EP1569637A1 - Amines bicycliques substituees utilisees comme ligands des recepteurs de l'histamine-3 - Google Patents

Amines bicycliques substituees utilisees comme ligands des recepteurs de l'histamine-3

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Publication number
EP1569637A1
EP1569637A1 EP03768721A EP03768721A EP1569637A1 EP 1569637 A1 EP1569637 A1 EP 1569637A1 EP 03768721 A EP03768721 A EP 03768721A EP 03768721 A EP03768721 A EP 03768721A EP 1569637 A1 EP1569637 A1 EP 1569637A1
Authority
EP
European Patent Office
Prior art keywords
ethyl
methyl
pyrrolidinyl
pyrrolidin
compound
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Withdrawn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
EP03768721A
Other languages
German (de)
English (en)
Inventor
Robert J. Altenbach
Lawrence A. Black
Sou-Jen Chang
Marlon D. Cowart
Ramin Faghih
Gregory A.; Gfesser
Yi-Yin Ku
Huaqing Liu
Kirill A. Lukin
Diana L. Nersesian
Yu-Ming Pu
Padam N. Sharma
Youssef L. Bennani
Michael P. Curtis
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 US10/292,422 external-priority patent/US20040092521A1/en
Priority claimed from US10/689,735 external-priority patent/US7153889B2/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1569637A1 publication Critical patent/EP1569637A1/fr
Withdrawn legal-status Critical Current

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    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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Definitions

  • the invention relates to bicyclic-substituted amine compounds, compositions comprising such compounds, methods for making the compounds, and methods of treating conditions and disorders using such compounds and compositions.
  • Histamine is a well-known modulator of neuronal activity. At least four types of histamine receptors have been reported in the literature, typically referred to as histamine-1, histamine-2, histamine-3, and histamine-4.
  • the class of histamine receptor known as histamine-3 receptors is believed to play a role in neurotransmission in the central nervous system.
  • the histamine-3 (H 3 ) receptor was first characterized pharmacologically on histaminergic nerve terminals (Nature, 302:832-837 (1983)), where it regulates the release of neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs, cardiovascular system and gastrointestinal tract.
  • H 3 receptors are thought to be disposed presynaptically on histaminergic nerve endings, and also on neurons possessing other activity, such as adrenergic, cholinergic, serotoninergic, and dopaminergic activity.
  • the existence of H 3 receptors has been confirmed by the development of selective H 3 receptor agonists and antagonists ((Nature, 327:117-123 (1987); Leurs and Timmerman, ed. "The History of H 3 Receptor: a Target for New Drugs," Elsevier (1998)).
  • the activity at the H 3 receptors can be modified or regulated by the administration of H 3 receptor ligands.
  • the ligands can demonstrate antagonist, agonist or partial agonist activity.
  • H 3 receptors have been linked to conditions and disorders related to memory and cognition processes, neurological processes, cardiovascular function, and regulation of blood sugar, among other systemic activities. Although various classes of compounds demonstrating H 3 receptor-modulating activity exist, it would be beneficial to provide additional compounds demonstrating activity at the H 3 receptors that can be incorporated into pharmaceutical compositions useful for therapeutic methods.
  • the invention is directed to substituted amines and, more particularly, bicyclic-substituted amines. Accordingly, one aspect of the invention relates to compounds of formula (I):
  • Y, and Y' are each independently selected from the group consisting of CH, CF, and N;
  • X, X', Z, and Z' are each independently C or N;
  • one of R and R 2 is selected from the group consisting of halogen, cyano, and L 2 Re;
  • the other of R- ⁇ and R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, cycloalkyl, halogen, cyano, and thioalkoxy, provided that R 2 is absent when Z' is N;
  • R 3 is absent when X' is N or R 3 is selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, cyano, and thioalkoxy;
  • R 3a is absent when Z is N or R 3a is selected from the group consisting of hydrogen, methyl, alkoxy, halogen, and cyano;
  • R 3b is absent when X is N or R 3b is selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, and thioalkoxy;
  • R 4 and R 5 are each independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl and (NR A R B )alkyl, or R 4 and R 5 taken together with the nitrogen atom to which each is attached form a non-aromatic ring of the formula:
  • R 6 is selected from the group consisting of aryl, heteroaryl, heterocycle, and cycloalkyl
  • R 9 . and R 10 at each occurrence are each independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, and alkyl; or one of the pair R 7 and Re or the pair R 9 and R1 0 is taken together to form a C 3 -C 6 ring, wherein 0, 1 , or 2 heteroatoms selected from O, N, or S replace a carbon atom in the ring;
  • R11, R12, i3. and R are each independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, alkyl, and fluoro;
  • Q is selected from the group consisting of a bond, O, S, and NR 15 ;
  • L is -[C(R 16 )(R ⁇ 7 )]n- or -[C(R 16 )(R 17 )] p O-;
  • R 15 is selected from the group consisting of hydrogen, alkyl, acyl, amido, and formyl;
  • R1 6 and R ⁇ at each occurrence are independently selected from the group consisting of hydrogen, alkyl, alkoxy, and fluoro;
  • R ⁇ 8 and R 19 at each occurrence are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, and fluoro;
  • R x and R y at each occurrence are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino, dialkylamino, and fluoro, or one of R x or R y represents a covalent bond when taken together with R x or R y on an adjacent carbon atom such that a double bond is represented between the adjacent carbon atoms;
  • m is an integer from 1 to 5;
  • n is an integer from 1 to 6;
  • p is an integer from 2 to 6; and
  • q is an integer from 1 to 4; wherein 0, 1 , or 2 of X, X', Y, Y', Z, and Z' can be nitrogen; provided that R 3 is absent when X' is N; R 3a is absent when Z is N; R 2 is absent when Z' is N;
  • compositions comprising compounds of the invention.
  • Such compositions can be administered in accordance with a method of the invention, typically as part of a therapeutic regimen for treatment or prevention of conditions and disorders related to H 3 receptor activity.
  • Yet another aspect of the invention relates to a method of selectively modulating H 3 receptor activity.
  • the method is useful for treating and/or preventing conditions and disorders related to H 3 receptor modulation in mammals. More particularly, the method is useful for conditions and disorders related to memory and cognition processes, neurological processes, cardiovascular function, and body weight.
  • compositions comprising the compounds, methods for making the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are further described herein.
  • acyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of acyl include, but are not limited to, acetyl, 1- oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
  • acyloxy as used herein, means an acyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of acyloxy include, but are not limited to, acetyloxy, propionyloxy, and isobutyryloxy.
  • alkenyl as used herein, means 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-1-heptenyl, and 3-decenyl.
  • alkoxy as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkoxy means an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein.
  • Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.
  • alkoxyalkyl as used herein, means 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 means 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.
  • alkoxyimino means an alkoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein.
  • Representative examples of alkoxyimino include, but are not limited to, ethoxy(imino)methyl and methoxy(imino)methyl.
  • alkoxysulfonyl as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl, and propoxysulfonyl.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, is ⁇ -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.
  • alkylamino as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a NH group.
  • Representative examples of alkylamino include, but are not limited to, methylamino, ethylamino, isopropylamino, and butylamino.
  • alkylcarbonyl as used herein, means 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, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, n-propylcarbonyl, and the like.
  • alkylsulfonyl as used herein, means 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, methylsulfonyl and ethylsulfonyl.
  • alkynyl as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1- butynyl.
  • amido means an amino, alkylamino, or dialkylamino group appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of amido include, but are not limited to, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, and ethylmethylaminocarbonyl.
  • amino as used herein, means a -NH 2 group.
  • aryl as used herein, means a monocyclic aromatic ring system. Representative examples of aryl include, but are not limited to, phenyl.
  • aryl groups of this invention are substituted with 0, 1 , 2, 3, 4, or 5 substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano, cycloalkylcarbonyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, thioalkoxy, NR A RB, and (NR A RB)sulfonyl.
  • substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysul
  • arylalkoxy as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and 5-phenylpentyloxy.
  • arylalkoxycarbonyl as used herein, means an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl.
  • arylalkyl as used herein, means 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 and 3-phenylpropyl.
  • carboxy as used herein, means a -CO 2 H group, which may be protected as an ester group -CO 2 -alkyl.
  • cyano means a -CN group.
  • cycloalkenyl as used herein, means a cyclic hydrocarbon containing from 3 to 8 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of cycloalkenyl include, but are not limited to, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and 3-cyclopenten-1-yl.
  • cycloalkyl as used herein, means a saturated cyclic hydrocarbon group containing from 3 to 8 carbons.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the cycoalkyl groups of the invention are substituted with 0, 1,-2, 3, or 4 substituents selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkyl, alkynyl, amido, carboxy, cyano, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, methylenedioxy, thioalkoxy, and -NR A R B .
  • cycloalkylalkyl as used herein, means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.
  • cycloalkylcarbonyl means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, and cycloheptylcarbonyl.
  • dialkylamino means two independent alkyl groups, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
  • Representative examples of dialkylamino include, but are not limited to, dimethylamino, diethylamino, ethylmethylamino, butylmethylamino.
  • ethylenedioxy as used herein, means a -O(CH 2 ) 2 0- group wherein the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through one carbon atom forming a five-membered ring or the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through two adjacent carbon atoms forming a six-membered ring.
  • fluoro as used herein means -F.
  • fluoroalkyl as used herein, means at least one fluoro group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • fluoroalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, and 2,2,2- trifluoroethyl.
  • halo or halogen as used herein, means -CI, -Br, -I or -F.
  • haloalkoxy means 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 as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2- chloro-3-fluoropentyl.
  • heteroaryl refers to an aromatic five- or six- membered ring wherein 1 , 2, 3, or 4 heteroatoms are independently selected from nitrogen, oxygen, or sulfur, or a tautomer thereof.
  • Such rings include, but are not limited to, a ring wherein one carbon is replaced with an O or S atom; one, two, or three N atoms arranged in a suitable manner to provide an aromatic ring, or a ring wherein two carbon atoms in the ring are replaced with one O or S atom and one N atom.
