group consisting of hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl and (NRARB)carbonyl;
R9 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARβ)carbonyl and (NRARB)sulfonyl;
X is selected from the group consisting of CH, CRx and N;
Y is selected from the group consisting of CH, CRy and N;
Z is selected from the group consisting of CH, CRz and N; and
Rx, Ry and Rz are each independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl.
137. A compound according to claim 136 wherein A is a covalent bond.
138. A compound according to claim 136 wherein A is a covalent bond; and
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle.
139. A compound according to claim 136 wherein A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; and
R8 is cyano.
140. A compound according to claim 136 wherein A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l-pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl; and Rg is cyano.
141. A compound according to claim 136 wherein L is -CH2CH2-;
A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl;
R3, R5, Re, R7 and R9 are hydrogen;
R8 is cyano;
X is CH;
Y is CH; and
Z is CH.
142. A compound according to claim 136 wherein L is -CH2CH2-;
A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2 S)-2-methyl-l -pyrrolidinyl, (2R)-2-methyl-5-oxo-l -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2 -ethyl- 1 -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl; R3, R5, Re, R7 and R are hydrogen; R8 is cyano; X is CH; Y is CH; and Z is CH.
143. A compound according to claim 142 that is 4-(2-{2-[(2R)-2 -methyl- 1- pyrrolidinyl]ethyl} - 1 -benzofuran-4-yl)benzonitrile.
144. A compound according to claim 1 of formula (VII)
(VII), or a pharmaceutical acceptable salt, ester, amide, or prodmg thereof, wherein
R-t, R6, and R are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl;
R8 is selected from the group consisting of hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl and (NRARB)carbonyl;
R9 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARβ)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl;
X is selected from the group consisting of CH, CRx and N;
Y is selected from the group consisting of CH, CRy and N; Z is selected from the group consisting of CH, CRZ and N; and Rx, Ry and Rz are each independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl.
145. A compound according to claim 144 wherein A is a covalent bond.
146. A compound according to claim 144 wherein A is a covalent bond; and
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle.
147. A compound according to claim 144 wherein A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl; and
Rg is cyano.
148. A compound according to claim 144 wherein A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo-l- pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)- 1 -pyrrolidinyl, (2S)-2-(fluoromethyl)- 1 -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl- 1 -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l,4-dioxa-8- azaspiro[4.5]dec-8-yl; and Rg is cyano.
149. A compound according to claim 144 wherein L is -CH2CH2-;
A is a covalent bond;
R\ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, moφholinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomoφholinyl, and 1,1- dioxidothiomoφholinyl ;
R3, R , Re, R and R9 are hydrogen;
R8 is cyano;
X is CH;
Y is CH; and
Z is CH.
150. A compound according to claim 144 wherein L is -CH2CH2-;
A is a covalent bond;
Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, (2S)-2-methyl- 1 -pyrrolidinyl, (2R)-2-methyl-5-oxo- 1 -pyrrolidinyl, (2S)-2-methyl-5-oxo- 1 - pyrrolidinyl, 3,6-dihydro-l(2H)-pyridinyl, (2S)-2-(methoxycarbonyl)-l -pyrrolidinyl, (2R)-2- (methoxycarbonyl)-l -pyrrolidinyl, (2S)-2-(fluoromethyl)-l -pyrrolidinyl, (2R)-2- (fluoromethyl)-l -pyrrolidinyl, (2R)-2-ethyl-l -pyrrolidinyl, 2,2-dimethyl-l -pyrrolidinyl, (2S)- 2-ethyl-l -pyrrolidinyl 4-moφholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, and l ,4-dioxa-8- azaspiro[4.5]dec-8-yl;
R3, R , Re, R7 and R9 are hydrogen;
R8 is cyano;
X is CH;
Y is CH; and
Z is CH.
151. A compound according to claim 1 wherein one substituent of ;, R5, Re and R7 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl, (NRARB)sulfonyl, -L2R20, and -R20L3R22; and the other substituents of R-4, R5, R6 and R7 are each independently selected from the group consisting of hydrogen and alkyl.