  • the heteroaryl groups are connected to the parent molecular moiety through a carbon or nitrogen atom.
  • heteroaryl examples include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridazinonyl, pyridinyl, pyridinonyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl or thiophenyl, triazinyl, and triazolyl.
  • Specific heteroaryl groups include, but are not limited to, 2H-pyridazin-3-one-2-yl.
  • heteroaryl groups of the invention are substituted with 0, 1 , 2, 3, or 4 substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, thioalkoxy, -NR A R B , (NR A R B )carbonyl, and (NR A R B )sulfonyl.
  • heterocycle refers to a three-, four-, five-, six-, seven-, or eight-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • Rings containing at least four members can be saturated or unsaturated.
  • the four- and five- membered ring has zero or one double bond.
  • the six-membered ring has zero, one, or two double bonds.
  • the seven-and eight- membered rings have zero, one, two, or three double bonds.
  • the heterocycle groups of the invention can be attached to the parent molecular moiety through a carbon atom or a nitrogen atom.
  • nitrogen-containing heterocycles include, but are not limited to, azepanyl, azetidinyl, aziridinyl, azocanyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, dihydrothiazolyl, and thiomorpholinyl.
  • non-nitrogen containing heterocycles include, but are not limited to, tetrahydrofuryl and tetrahydropyranyl.
  • heterocycles of the invention are substituted with 0, 1 , 2, 3, or 4 substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl, alkynyl, amido, arylalkyl, arylalkoxycarbonyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, thioalkoxy, -NR A R B , and (NR A R B )sulfonyl.
  • substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino
  • hydroxy as used herein means a -OH group.
  • hydroxyalkyl as used herein, means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxy methyl, 2-hydroxyethyl, 2-methyl-2-hydroxyethyl, 3- hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.
  • hydroxy-protecting group means a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures.
  • examples of hydroxy-protecting groups include, but are not limited to, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-
  • Hydroxy-protecting groups are appended onto hydroxy groups by reaction of the compound that contains the hydroxy group with a base, such as triethylamine, and a reagent selected from an alkyl halide, alkyl trifilate, trialkylsilyl halide, trialkylsilyl triflate, aryldialkylsilyltriflate, or an alkylchloroformate, CH 2 I 2 , or a dihaloboronate ester, for example with methyliodide, benzyl iodide, triethylsilyltriflate, acetyl chloride, benzylchloride, or dimethylcarbonate.
  • a protecting group also may be appended onto a hydroxy group by reaction of the compound that contains the hydroxy group with acid and an alkyl acetal.
  • mercapto as used herein, means a -SH group.
  • methylenedioxy as used herein, means a -OCH 2 0- group wherein the oxygen atoms of the methylenedioxy are attached to the parent molecular moiety through two adjacent carbon atoms.
  • -NR A R B means 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 independently selected from hydrogen, alkyl, acyl and formyl.
  • Representative examples of -NR A R B include, but are not limited to, amino, dimethylamino, methylamino, acetylamino, and acetylmethylamino.
  • (NR A R B )alkyl as used herein, means an -NR A R B group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of (NR A R B )alkyl include, but are not limited to, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 2-(amin ⁇ )ethyl, 2- (ethylmethylamino)ethyl, and the like.
  • (NR A R B )carbonyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkylcarbonyl include, but are not limited to, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, n- propylcarbonyl, and the like.
  • (NR A R B )sulfonyl as used herein, means a -NR A R B group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of (NR A R B )sulfonyl include, but are not limited to, aminosulfonyl, (methylamino)sulfonyl, (dimethylamino)sulfonyl and (ethylmethylamino)sulfonyl.
  • nitro as used herein means a -NO 2 group.
  • nitrogen protecting group means those groups intended to protect a nitrogen atom against undesirable reactions during synthetic procedures. Nitrogen protecting groups comprise carbamates, amides, N-benzyl derivatives, and imine derivatives. Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc), tert-butylacetyl, thfluoroacetyl, and thphenylmethyl (trityl).
  • hydroxy protecting group or "O-protecting group” or “oxygen protecting group” means a substituent which protects hydroxy groups against undesirable reactions during synthetic procedures.
  • hydroxy protecting groups include, but are not limited to, substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, benzyl, and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example, trimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide, and benzylidene acetal; cyclic ortho esters, for example, methoxym
  • sulfonyl as used herein means a -S(O) 2 - group.
  • thioalkoxy as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom. Representative examples of thioalkoxy include, but are no limited to, methylthio, ethylthio, and propylthio.
  • antagonist encompasses and describes compounds that prevent receptor activation by an H 3 receptor agonist alone, such as histamine, and also encompasses compounds known as "inverse agonists”.
  • Inverse agonists are compounds that not only prevent receptor activation by an H 3 receptor agonist, such as histamine, but also inhibit intrinsic H 3 receptor activity.
  • Y, and Y' each can be CH, CF, or N
  • X, X', Z, and Z' each can be independently selected from C or N.
  • R 6 is selected from the group consisting of aryl, heteroaryl, heterocycle, and cycloalkyl.
  • the substituent for R is selected from bromo, cyano, or L 2 R 6 .
  • groups for Ri wherein the substituent is halogen or cyano include, but are not limited to, bromo and cyano.
  • L 2 as a bond is most preferred.
  • Preferred groups for R 6 are aryl, heteroaryl, and cycloalkyl.
  • the aryl, heteroaryl, and heterocyclic groups can be unsubstituted or substituted, for example as described in the Definition of Terms.
  • Examples of aryl groups for Re can include, but are not limited to, phenyl.
  • the ' phenyl groups can be substituted with at least 0, 1, or 2 substituents.
  • Preferred substituents for aryl are cyano, halogen, -NR A R B , alkoxy, hydroxyalkyl, . alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, thioalkoxy, alkylsulfonyl, and haloalkyl.
  • the more preferred substituent is cyano.
  • Specific examples include, but are not limited to, 4-chlorophenyl, 3-cyanophenyl, 4-cyanophenyl, 3,5- difluorophenyl, 4-(dimethylamino)phenyl, 4-ethoxyphenyl, 3-fluorophenyl, 4- fluorophenyl, 3-hydroxymethylphenyl, 4-(1-hydroxy-1-methylethyl)phenyl, 3-
  • One particular embodiment is a compound of formula (I) wherein Ri is
  • L 2 R 6 , L 2 is a bond and Re is aryl wherein the aryl is phenyl substituted with 0, 1 , or
  • substituents selected from the group consisting of cyano, halogen, -NR A R B , alkoxy, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, cycloalkylcarbonyl, alkylsulfonyl, haloalkyl, and thioalkoxy.
  • heteroaryl groups for Re can include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridazinonyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, and triazolyl.
  • heteroaryl groups for the invention include, but are not limited to, for example, furan-3-yl, pyrazin-2-yl, pyrazol-3-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-5-yl, pyrrol-2-yl, 1 ,3-thiazol-2-yl, 1 ,3-thiazol-5-yl, thiophen-3-yl, and thiophen-2-yl.
  • heteroaryl groups of the invention are 2H- pyridazin-3-one, particularly 2H-pyridazin-3-one-2-yl, and 1H-pyridin-2-one, particularly 1H-pyridin-2-one-1-yl.
  • a preferred heteroaryl group is 2H-pyridazin-3- one-2-yl.
  • the heteroaryl groups can be substituted with at least 0, 1 , 2, or 3 substituents.
  • Preferred substituents for the heteroaryl groups are -NR A R B , halogen, alkyl, cyano, alkoxyimino, alkoxycarbonyl, (NR A R B )carbonyl, alkylcarbonyl, haloalkyl, and alkoxy.
  • substituted heteroaryl groups for the invention include, but are not limited to, 2-aminopyrimidin-5-yl, 3- bromoisoxazol-5-yl, 3-chloropyridin-4-yl, 6-chloropyridin-3-yl, 5-cyanopyridin-3-yl, 3-cyano-2,6-dimethylpyridin-3-yl, 2,6-dichloropyridin-3-yl, 2,6-dimethylpyridin-3-yl, 1 ,3-dimethylpyrazol-4-yl, 1 ,5-dimethylpyrazol-4-yl, 3,5-dimethylpyrazol-4-yl, 5- cyanothien-2-yl, 2-cyanopyrimidin-5-yl, 2,5-dimethylfur-3-yl, 3,5-dimethylthien-2-yl,.
  • a particular embodiment is a compound of formula (I) wherein Ri is L 2 R 6 ,
  • L 2 is a bond
  • R 6 is selected from the group consisting of furyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyridinonyl, pyridazinyl, pyridazinonyl, pyrimidinyl, pyrrolyl, thiazolyl, and thienyl, substituted with 0, 1 , 2, or 3 substituents selected from the group consisting of -NR A R B , halogen, alkyl, cyano, alkoxyimino, alkoxycarbonyl, (NR A R B )carbonyl, alkylcarbonyl, haloalkyl, and alkoxy.
  • Heterocycle groups for R 6 can include, but are not limited to, azepanyl, azetidinyl, aziridinyl, azocanyl, dihydrothiazolyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, thiomorpholinyl, and tetrahydropyridinyl, as well as non-nitrogen containing heterocycles, for example, tetrahydrofuryl and tetrahydropyranyl.
  • Heterocycles can be substituted with 0, 1 , or 2 substituents as described in the Definition of Terms.
  • heterocycles for the invention include, but are not limited to, morpholin-4-yl, thiomorpholin-4-yl, and 4,5-dihydrothiazol-2-yl.
  • Preferred heterocycles are dihydrothiazolyl, morpholinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, and tetrahydropyranyl.
  • Specific cycloalkyl groups for R 6 can include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • R 2 in a compound of formula (I) is absent when Z' is N.
  • R 2 also can be independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, cycloalkyl, halogen, cyano, and thioalkoxy when Z' is C.
  • Preferred groups for R 2 are hydrogen, alkyl, and cycloalkyl.
  • R 2 can be halogen, cyano, or L 2 R 6 , as defined for R ⁇
  • R can be selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, cycloalkyl, halogen, cyano, and thioalkoxy.
  • R 3 in a compound of formula (I) is absent when X' is N.
  • R 3 can be independently selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, halogen, cyano, and thioalkoxy when X' is C.
  • Preferred groups for R 3 are hydrogen, alkyl, and cycloalkyl.
  • R 3a in a compound of formula (I) is absent when Z is N.
  • R 3a can be independently selected from the group consisting of hydrogen, methyl, alkoxy, halogen, and cyano when Z is C.
  • Preferred groups for R 3a are hydrogen and methyl.
  • R 3 in a compound of formula (I) is absent when X is N.
  • R 3b can be independently selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, hydroxy, cyano, and thioalkoxy when X is C.
  • Preferred groups for R 3b are hydrogen and hydroxy.
  • R 4 and R5 in a compound of formula (I) are each independently selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, and (NR A R B )alkyl.
  • Preferred compounds of formula (I), wherein R 4 and R 5 are independently selected are those wherein R4 and R 5 are each independently selected from methyl, ethyl, and propyl, particularly isopropyl.
  • R 4 and R 5 also can be taken together with the nitrogen atom to which each is attached form a non-aromatic ring of the formula:
  • R 7 , R 8 , Rg, R10, Rn, R12, R13, Ru, R ⁇ > Ry, and m are as described herein.
  • R 4 and R 5 taken together with the nitrogen atom to which each is attached form a 4- to 8-membered non-aromatic ring represented by formula (a).
  • R , R 8 , Rg, and R 10 each can be independently selected from the group consisting of hydrogen, hydroxyalkyl, fluoroalkyl, and alkyl.
  • each pair of R and R 8 or R 9 and R 10 taken together can form a C 3 -C ⁇ ring, including the carbon atom to which each is attached.
  • the C 3 -C 6 ring can include 0, 1 , or 2 heteroatoms selected from O, N, or S to replace a carbon atom in the ring.
  • C 3 -C 6 rings can include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxirane, and the like.
  • Rx and R y each can be independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkylamino, dialkylamino, and fluoro.
  • one of R x and R y can represent a bond when taken with R x or R y on an adjacent carbon atom, such that a double bond is represented between the adjacent carbon atoms.
  • the value represented by m can be selected from 1 to 5, inclusive. Preferred values for m are 2 and 3.
  • Compounds of formula (I) also are those wherein R 4 and R 5 are taken together with the nitrogen atom to which each is attached to form a non-aromatic ring of formula (b), wherein R 7 , R 8 , Rg, and Rio are as previously defined for a ring of formula (a); Rn, R 12 , R 13 , and R 14 are each independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, alkyl, and fluoro; and Q is a bond or Q is selected from the group consisting of O, S, and NR ⁇ 5 , wherein R 15 is selected from the group consisting of hydrogen, alkyl, acyl, amido, and formyl.
  • R , R 8 , Rg, and R 10 are each independently selected from hydrogen, methyl, ethyl, fluoromethyl, and hydroxymethyl.
  • Rn, R1 2 , R 1 3, and R preferably each are hydrogen.
  • Rn and R 12 are hydrogen
  • R ⁇ 3 and R 14 are each independently selected from hydrogen or alkyl
  • R 7 , R 8 , Rg, and R 10 are as previously defined.
  • R 4 and R 5 taken together with the nitrogen atom to which each is attached to form a 4- to 8-membered non-aromatic ring of formula (a) can include, but are not limited to, those wherein the 4- to 8-membered non- aromatic ring is selected from azetidinyl, azepanyl, azepinyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, and tetrahydropyridinyl.
  • the ring can be substituted with 0, 1 , or 2 substituents as previously described for heterocycle groups in the Definition of Terms.
  • Preferred substituents are selected from the group consisting of alkyl, halogen, hydroxyalkyl, fluoroalkyl, and -NR A R B .
  • Groups for R 4 and R 5 also can be taken together with the nitrogen atom to which each is attached to form a 4- to 8-membered non-aromatic ring of formula (a) or formula (b), wherein the ring is substituted with at least one substituent selected from hydroxy, alkyl, halogen, fluoroalkyl, or hydroxyalkyl.
  • R 4 and R 5 include, for example, those wherein R 4 and R 5 are taken together with the nitrogen atom to which each is attached to form a 4- to 8-membered non-aromatic ring selected from morpholinyl and thiomorpholinyl, and unsubstituted or substituted pyrrolidinyl, for example, methylpyrrolidinyl, ethylpyrrolidinyl, dimethylaminopyrrolidinyl, isopropylpyrrolidinyl, isobutylpyrrolidinyl, hydroxymethylpyrrolidinyl, and fluoromethylpyrrolidinyl.
  • groups for R 4 and R 5 are taken together with the nitrogen atom to which each is attached to form a non-aromatic ring of formula (a) or formula (b) and at least one of the substituents R 7 , R 8> Rg, and R ⁇ 0 is selected from hydroxyalkyl, fluoroalkyl, or alkyl.
  • at least one of R 7 , R 8 , Rg, and R ⁇ 0 can be selected from methyl, ethyl, fluoromethyl, or hydroxymethyl, and the like.
  • R 15 preferably is selected from hydrogen, alkyl, amido, or formyl.
  • the moiety represented by L can be -[C(R ⁇ 6 )(R ⁇ )] n - or -[C(R ⁇ 6 )(R ⁇ )] p O-, wherein R ⁇ 6 and R ⁇ 7 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, and fluoro, and n is an integer selected from 1 to 6, inclusive, and p is an integer selected from 2 to 6, inclusive.
  • R 16 and R ⁇ 7 preferably are hydrogen.
  • the preferred value of n is 2 or 3.
  • the preferred value for p is 2.
  • the alkyl group of -N(alkyl)- preferably contains from 1 to 6 carbons.
  • Compounds of the invention can have the formula (I) wherein L 2 is -[C(R ⁇ 8 )(R ⁇ g)] q -, R ⁇ 8 and R19 are hydrogen, and q is 1 , 2, 3 or 4. The preferred value for q is 1.
  • Preferred compounds of formula (I) are those wherein Ri is a group L 2 R 6 , wherein L 2 is a bond and R 6 is heteroaryl or heterocycle; R 2 , R 3 , R 3a , and R 3 are hydrogen; L is -[C(R ⁇ 6 )(Ri7)]n-; n is 2; R 16 and R ⁇ 7 are hydrogen at each occurrence; R 4 and R 5 are taken together to form a methylpyrrolidinyl ring of formula (a), wherein one of R 7 , R 8 , R 9 , and R 10 is methyl and the remaining three substituents are hydrogen; Y and Y' are CH; X, X * , Z, and Z' are C.
  • a preferred heteroaryl group is pyridazinonyl and, more particularly, 2H-pyridazin-3-one-2-yl.
  • X, X', Y, Y', Z, and Z' can be nitrogen.
  • Compounds of the invention can have the formula (I) wherein Y and Y' are
  • compounds of the invention have formula (I) wherein Y and Y' are CH; X, X', and Z are C; R 3 , R 3a , and R 3b are hydrogen; Z' is N; and R 2 is absent.
  • Compounds of the invention also can have the formula (I) wherein Y and Y' are CH; X', Z', and Z are C; R 2 , R 3 , and R 3a are hydrogen; X is N; and R 3b is absent.
  • the invention also includes compounds having the formula (I) wherein Y and Y' are CH; X, X', and Z' are C; R 2 , R 3 , and R 3 are hydrogen; Z is N; and R 3a is absent.
  • compounds of the invention can have formula (I) wherein Y is CH; X, X', Z, and Z' are C; R 2 , R3, R3a, and R 3b are hydrogen; and Y 1 is N.
  • compounds of the invention have formula (I) wherein Y and Y' are CH; X and Z' are C; R 2 and R 3b are hydrogen; X' is N; Z is N; and R 3 and R 3a are absent.
  • Another embodiment relates to compounds of the invention having the formula (I) wherein Y' is CH; X, Z, and Z' are C; R 2 , R3a, and R 3b are hydrogen; Y is N; X' is N; and R 3 is absent.
  • Still yet another embodiment relates to compounds of the invention having the formula (I) wherein Y * is CH; X, X', and 71 are C; R 2 , R 3 , and R 3 b are hydrogen;
  • Y is N; Z is N; and R 3a is absent. Still yet another embodiment relates to compounds of the invention having the formula (I) wherein Y is CH; X, X', and Z are C; R 3 , R 3a , and R 3b are hydrogen; Y' is N; Z' is N; and R 2 is absent.
  • Still yet another embodiment relates to compounds of the invention having the formula (I) wherein Y and Y' are CH; Z' and Z are C; R 2 and R 3a are hydrogen; X' is N; X is N; and R 3 and R 3b are absent.
  • Compounds of the invention also can have the formula (I) wherein Y' is CH; X, X', Z and Z' are C; R 2 , R3, R 3a . and R 3b are hydrogen; and Y is N.
  • compounds of the invention have formula (I) wherein Y and Y' are CH; X' and Z' are C; R 2 and R 3 are hydrogen; X is N; Z is N; and R 3a and R 3b are absent.
  • Still yet another embodiment relates to compounds of the invention having the formula (I) wherein Y is CH; X, Z', and Z are C; R 2 , R 3a , and R 3b are hydrogen; Y' is N; X' is N; and R 3 is absent.
  • substituents represented by R 2 , R 3 , R 3a , and R 3b are present, Z', X',
  • Z, and X respectively, represent a carbon atom to allow for the substituents represented by R 2 , R 3 , R 3a , and R 3b .
  • Specific examples of compounds of the invention include, but are not limited to:
  • a preferred compound is 2-(6- ⁇ 2-[(2R)-2-methyl-1-pyrrolidin-1-yl]-ethyl ⁇ -2- naphthalen-2-yl)-2H-pyridazin-3-one, which also can be named 2-(6- ⁇ 2-[(2R)-2- methyl-1-pyrrolidinyl]ethyl ⁇ -2-naphthyl)-3(2H)-pyridazinone.
  • Stereoisomers 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.
  • 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.
  • Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of compounds of the 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 optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods.
  • 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 1-24.