152. A compound according to claim 151 wherein
R-4, R5, Re and R7 are each independently selected from the group consisting of hydrogen, alkyl, heterocycle, -L2R2Q, and -R20L3R22.
153. A compound according to claim 151 selected from the group consisting of 3,5-dimethyl-4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}- isoxazole;
5-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-2-phenyl-oxazole;
2-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-thiazole;
4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-lH-pyrazole;
4- {2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-l -phenyl- 1 H-pyrazole; 1 -methyl-4- {2-[(2R)-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-4-yl} - 1 H- imidazole;
4- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-4-yl } -thiazole;
2-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-lH-imidazole;
4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-lH-benzoimidazole;
3-methyl-6- {(2R)-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-4-yl } -pyridazine;
2- {2-[2-(2R)-methyl-pyrrolidin-l -yl)-ethyl]-benzofuran-4-yl} -pyrazine;
5-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-pyrimidine;
5-{2-[2-(2R)-methyl-pyπOlidin-l-yl)-ethyl]-benzofuran-4-yl}-pyridazin-4-ylamine;
5-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-nicotinonitrile;
4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-lH-indole;
4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-phthalonitrile;
5- {2-[2-(2R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-4-yl} -indan- 1 -one;
1 - {2-[4-(5,6-dihydro-2H-pyran-3-yl)-benzofuran-2-yl]-ethyl} -(2R)-methyl- pyrrolidine; l-[2-(4-cyclohept-l-enyl-benzofuran-2-yl)-ethyl]-(2R)-methyl-pyrrolidine;
(2R)-methyl-l-(2-{4-[2-(l lH-10-thia-dibenzo[a,d]cyclohepten-5-ylidene)-ethyl]- benzofuran-2-yl}-ethyl)-pyrrolidine;
4-{2-[2-(2R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-4-yl}-pyridine;
3,5-dimethyl-4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}- isoxazole;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofliran-6-yl}-2-phenyl-oxazole;
2- {2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl} -thiazole;
4- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} - 1 H-pyrazole;
4- {2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-l-phenyl-l H-pyrazole;
1 -methyl-4- {2-[2(R)-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} - 1 H- imidazole;
4- {2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl} -thiazole;
2-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-lH-imidazole;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-lH-benzoimidazole;
3-methyl-6-{2(R)-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl} -pyridazine;
2- {2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl} -pyrazine; 5- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} -pyrimidine;
5- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} -pyridazin-4-ylamine;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-nicotinonitrile;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-lH-indole;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-phthalonitrile;
5- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-6-yl} -indan- 1 -one; l-{2-[6-(5,6-dihydro-2H-pyran-3-yl)-benzofuran-2-yl]-ethyl}-2(R)-methyl- pyrrolidine; l-[2-(6-cyc lohept- 1 -enyl-benzofuran-2 -yl)-ethyl] -2(R) -methyl-pyrrolidine ;
2(R)-methyl-l-(2-{6-[2-(l lH-10-thia-dibenzo[a,d]cyclohepten-5-ylidene)-ethyl]- benzofuran-2-yl}-ethyl)-pyrrolidine;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl}-pyridine;
3,5-dimethyl-4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}- isoxazole;
5- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-7-yl } -2-phenyl-oxazole;
2-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-thiazole;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-lH-pyrazole;
4- {2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-l-phenyl-l H-pyrazole; l-methyl-4-{2-[2(R)-(2-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-lH- imidazole;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-thiazole;
2- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-7-yl} - 1 H-imidazole;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-lH-benzoimidazole;
3-methyl-6-{2(R)-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl} -pyridazine;
2-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-pyrazine;
5- {2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl} -pyrimidine;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-pyridazin-4-ylamine;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-nicotinonitrile;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-lH-indole;
4-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-phthalonitrile;
5-{2-[2-(2(R)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-7-yl}-indan-l-one; l-{2-[7-(5,6-dihydro-2H-pyran-3-yl)-benzofuran-2-yl]-ethyl}-2(R)-methyl- pyrrolidine;
1 -[2-(7-cyclohept- 1 -enyl-benzofuran-2-yl)-ethyl]-2(R)-methyl-pyrrolidine;
2(R)-methyl-l-(2-{7-[2-(l lH-10-thia-dibenzo[a,d]cyclohepten-5-ylidene)-ethyl]- benzofuran-2-yl} -ethyl)-pyrrolidine; and
4- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-7-yl} -pyridine.