  • Alcohols of formula (3) can be treated with a base such as, but not limited to, triethylamine and a sulfonate such as, but not limited to, methanesulfonyl chloride or p-toluensulfonyl chloride or triflic anhydride to provide sulfonates of formula (4).
  • Sulfonates of formula (4) can be treated with an optional base such as, but not limited to, potassium carbonate or sodium carbonate and an amine of formula (5) with or without heat to provide amines of formula (6).
  • the Suzuki reaction can be used to produce compounds of formula (I), wherein Ri is an aryl, heteroaryl, heterocyclic, or cycloalkyl ring.
  • compounds of formula (I) wherein Ri is a triflate or halogen are reacted with boronic acids of formula (7), a metal catalyst such as, but not limited to, palladium diacetate or Pd(PPh 3 ) 4 , optionally with a Pd ligand added such as (dicyclohexylphosphinyl)biphenyl or trifurylphosphine, and a base such as, but not limited to, aqueous 0.2 M K 3 PO to provide products of formula (I) wherein Ri is an aryl, heteroaryl, heterocyclic or cycloalkyl ring.
  • Boronic acid esters of formula (7a) can be used in place of boronic acids. Boronic acids can be esterified to the corresponding boronic acid esters with alcohols such as methanol or with diols such as pinacol. Likewise, amines of formula (6) can be subjected to the Suzuki reaction to provide amines of formula (8).
  • compounds of formula (8) may be prepared from compounds of formula (6) by treatment with aryl, heteroaryl, and heterocyclic stannanes (Me 3 SnR 6 , Bu 3 SnRe), a palladium source such as tris(dibenzylidineacetone)dipalladium (CAS # 52409-22-0) or palladium diacetate, and a ligand such as tri(2-furyl)phosphine (CAS # 5518-52-5) or triphenyl arsine in a solvent, for example in DMF at 25-150 °C.
  • aryl, heteroaryl, and heterocyclic stannanes Me 3 SnR 6 , Bu 3 SnRe
  • a palladium source such as tris(dibenzylidineacetone)dipalladium (CAS # 52409-22-0) or palladium diacetate
  • a ligand such as tri(2-furyl)phosphine (CAS # 5518-52-5) or triphenyl ar
  • organotin reagents for the Stille coupling are commercially available or described in the literature
  • new organotin reagents can be prepared from arylhalides, aryltriflates, heteroarylhalides, heteroaryltriflates by reaction with distannanes like (Me 3 Sn) 2 (hexamethyl distannane) in the presence of a palladium source like Pd(Ph 3 P) .
  • distannanes like (Me 3 Sn) 2 (hexamethyl distannane)
  • Pd(Ph 3 P) palladium source
  • a base such as, but not limited to, sodium t- butoxide or cesium carbonate
  • a metal catalyst such as, but not limited to copper metal or Cul, palladium diacetate
  • a ligand such as, but not limited to, BINAP, tri-tertbutylphosphin
  • Compounds of structure (6) can be transformed to heterocyclic or heteroaryl compounds of structure (8) where the R & moiety is, for instance, a N- pyridazinone by heating with 3(2H)-pyridazinone (or an optionally functionalized heterocycle that contains an acidic NH group in the heterocycle, such as pyridin-2- one) with copper powder and base as described in WO 0024719, p. 127, Example
  • Compounds of formula (6) can also be treated with an organolithium reagent such as, but not limited to, n-butyllithium, methyllithium, or tert-butyllithium and an amide of formula (9) to provide compounds of formula (10).
  • organolithium reagent such as, but not limited to, n-butyllithium, methyllithium, or tert-butyllithium and an amide of formula (9) to provide compounds of formula (10).
  • Compounds of formula (11), wherein L 2 is -NH- or -N(alkyl)- and R 6 is as defined for a compound of formula (I) can be prepared by heating compounds of formula (6) with a compound of formula H 2 N-R 6 or HN(alkyl)-R 6 with a base such as, but not limited to sodium t-butoxide or cesium carbonate in the presence of a metal catalyst such as, but not limited to copper metal or Cul, palladium diacetate, and also optionally with a ligand such as, but not limited to, BINAP, tri- tertbutylphosphine in solvents such as dioxane, toluene, pyridine.
  • a base such as, but not limited to sodium t-butoxide or cesium carbonate
  • a metal catalyst such as, but not limited to copper metal or Cul, palladium diacetate
  • a ligand such as, but not limited to, BINAP, tri- tert
  • Compounds of formula (11), wherein L 2 is oxygen and R 6 is defined in formula (I) can be prepared by heating compounds of formula (6) with a compound of formula HOR ⁇ using a base such as but not limited to sodium hydride in a solvent such as toluene or N,N-dimethylformamide in the presence of a metal containing catalyst such as Cul or palladium diacetate.
  • a base such as but not limited to sodium hydride in a solvent such as toluene or N,N-dimethylformamide
  • a metal containing catalyst such as Cul or palladium diacetate.
  • Suitable reagents for example, alkyl Grignard reagents, boronic acids or ester, tin intermediates, alkenes and alkynes can be coupled with compounds of formulas (6) in the presence of a metal catalyst such as palladium, nickel, silver or indium, to prepare compounds of formula (11) wherein L 2 is a substituted or unsubstituted alkyl, alkenyl or alkynyl chain.
  • esters of formula (13)' can be treated with a reducing agent such as, but not limited to, lithium aluminum hydride to provide alcohols of formula (14).
  • Alcohols of formula (14) can be treated with thionyl chloride to provide chlorides of formula (15).
  • Chlorides of formula (15) can be treated with sodium cyanide or potassium cyanide to provide the nitrile which can be treated with aqueous acid to provide acids of formula (16).
  • Acids of formula (16) can be treated with a reducing agent such as, but not limited to, diborane or borane THF complex to provide alcohols of formula (17).
  • Alcohols of formula (17) can be treated with a hydroxy-protecting reagent such as, but not limited to, tert- butyldimethylsilyl chloride.
  • the protected compounds of formula (18) can be processed as described in Scheme 1 to provide compounds of formula (19).
  • Compounds of formula (19) can be deprotected using methods known to those of ordinary skill in the art and then treated with a sulfonyl chloride such as, but not limited to, methanesulfonyl chloride or p-toluensulfonyl chloride to provide sulfonates of formula (20).
  • Sulfonates of formula (20) can be treated with an amine of formula (5) to provide compounds of formula (8).
  • Hydroxyacids of formula (30) can be treated with a strong acid such as, but not limited to, concentrated sulfuric acid with heat in a solvent such as methanol to provide esters of formula (31).
  • Esters of formula (31) can be treated with a reducing agent such as, but not limited to, lithium aluminum hydride to provide alcohols of formula (32).
  • Alcohols of formula (32) can be treated with ozone followed by dimethylsulfide and ammonium hydroxide to provide isoquinolines of formula (33).
  • Isoquinolines of formula (33) can be processed as described in Schemes 1 and 2 to provide compounds of formula (34).
  • Protected anilines of formula (38) can be treated with an organolithium reagent such as, but not limited to, n-butyllithium, sec-butyllithium, or tert-butyllithium and N,N-dimethylformamide to provide aldehydes of formula (39).
  • organolithium reagent such as, but not limited to, n-butyllithium, sec-butyllithium, or tert-butyllithium and N,N-dimethylformamide to provide aldehydes of formula (39).
  • the aniline of aldehydes of formula (39) can be deprotected using methods well know to those skilled in the art such as, but not limited to, heating in aqueous hydrochloric acid to provide aldehydes of formula (40).
  • Aldehydes of formula (40) can be treated with ketones of formula (41) and a base such as, but not limited to, potassium ethoxide to provide compounds of formula (42).
  • Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be prepared using the procedures described in Synthetic Comm., 17(14):1647-1653 (1987).
  • Ethyl 7-methoxy-2- methyl-3-quinolinecarboxylate can be treated with a reducing agent, such as, but not limited to, lithium aluminum hydride or sodium borohydride, to provide (7- methoxy-2-methyl-3-quinolinyl)methanol.
  • (7-Methoxy-2-methyl-3- quinolinyl)methanol can be treated with a chlorinating reagent, such as, but not limited to, thionyl chloride to provide 3-(chloromethyl)-7-methoxy-2- methylquinoline.
  • a chlorinating reagent such as, but not limited to, thionyl chloride
  • 3-(Chloromethyl)-7-methoxy-2-methylquinoline can be treated with sodium cyanide or potassium cyanide to provide (7-methoxy-2-methyl-3- quinolinyl)acetonitrile.
  • (7-Methoxy-2-methyl-3-quinolinyl)acetonitrile can be treated with acid, such as, but not limited to, glacial acetic acid and concentrated sulfuric acid, in water and 1 ,4-dioxane with heat to provide (7-methoxy-2-methyl-3- quinolinyl)acetic acid.
  • (7-Methoxy-2-methyl-3-quinolinyl)acetic acid can be treated with a reducing agent, such as, but not limited to, B 2 H 6 , borane-THF complex, or borane-pyridine complex, to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethanol.
  • 2-(7-Methoxy-2-methyl-3-quinolinyl)ethanol can be treated with methanesulfonyl chloride and a base, such as, but not limited to, triethylamine or diisopropylamine to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate.
  • 2-(7- Methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate can be treated with an amine of formula (5) to provide amines of formula (47).
  • Amines of formula (47) can be treated with BBr 3 to provide hydroxy compounds of formula (48).
  • Hydroxy compounds of formula (48) can be treated with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to provide triflates of formula (49).
  • Triflates of - formula (49) can be treated with boronic acids of formula (7) as described in Scheme 1 to provide compounds of formula (50).
  • Chem., 33:1384 (1968) can be treated with (2-ethoxyvinyl)tributylstannane, a halide source, such as, but not limited to, tetraethylammonium chloride, and a palladium source, such as, but not limited to, dichlorobis(triphenylphosphine)palladium (II) in a solvent, such as, but not limited to, N,N-dimethylformamide with heat (about 50 °C to about 150 °C) to provide 3- bromo-7-[2-ethoxyvinyl]-1 ,5-naphthyridine.
  • a halide source such as, but not limited to, tetraethylammonium chloride
  • a palladium source such as, but not limited to, dichlorobis(triphenylphosphine)palladium (II) in a solvent, such as, but not limited to, N,N-dimethylform
  • 3-Bromo-7-[2-ethoxyvinyl]-1 ,5- naphthyridine can be treated with an acid, such as, but not limited to, formic acid at about 0 °C to about 60 °C in a solvent, such as, but not limited to, 1 ,2- dichloroethane to provide (7-bromo-1,5-naphthyridin-3-yl)acetaldehyde.
  • an acid such as, but not limited to, formic acid at about 0 °C to about 60 °C
  • a solvent such as, but not limited to, 1 ,2- dichloroethane
  • 3-bromo-7-[2-ethoxyvinyl]-1 ,5-naphthyridine in a solvent can be treated with an aqueous acid, such as, but not limited to, hydrochloric acid at about 0 °C to about 60 °C to provide (7- bromo-1 ,5-naphthyridin-3-yl)acetaldehyde.
  • a solvent such as, but not limited to, tetrahydrofuran
  • an aqueous acid such as, but not limited to, hydrochloric acid at about 0 °C to about 60 °C to provide (7- bromo-1 ,5-naphthyridin-3-yl)acetaldehyde.
  • (7-Bromo-1 ,5-naphthyridin-3- yl)acetaldehyde can be treated with an amine of formula (5) under reductive amination conditions, such as, but not limited to, sodium triacetoxyborohydride and an acid, such as, but not limited to, acetic acid in a solvent, such as, but not limited to, 1 ,2-dichloroethane at about 0 °C to about 50 °C to povide amines of formula (52).
  • a solvent such as, but not limited to, 1 ,2-dichloroethane at about 0 °C to about 50 °C to povide amines of formula (52).
  • Amines of formula (52) can be treated with boronic acids of formula (7), a palladium source, such as, but not limited to, tris(dibenzylideneacetone)dipalladium (0), a ligand, such as, but not limited to, tri(tert-butyl)phosphine, and a base, such as, but not limited to, potassium fluoride in a solvent, such as, but not limited to, tetrahydrofuran at about 20 °C to about 80 °C to provide 1 ,5-naphthyridines of formula (53).
  • a palladium source such as, but not limited to, tris(dibenzylideneacetone)dipalladium (0)
  • a ligand such as, but not limited to, tri(tert-butyl)phosphine
  • a base such as, but not limited to, potassium fluoride in a solvent, such as, but not limited to, tetrahydrofuran at
  • Cinnolines of formula (60), wherein R and R 5 are as defined in formula (I) and Re is aryl or heteroaryl, can be prepared as described in Scheme 8.
  • Amines of formula (5) can be treated with 3-butynyl methanesulfonate at room temperature with stirring for about 1 hour and then heated at about 50 °C for about 24 hours. The mixture is allowed to cool to room temperature, and filtered. The filtrate is diluted with acetonitrile to provide a 0.1 M solution of alkynes of formula (55) for use in subsequent steps.
  • 5-Bromo-2-iodophenylamine prepared as described by Sakamoto in Chem. Pharm.
  • Bull., 35:1823 (1987), can be treated with alkynes of formula (55), a source of palladium (II), such as, but not limited to, Pd(Ph 3 P) 2 CI 2 , Cul, and a base, such as, but not limited to, triethylamine in an organic solvent, such as, but not limited to, DMF at about 50 °C to about 80 °C to provide alkynes of formula (56).
  • Alkynes of formula (56) can be treated with aqueous acid, such as but not limited to aqueous HCI in the presence of sodium nitrite at about 0 °C to about 100 °C to provide hydroxy cinnolines of formula (57).
  • Hydroxy cinnolines of formula (57) can be treated with boronic acids of formula (7) as described in Scheme 1 to provide hydroxy cinnolines of formula (58).
  • Hydroxy cinnolines of formula (58) can be treated with N- phenylbis(trifluoromethanesulfonimide) and a base, such as, but not limited to, diisopropylethylamine in an organic solvent, such as, but not limited to, 1 ,2-
  • Triflates of formula (59) can be treated with a catalytic palladium source, such as, but not limited to, palladium (II) acetate and a hydrogen donor, such as, but not limited to, formic acid at about 25 °C to about 50 °C to provide cinnolines of formula (60).
  • a catalytic palladium source such as, but not limited to, palladium (II) acetate
  • a hydrogen donor such as, but not limited to, formic acid at about 25 °C to about 50 °C to provide cinnolines of formula (60).
  • trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride can be treated with trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride and a base, such as, but not limited to, triethylamine or pyridine in a solvent, such as, but not limited to, dichloromethane at about 0 °C or room temperature to provide 7-chloro-3-cinnolinyl trifluoromethanesulfonate.
  • 7-Chloro-3-cinnolinyl trifluoromethanesulfonate can be treated with (2-ethoxyvinyl)tributylstannane, a halide source, such as, but not limited to, tetraethylammonium chloride, and a palladium source, such as, but not limited to, dichlorobis(triphenylphosphine)palladium (II) in a solvent, such as, but not limited to, N.N-dimethylformamide at about 50 °C to about 150 °C to provide 7-chloro-3-(2-ethoxyvinyl)cinnoline.
  • a halide source such as, but not limited to, tetraethylammonium chloride
  • a palladium source such as, but not limited to, dichlorobis(triphenylphosphine)palladium (II) in a solvent, such as, but not limited to, N.N-d
  • 7-Chloro-3-(2-ethoxyvinyl)cinnoline can be processed as described in Scheme 7 to provide amines of formula (62).
  • Amines of formula (62) can be treated with boronic acids of formula (7), a palladium source, such as, but not limited to, dichloro(di-tert-butylphosphinous acid)palladium (II) dimer) or tris(dibenzylideneacetone)dipalladium (0), tri(tert- butyl)phosphine, and a base, such as, but not limited to, cesium fluoride, in a solvent, such as, but not limited to, 1 ,4-dioxane at about 30 °C to about 120 °C to provide cinnolines of formula (60).
  • a palladium source such as, but not limited to, dichloro(di-tert-butylphosphinous acid)palladium (II) dimer) or tris
  • Cinnolines of formula (67), wherein R 4 and R 5 are as defined in formula (I) and R 6 is aryl or heteroaryl, can be prepared as described in Scheme 10.
  • 7- Chloro-3-cinnolinyl trifluoromethanesulfonate, prepared as described in Scheme 9, can be treated with boronic acids of formula (7), a palladium source, such as, but not limited to, tris(dibenzylideneacetone)dipalladium (0), tricyclohexylphosphine (or triphenylphosphine or tri(tert-butyl)phosphine), and a base, such as, but not limited to, potassium fluoride, in a solvent, such as, but not limited to, tetrahydrofuran at about 20 °C to about 80 °C to provide chlorides of formula (64).
  • a palladium source such as, but not limited to, tris(dibenzylideneacetone)dipalladium
  • Chlorides of formula (64) can be treated with 2-(2-ethoxy-vinyl)- 4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolane, prepared as described by C. M. Vogels in Chem. Commun.
  • a palladium source such as, but not limited to, tris(dibenzylideneacetone)dipalladium (0), tri(tert-butyl)phosphine or, in place of both, dichloro(di-tert-butylphosphinous acid)palladium (II) dimer and a base such as cesium fluoride, in a solvent, such as, but not limited to, 1 ,4-dioxane at about 30 °C to about 120 °C to provide ethers of formula (65).
  • Ethers of formula (65) can be processed as described in Scheme 7 to provide cinnolines of formula (67).
  • R B r rTCHH 2 Quinolines of formula (73), wherein R 4 and R 5 are as defined in formula (I) and RQ is aryl or heteroaryl, can be prepared as described in Scheme 11.
  • 2-(3- Nitrophenyl)ethanol, CAS 100-27-6 can be treated with methanesulfonyl chloride (or toluenesulfonyl chloride), and a base, such as, but not limited to, triethylamine in a solvent, such as, but not limited to, methylene chloride to provide 2-(3- nitrophenyl)ethyl methanesulfonate.
  • 2-(3-Nitrophenyl)ethyl methanesulfonate can be treated with amines of formula (5) and a base, such as, but not limited to, potassium carbonate in a solvent, such as, but not limited to, acetonitrile to provide amines of formula (70).
  • Amines of formula (70) can be treated with hydrogen with a palladium source, such as but not limited to palladium on carbon in a solvent, such as, but not limited to, methanol, ethanol, or ethyl acetate to provide anilines of formula (71).
  • Anilines of formula (71) can be treated with 2,2,3- tribromopropanal as described in S.W. Tinsley, J. Amer. Chem. Soc. 77:4175- 4176 (1955), to provide quinolines of formula (72).
  • Quinolines of formula (72) can be treated with boronic acids of formula (7) and treated as described in Scheme 1 to provide quinolines of formula (73).
  • Naphthyridines of formula (80), wherein R 4 and R 5 are as defined in formula (I) and R 6 is aryl or heteroaryl, can be prepared as described in Scheme 12.
  • 3-Bromo-1-(phenoxycarbonyl)pyridinium chloride can be treated with Grignard reagents of formula (75) as described in D. Comins et al., J. Het. Chem. 1239-1243 (1983) to provide compounds of formula (76).
  • Compounds of formula (76) can be treated with a base, such as, but not limited to, lithium diisopropylamide and N,N-dimethylformamide, as described in Numata et al,
  • Naphthyridines of formula (86), wherein R 4 and R 5 are as defined in formula (I) and R 6 is aryl or heteroaryl, can be prepared as described in Scheme 13.
  • 6-Bromo-2-pyridinecarbaldehyde can be treated with N-iodosuccinimide in sulfuric acid and acetic acid to provide 6-bromo-3-iodo-2-pyridinecarbaldehyde and 6-bromo-5-iodo-2-pyridinecarbaldehyde.
  • 6-Bromo-3-iodo-2- pyridinecarbaldehyde can be treated with tert-butylamine in a solvent, such as, but not limited to, THF to provide imine (84).