154. A compound according to claim 1 selected from the group consisting of
(3-fluorophenyl)[3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl}-l-benzofuran-5- yl)phenyl] methanone ;
(2R)-2-methyl- 1 -[2-(5-phenoxy- 1 -benzofuran-2 -yl)ethyl]pyrrolidine;
(2R)-l-(2-{5-[(3-fluorophenyl)thio]-l-benzofuran-2-yl}ethyl)-2-methylpyrrolidine;
4-(4- {2-[2-(2S)-methyl- 1 -pyrrolidinyl)ethyl]- 1 -benzofuran-5-yl}benzoyl)moφholine;
4- {4-methyl-2-oxo-3-[2-(2S)-methyl-l -pyrrolidinyl ethyl]-2H-chromen-6- yl} benzonitrile;
4-{4-methyl-2-oxo-3-[2-(2R)-methyl-l-pyrrolidinyl ethyl]-2H-chromen-6- yl} benzonitrile;
4-{[6-(2-{2-[(2S)-methylpyrrolidinyl]ethyl}-l-benzofuran-5-yl)-3- pyridinyl]carbonyl}moφholine;
4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-2,3-dihydro-l-benzofuran-5- yl)benzonitrile;
4-(2- {2-[(2S)-2-methyl- 1 -pyrrolidinyl]ethyl} - 1 -benzofuran-4-yl)benzonitrile;
4-{2-[2-(2(S)-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-6-yl} -benzonitrile;
3-(2-{2-[(2S)-2-methyl-l -pyrrolidinyljethyl} -l-benzofuran-5-yl)benzonitrile;
(4-methoxy-phenyl)-methyl- {2-[2-(2(R)-methyl-pyrrolidin- 1 -yl)-ethyl]-benzofuran-5- yl} -amine; benzo[l,3]dioxol-5-yl-methyl-{2-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-benzofuran-5- yl} -amine; cyclohexyl-methyl- {2-[2-(2(R)-methyl-pyrrolidin-l -yl)-ethyl]-benzofuran-5-yl} - amine; and
{2-[2-(2(R)-methyl-pyπOlidin-l-yl)-ethyl]-benzofuran-5-yl}-(tetrahydro-pyran-4-yl)- amine.
155. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
156. A method of selectively modulating the effects of histamine-3 receptors in a mammal comprising administering an effective amount of a compound of claim 1.
157. A method of treating a disorder wherein the disorder is ameliorated by modulating the histamine-3 receptors in a mammal comprising administering an effective amount of a compound of claim 1.
158. The method according to claim 157 wherein the disorder is selected from the group consisting of acute myocardial infarction, asthma, bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric disorders, cutaneous carcinoma, dmg abuse, depression, gastrointestinal disorders, inflammation, jet lag, medullary thyroid carcinoma, melanoma, allergic rhinitis, Meniere's disease, migraine, mood and attention alteration, motion sickness, neurogenic inflammation, obsessive compulsive disorder, pain, Parkinson's disease, schizophrenia, seizures, septic shock, Tourette's syndrome, vertigo, and wakefulness.
159. The method according to claim 157 wherein the disorder is Alzheimer's disease.
160. The method according to claim 157 wherein the disorder is attention-deficit hyperactivity disorder.
161. The method according to claim 157 wherein the disorder is epilepsy.
162. The method according to claim 157 wherein the disorder is narcolepsy.
163. The method according to claim 157 wherein the disorder is obesity.
164. The method of claim 157 wherein the disorder is selected from the group consisting of mild cognitive impairment, deficits of memory, deficits of learning and dementia.
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CA2440238C (en) 2011-09-13
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