  • Imine (84) can be treated with 3-butyn- 1-ol, Cul, a base, such as, but not limited to, triethylamine or diisopropylamine, and a palladium source, such as, but not limited to, Pd(PPh 3 ) 2 CI 2 in a solvent, such as but not limited to N,N-dimethylformamide to provide alcohols of formula
  • Alcohols of formula (85) can be processed as described in Scheme 1 to provide naphthyridines of formula (86).
  • Naphthyridines of formula (91), wherein R 4 and R 5 are as defined in formula (I) and Re is aryl or heteroaryl can be prepared as described in Scheme 14.
  • Imines of formula (84), prepared as described in Scheme 13 can be treated with alkynes of formula (88), Cul, a base, such as, but not limited to, triethylamine or diisopropylamine, and a palladium source, such as, but not limited to, Pd(PPh 3 ) 2 CI 2 in a solvent, such as but not limited to N,N-dimethylformamide to provide naphthyridines of formula (89).
  • Naphthyridines of formula (89) can be treated with an alkyllithium reagent, such as, but not limited to, methyllithium, n- butyllithium, sec-butyllithium, or t-butyllithium, and ethylene oxide in a solvent, such as ' , but not limited to, THF or diethyl ether to provide alcohols of formula (90).
  • Alcohols of formula (90) can be treated as described in Scheme 1 to provide naphthyridines of formula (91).
  • (I) and Re is aryl or heteroaryl, can be prepared as described in Scheme 15.
  • Methyl 2-iodobenzoate can be treated with N-bromosuccinimide in acetic acid and sufuric acid to provide methyl 5-bromo-2-iodobenzoate.
  • Methyl 5-bromo-2- iodobenzoate can be treated with a reducing agent, such as, but not limited to, sodium borohydride or lithium aluminum hydride in a solvent, such as, but not limited to, THF, ethanol, or a mixture thereof, to provide (5-bromo-2- iodophenyl)methanol.
  • (5-Bromo-2-iodophenyl)methanol can be treated with an oxidizing agent, such as, but not limited to, pyridinium chlorochromate, pyridinium dichromate, Mn0 2 , a peracid such as meta-chloroperoxybenzoic acid, or Swern conditions (DMSO/CI(CO) 2 CI/TEA) to provide 5-bromo-2-iodobenzaldehyde.
  • an oxidizing agent such as, but not limited to, pyridinium chlorochromate, pyridinium dichromate, Mn0 2 , a peracid such as meta-chloroperoxybenzoic acid, or Swern conditions (DMSO/CI(CO) 2 CI/TEA) to provide 5-bromo-2-iodobenzaldehyde.
  • 5- Bromo-2-iodobenzaldehyde can be treated with tert-butylamine in a solvent, such as, but not limited to, THF to provide N-[(5-bromo-2-iodophenyl)methylene]-N- (tert-butyl)amine.
  • a solvent such as, but not limited to, THF
  • N-[(5-Bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine can be treated with alkynes of formula (88), Cul, a base, such as, but not limited to, triethylamine or diisopropylamine, and a palladium source, such as, but not limited to, Pd(PPh 3 ) 2 CI 2 in a solvent, such as but not limited to N,N-dimethylformamide to provide isoquinolines of formula (93).
  • Isoquinolines of formula (93) can be treated with an alkyllithium reagent, such as, but not limited to, methyllithium, n- butyllithium, sec-butyllithium, or t-butyllithium, and ethylene oxide in a solvent, such as, but not limited to, THF or diethyl ether to provide alcohols of formula (94).
  • Alcohols of formula (94) can be treated as described in Scheme 1 to provide isoquinolines of formula (95).
  • Isoquinolines of formula (34a) are a subgenus of compounds (34), wherein X, Y', and 71 are all carbon atoms, for instance CH, and R and R 5 are as defined in formula (I) and R 6 is aryl or heteroaryl, and the compounds of the subgenus (34a) can be prepared as described in Scheme 16.
  • Methyl 2-iodobenzoate can be treated with N-bromosuccinimide in acetic acid and sufuric acid to provde methyl 5-bromo-2-iodobenzoate.
  • Methyl 5-bromo-2-iodobenzoate can be treated with a reducing agent, such as, but not limited to, sodium borohydride or lithium aluminum hydride in a solvent, such as, but not limited to, THF, ethanol, or a mixture thereof, to provide (5-bromo-2-iodophenyl)methanol.
  • a reducing agent such as, but not limited to, sodium borohydride or lithium aluminum hydride in a solvent, such as, but not limited to, THF, ethanol, or a mixture thereof.
  • (5-Bromo-2- iodophenyl)methanol can be treated with an oxidizing agent, such as, but not limited to, pyridinium chlorochromate, pyridinium dichromate, MnO 2 , a peracid such as meta-chloroperoxybenzoic acid, or Swern conditions (DMSO/CI(CO) 2 CI/TEA) to provide 5-bromo-2-iodobenzaldehyde.
  • an oxidizing agent such as, but not limited to, pyridinium chlorochromate, pyridinium dichromate, MnO 2 , a peracid such as meta-chloroperoxybenzoic acid, or Swern conditions (DMSO/CI(CO) 2 CI/TEA) to provide 5-bromo-2-iodobenzaldehyde.
  • 5-Bromo-2- iodobenzaldehyde can be treated with tert-butylamine in a solvent, such as, but not limited to, THF to provide N-[(5-bromo-2-iodophenyl)methylene]-N-(tert- butyl)amine.
  • a solvent such as, but not limited to, THF
  • N-[(5-Bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine can be treated with the alkyne but-3-yn-1-ol, Cul, a base, such as, but not limited to, triethylamine or diisopropylamine, and a palladium source, such as, but not limited to, Pd(PPh 3 ) 2 Cl 2 in a solvent, such as, but not limited to, N,N-dimethylformamide to provide an isoquinoline.
  • a base such as, but not limited to, triethylamine or diisopropylamine
  • a palladium source such as, but not limited to, Pd(PPh 3 ) 2 Cl 2
  • a solvent such as, but not limited to, N,N-dimethylformamide
  • Quinoxalines of formula (105), wherein R 4 and R 5 are as defined in formula (I) and Re is aryl, heteroaryl, heterocycle, or cycloalkyl, can be prepared as described in Scheme 17.
  • Amines of formula (37), prepared as described in Scheme 5 can be treated with palladium on carbon under a hydrogen atmosphere to provide anilines that can then be treated with acetic anhydride in a : solvent such as a mixture of sulfuric acid and water to provide acetamides of formula (100).
  • Acetamides of formula (100) can be nitrated using conditions well known to those skilled in the art such as, but not limited to, nitric acid in sulfuric acid in the presence of acetic anhydride to provide acetamides of formula (101).
  • Acetamides of formula (101) can be converted to Boc protected nitroanilines using a procedure described in Grehen, L, et.al, Acta Chem. Scand. Ser. B. 41 , 1 , 18- 23, in which the acetamide is reacted with di-tert-butyldicarbonate in the presence of 4-dimethylaminopyridine followed by treatment with 2-diethylaminodiethylamine to provide a Boc protected nitroaniline which can be treated with palladium on carbon under a hydrogen atmosphere to provide anilines of formula (102).
  • Anilines of formula (102) can be reacted with an acetyl bromide of formula (103) to provide amines of formula (104).
  • Amines of formula (104) can be treated with an acid such as trifluoroacetic acid with heating to provide quinoxalines of formula (105). Treatment of amines of formula (104) may result in the formation of dihydroquinoxalines of formula (106). Dihydroquinoxalines of formula (106) may be oxidized with an oxidant such as silver nitrate to provide quinoxalines of formula (105).
  • Quinoxalinones of formula (112) can be treated with triflic anhydride in the presence of a base such as 2,6-lutidine in a solvent such as dichloromethane to provide triflates of formula (113).
  • Triflates of formula (113) can be treated with boronic acids of formula (7) as described in Scheme 1 to provide quinoxalines of formula (105).
  • Quinazolines of formula (123), wherein R 4 and R 5 are as defined in formula (I) and R 6 is aryl, heteroaryl, heterocycle, or cycloalkyl, can be prepared as described in Scheme 19.
  • Anilines of formula (40), prepared as described in Scheme 5, can be treated with acid chlorides of formula (121) in the presence of a base such as pyridine in a solvent such as dichloromethane to provide amides of formula (122).
  • Amides of formula (122) can be treated with a source of ammonia, such as aqueous ammonium hydroxide, and heated to provide quinazolines of formula (123).
  • Quinazolines of formula (123), wherein R 4 and R 5 are as defined in formula (I) and R 6 is aryl or heteroaryl can also be prepared as described in Scheme 20.
  • Anilines of formula (40), prepared as described in Scheme 5, can be teated with urea and heated as described in Troeger, et. al. .Prakt.Chem. 117, 1927, 181 , to provide quinazolinones of formula (130).
  • Quinazolinones of formula (130) can be treated with triflic anhydride in the presence of a base such as 2,6-lutidine in a solvent such as dichloromethane to provide triflates of general strucure (131).
  • Triflates of formula (131) can be treated with boronic acids of general structure (7) as described in Scheme 1 to provide quinoxalines of formula (123).
  • Nitrobenzenes of formula (138) can be treated with a reducing agent such as, but not limited to, platinum on carbon under a hydrogen atmosphere to provide diaminobenzenes of formula (139).
  • Diaminobenzenes of formula (139) can be treated with 2-oxopropanal to provide a mixture of bromides of formula (140) and (141 ).
  • Bromides of formula (140) and (141) can be treated with formaldehyde and amines of formula (5) to provide a mixture of aminobromides of formula (142) and (143).
  • Aminobromides of formula (142) and (143) can be processed as described in Scheme 1 to provide compounds of formula (144) and (145).
  • Compounds of formula (154), wherein Y, Y', Z', R 2 , R 4 , and R 5 are as defined in formula (I) and R 6 is aryl or heteroaryl, can be prepared as described in Scheme 22.
  • Compounds of formula (147), purchased or prepared using known methods in the art, can be treated with NaNO 2 and acid, such as, but not limited to, concentrated sulfuric acid followed by treatment with KI to provide iodo compounds of formula (148).
  • Iodo compounds of formula (148) can be treated with SnCI 2 and an acid such as, but not limited, concentrated HCI to provide compounds of formula (149).
  • Compounds of formula (149) can be treated with but-3-yn-1-ol, copper (I) iodide, base such as, but not limited to triethylamine, and a metal catalyst such as but not limited to PdCI 2 (PPh3) 2 to provide alkynes of formula (150).
  • Alkynes of formula (150) can be treated with NaNO 2 and an acid such as, but not limited to, 6M HCI to provide compounds of formula (151).
  • Compounds of formula (151) can be treated with POCI 3 to provide chlorides of formula (152).
  • Chlorides of formula (152) can be treated with boronic acids of formula (7) as described in Scheme 1 to provide compounds of formula (153).
  • Compounds of formula (153) can be treated with amines of formula (5) to provide compounds of formula (154).
  • Compounds of formula (159-161) wherein Y, Y', Z', R 2 , R 4 , and R 5 are as defined in formula (I) and Re is aryl or heteroaryl, can be prepared as described in Scheme 23.
  • Compounds of formula (149) can be treated with amines of formula (55), copper (I) iodide, a base such as, but not limited to triethylamine, and a metal catalyst such as, but not limited to, PdCI 2 (PPh 3 ) 2 to provide alkynes of formula (157).
  • Alkynes of formula (157) can be treated with NaN0 2 and an acid such as, but not limited to, 6 M HCI to provide compounds of formula (158).
  • Compounds of formula (158) can be treated with boronic acids of formula (7) as described in Scheme 1 to provide compounds of formula (159).
  • Compounds of formula (159) can be treated with an alkyl halide such as, but not limited to, iodomethane or iodoethane and a base such as, but not limited to, triethylamine to provide compounds of formula (160).
  • Compounds of formula (159) can be treated with phosphorus oxychloride to provide chlorides of formula (161 ), phosphorus oxybromide may also be used to generate the corresponding bromides.
  • Compounds of formula (163) can be treated with methanesulfonyl chloride (or toluenesulfonyl chloride) and a base such as, but not limited to, diisopropylamine or triethylamine to provide sulfonates of formula (164).
  • Sulfonates of formula (164) can be treated with amines of formula (5) to provide compounds of formula (165).
  • Compounds of formula (165) can be treated with boronic acids of formula (7) as described in Scheme 1 to provide compounds of formula (166).
  • the hydroxy protecting group of compounds of formula (166) can be removed using methods known to those in the art such as, but not limited to, treatment with fluoride ion, acid, or hydrogenation in the presence of a metal catalyst (H 2 and Pd/C) followed by treatment with phosphorus oxychloride to provide chlorides of formula (161), phosphorus oxybromide may also be used to generate the corresponding bromides.
  • Chlorides of formula (161) can be treated with nucleophiles such as, but not limited to, alkoxides, alkyl mercaptans, alkyl grignards, or sodium cyanide to provide compounds of formula (167-169).
  • the invention also relates to preparing a compound of formula (I)
  • Ri is L 2 R ⁇ wherein L 2 is a bond and Re is 3(2H)-pyridazinon-2-yl; R 2 , R 3 , R 3a , and R 3b are hydrogen; L is -[C(R 16 )(R ⁇ 7 )] n -; n is 2; R ⁇ 6 and R ⁇ at each occurrence are hydrogen; R 4 and R 5 are taken together to form a methylpyrrolidinyl ring of formula (a), wherein one of R , Re, Rg, and R 10 is methyl and the remaining three substituents are hydrogen; Y and Y' are CH; and X, X', Z, and Z' are C.
  • the process comprises the steps of:
  • Compound (II) can be reduced by treatment with borane-THF, preferably using from about three to four equivalents while maintaining the reaction below 0 °C.
  • Compound (III) can be reacted with 3(2/-/)- pyridazinone by the method described in WO 0024719, Example 62, using about one equivalent of copper powder and about three equivalents of base.
  • the preferred base is K 2 CO 3 .
  • Compound (IV) can be activated by treatment with methanesulfonyl chloride or toluensulfonyl chloride, preferably in the presence of a base, for example triethylamine.
  • the resulting compound can be reacted with an amine, for example methylpyrrolidine and, more particularly, 2- methylpyrrolidine, to provide a compound within the scope of formula (I).
  • the compounds and intermediates of the invention may be isolated and purified by methods well-known to those skilled in the art of organic synthesis.
  • Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin- layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in "Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.
  • the compounds of the invention have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt.
  • a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling.
  • acids suitable for the reaction include, but are not limited to tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, carbonic, fumaric, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, or hydroxy butyric acid, camphorsulfonic, malic, phenylacetic, aspartic, glutamic, and the like.
  • compositions of the Invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.
  • the compositions comprise compounds of the 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.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • 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; 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; iso
  • 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.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion.
  • Pharmaceutical compositions 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.
  • aqueous and nonaqueous carriers, diluents, solvents or vehicles examples include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like, and suitable mixtures thereof), vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate, or suitable mixtures thereof.
  • Suitable fluidity of the composition 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.
  • 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 like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption 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, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.
  • the compounds of the invention can be inco ⁇ orated 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 incorporation 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.
  • 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 also are 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 incorporating 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.
  • 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.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • 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.
  • one or more compounds of the invention is mixed with at least one inert pharmaceutically acceptable 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) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • 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 materials which can be useful for delaying release of the active agent can 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 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.
  • suitable non-irritating 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.
  • 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.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • 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.
  • a desired compound of the invention 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, 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, 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.
  • 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 invention, stabilizers, preservatives, and the like.
  • the preferred lipids are the natural and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together.
  • 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 contemplated as being within the scope of this invention.
  • Aqueous liquid compositions comprising compounds of the invention also are contemplated.
  • the compounds of the invention can be used in the form of pharmaceutically acceptable salts, esters, or amides derived from inorganic or organic acids.
  • pharmaceutically acceptable salts, esters and amides refer to carboxylate salts, amino acid addition salts, zwitterions, esters and amides of compounds of formula (I) which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. 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, camphorsulfonate, 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.
  • the basic nitrogen-containing groups can be quaternized 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.
  • 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 de
  • 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.
  • 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 like, 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, and piperazine.
  • esters of compounds of the 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 invention include C ⁇ -to-C 6 alkyl esters and C 5 -to-C cycloalkyl esters, although C ⁇ - to-C 4 alkyl esters are preferred.
  • Esters of the compounds of formula (I) may be prepared according to conventional methods.
  • esters may be appended onto hydroxy groups by reaction of the compound that contains the hydroxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid.
  • the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide, alkyl trifilate, for example with methyliodide, benzyl iodide, cyclopentyl iodide. They also may be prepared by reaction of the compound with an acid such as hydrochloric acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid.
  • pharmaceutically acceptable amide refers to non-toxic amides of the invention derived from ammonia, primary C to-C ⁇ alkyl amines and secondary Crto-C ⁇ 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, Crto-C 3 alkyl primary amides and C ⁇ -to-C 2 dialkyl secondary amides are preferred. Amides of the compounds of formula (I) may be prepared according to conventional methods.
  • Pharmaceutically acceptable amides are prepared from compounds containing primary or secondary amine groups by reaction of the compound that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aryl halide.
  • the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine, for example with methylamine, diethylamine, piperidine.
  • compositions can contain a compound of the invention in the form of a pharmaceutically acceptable prodrug.
  • pharmaceutically acceptable prodrug or “prodrug,” as used herein, represents those prodrugs of the compounds of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Prodrugs of the invention may be rapidly transformed in vivo to a parent compound of formula (I), 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 incorporated by reference.
  • the invention contemplates pharmaceutically active compounds either chemically synthesized or formed by in vivo biotransformation to compounds of formula (I).
  • Compounds and compositions of the invention are useful for modulating the effects of histamine-3 receptors.
  • the compounds and compositions of the invention can be used for treating and preventing disorders modulated by the histamine-3 receptors.
  • disorders can be ameliorated by selectively modulating the histamine-3 receptors in a mammal, preferably by administering a compound or composition of the invention, either alone or in combination with another active agent as part of a therapeutic regimen.
  • the compounds of the invention including but not limited to those specified in the examples, possess an affinity for the histamine-3 receptors.
  • the compounds of the invention may be useful for the treatment and prevention of diseases or conditions such as acute myocardial infarction, Alzheimer's disease, asthma, attention-deficit hyperactivity disorder, bipolar disorder, cognitive dysfunction, cognitive deficits in psychiatric disorders, deficits of memory, deficits of learning, dementia, cutaneous carcinoma, drug abuse, diabetes, type II diabetes, depression, epilepsy, gastrointestinal disorders, inflammation, insulin resistance syndrome, jet lag, medullary thyroid carcinoma, melanoma, Meniere's disease, metabolic syndrome, mild cognitive impairment, migraine, mood and attention alteration, motion sickness, narcolepsy, neurogenic inflammation, obesity, obsessive compulsive disorder, pain, Parkinson's disease, polycystic ovary syndrome, schizophrenia, cognitive deficits of schizophrenia, seizures, septic shock, Syndrome X, Tourette's syndrome, vertigo, and sleep disorders.
  • diseases or conditions such as acute myocardial infarction, Alzheimer's disease, asthma, attention-deficit hyperactivity disorder, bipolar disorder,
  • ADHD attention-deficit hyperactivity disorder
  • Delaunois A., et al. "Modulation of acetylcholine, capsaicin and substance P effects by histamine H 3 receptors in isolated perfused rabbit lungs," European Journal of Pharmacology 277(2-3):243-250 (1995); and Dimitriadou, et al., "Functional relationship between mast cells and C-sensitive nerve fibres evidenced by histamine H 3 -receptor modulation in rat lung and spleen," Clinical Science 87(2):151-163 (1994).
  • Compounds of the invention are particularly useful for treating and preventing a condition or disorder affecting the memory or cognition, for example Alzheimer's disease, attention-deficit hyperactivity disorder, schizophrenia, or the cognitive deficits of schizophrenia ⁇
  • a condition or disorder affecting the memory or cognition for example Alzheimer's disease, attention-deficit hyperactivity disorder, schizophrenia, or the cognitive deficits of schizophrenia ⁇
  • 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 to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • a therapeutically effective amount of one of the compounds of the invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester, amide or prodrug form.
  • the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable carriers.
  • therapeutically effective amount 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 invention will be decided by the attending physician within the scope of sound medical judgment.
  • 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; drugs used in combination or coincidental with the specific compound employed; and like 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.
  • more preferable doses can be in the range of from about 0.01 to about 0.1 mg/kg/day.
  • the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • (2R)-2-Methylpyrrolidine tartrate was prepared via resolution of 2-methylpyrrolidine with D-tartaric acid using procedures described by William
  • (2R)-2-methylpyrrolidine hydrobromide also is a suitable source of (2R)-2-methylpyrrolidine, and was prepared using the procedure described by Nijhuis, Walter H.N., et al., J.Org.Chem., 54(1): 209-216, 214 (1989).
  • Other procedures describing the synthesis of (2R)-2-methylpyrrolidine and salts thereof can be found in Andres, Jose M., et al. Eur. J.Org.Chem., 9:1719-1726 (2000); and Elworthy, Todd R.; Meyers, A. I., Tetrahedron, 50(20): 6089-6096 (1994).
  • (2S)-2-Methylpyrrolidine can be substituted for (2R)-2-methylpyrrolidine in the experimental procedures provided herein.
  • the (2S)-2-methylpyrrolidine can be prepared by procedures described in Kim, Mahn-Joo, et al., Bioorg.Med.Chem.Lett. 6(1):71-76 (1996).
  • R e O) (RfO)B-Re (7a) may serve as synthetic replacements for boronic acids of formula (7) in the Schemes.
  • the substituents represented by R e and R f in compounds of formula (7a) may be alkyl, or alternatively R e and R f can be taken together to form a ring, which may itself be substituted with alkyl or aryl groups.
  • suitable compounds of formula (7a) include, but are not limited to (CH 3 O) 2 BPh and (4- cyanomethylphenyl)boronic acid, pinacol ester (CombiBlocks Inc., San Diego)).
  • Boronic acids of formula (7) and boronic acid esters of formula (7a) are commercially available or can be prepared by methods well known to those skilled in the art of synthetic organic chemistry. For instance, Takagi et al. (Tetrahedron Letters, 43:5649-5651 (2002)) prepared heteroaryl pinacolborane esters of formula (7a) using heteroaromatic compounds and reaction with bis(pinacolborane) in the presence of an iridium catalysis of lrCI[COD]2-(4, 4'-di-t- butyl-2,2'-bipyridine in octane.
  • reagents such as Me 3 SnR 6 , Bu 3 SnR 6 , and R 6 ZnCI are suitable for reactions under Stille conditions in Scheme 1 and are commercially available.
  • R 6 is heteroaryl, heterocyclic, or aryl
  • they may be prepared by methods available to one with skill in the art. Examples of such methods include lithium halogen-metal exchange of heteroaryl, heterocyclic or aryl halides, followed by treatment with Me 3 SnCI (Li, et al. J. Med. Chem. 1996, 39, 1846), Bu 3 SnCI, ZnCI 2 , or B(OCH 3 ) 3 (O'Neill, et al. Org. Lett.
  • Heteroaryl halides and triflates can be treated wtih hexamethyldistannane as described in W. C. Black, et al. J. Med. Chem. 1999, 42, 1274., to give Me 3 SnR 6 .
  • Example 1C (6-bromo-2-naphthyl)acetonitrile A mixture of the product from Example 1 B (32.2 g, 126 mmol) and NaCN (7.44 g, 152 mmol, 1.2 equiv.) in acetonitrile (314 mL) and distilled water (32 mL) under a dry nitrogen atmosphere was stirred at reflux for 21 hr. The reaction mixture was cooled to room temperature then concentrated under reduced pressure. The residue was stirred with distilled water (314 mL) for 45 min. The resulting white solid was isolated by filtration and washed with distilled water (1500 mL). Drying under vacuum overnight at 40 °C provided the product (32.2 g, 97% yield). M.p.
  • Example 1F 4-f6-(2-hvdroxyethyl)-2-naphthvHbenzonitrile
  • reaction mixture was cooled to room temperature then concentrated under reduced pressure.
  • the residue was partitioned between ethyl acetate and brine.
  • the aqueous layer was washed with ethyl acetate, and the combined organic extracts were washed with saturated aqueous NH 4 CI, dried (MgS0 4 ), and filtered.
  • the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (7:3 hexane/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to provide the product as an off-white solid (0.59 g, 90% yield).
  • Example 1G 2-f6-(4-cyanophenyl)-2-naphthyl1ethyl 4-methylbenzenesulfonate
  • Example 1 H 4-(6-(2-r(2R)-2-methyl-1-pyrrolidinvnethyl)-2-naphthyl)benzonitrile
  • a mixture of the product from Example 1G (0.30 g, 1.08 mmol), (2R)-2- methylpyrrolidine (0.30 g, 3.52 mmol, 5.0 equiv.), and cesium carbonate (0.70 g, 2.1 mmol, 3.0 equiv.) in anhydrous acetonitrile (5 mL) was stirred in a sealed tube at 50 °C under a dry nitrogen atmosphere for 2 days. The reaction mixture was cooled to room temperature then concentrated under reduced pressure.
  • Example 3A 1- ⁇ 3-[6-(2-hydroxyethyl)-2-naphthyllphenyl)ethanone
  • a mixture of the product from Example 1E (0.78 g, 3.11 mmol), 3- acetylphenylboronic acid (0.61 g, 3.72 mmol, 1.2 equiv.), PdCI 2 (PPh 2 ) 2 (0.044 g, 0.062 mmol, 0.02 equiv), and K 3 P0 4 H 2 O (1.80 g, 9.35 mmol, 3 equiv) in isopropanol (40 mL) and distilled water (15 mL) was stirred at 65 °C under a dry nitrogen atmosphere for 1.5 hr.
  • reaction mixture was cooled to room temperature then concentrated under reduced pressure.
  • the residue was partitioned between ethyl acetate and brine.
  • the aqueous layer was washed with ethyl acetate, and the combined organic extracts were washed with saturated aqueous NH 4 CI, dried (MgS0 ), and filtered.
  • the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (7:3 hexane/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to provide the product as an off-white solid (0.57 g, 63% yield).
  • Example 4 2-r3-(6-(2-r(2R)-2-methyl-1-pyrrolidinyllethyl)-2-naphthyl)phenyll-2-propanol
  • CH 3 MgCI 0.91 g, 7.64 mmol, 4 equiv
  • the reaction mixture was stirred at room temperature for 18 hrs.
  • the reaction was quenched by the addition of aqueous K 2 HPO 4 (25 mL).
  • the reaction mixture was concentrated under reduced pressure.
  • Example 5 6-(2-r(2R)-2-methyl-1-pyrrolidinvnethyl)-2-naphthonitrile
  • a mixture of the product from Example 2B (100 mg, 0.314 mmol), zinc cyanide (22 mg, 0.188 mmol, 0.6 equiv.), Pd 2 (dba) 3 (14 mg, 0.016 mmol, 0.05 equiv.), 1 ,1'-bis(diphenylphosphino)ferrocene (21 mg, 0.038 mmol, 0.12 equiv.) in DMF (5 mL) and distilled water (0.05 mL) was stirred under a dry nitrogen atmosphere at 120 °C for 24 hr.
  • reaction mixture was cooled to 80 °C and treated with 4:1:4 saturated aqueous NH 4 CI/NH 4 OH/water, and stirred overnight while cooling to room temperature.
  • the mixture was extracted with ethyl acetate.
  • the organic layer was washed first with 4: 1 :5 saturated aqueous
  • Example 6B 4-f6-(chloromethyl)-2-naphthvnbenzonitrile
  • a mixture of the product from Example 6A (90 mg, 0.347 mmol), 0.5 M ZnCI 2 in THF (0.21 mL, 0.104 mmol, 0.3 equiv.), and thionyl chloride (0.51 mL, 6.94 mmol, 20.0 equiv.) in dioxane (40 mL) was stirred at room temperature under a dry nitrogen atmosphere for 3 hr.
  • the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous Na 2 CO 3 .
  • the organic layer was dried (MgSO 4 ), and filtered.
  • Example 7A 3-[6-(2-hydroxyethyl)-2-naphthvnbenzonitrile
  • the title compound was prepared by the method of Example 3A, substituting 3-cyanophenylboronic acid in place of 3-acetylphenylboronic acid (0.21 g, 96% yield).
  • Example 7C 3-(6-(2-r(2R)-2-methyl-1-pyrrolidinvnethyl)-2-naphthyl)benzonitrile
  • the title compound was prepared by the method of Example 3C, substituting the product from Example 7B for the product from Example 3B (21 mg, 38% yield). M.p. 228.5-231.6 °C.
  • Example 8 4-(6-(2-r(2R)-2-methyl-1-pyrrolidinyllethyl)-2-naphthyl)pyridine
  • a mixture of the product from Example 2B (50 mg, 0.157 mmol), 4- pyridinylboronic acid (48 mg, 0.393 mmol, 2.5 equiv.), PdCI 2 (PPh 3 ) 2 (6 mg, 0.0085 mmol, 0.054 equiv.) and K 3 P0 4 H 2 O (181 mg, 0.943 mmol, 6.0 equiv.) in isopropanol (5 mL) and distilled water (2 mL) was stirred at 60 °C under a dry nitrogen atmosphere for 1 hr.
  • Example 9 3-(6-(2-r(2R)-2-methyl-1-pyrrolidinyllethyl)-2-naphthyl)pyridine The title compound was prepared by the method in Example 8, substituting 3-pyridinylboronic acid in place of 4-pyridinylboronic acid (16 mg, 26% yield).
  • Example 3A-3C The title compound was prepared by the methods of Example 3A-3C, substituting 3,5-dimethyl-4-isoxazolylboronic acid in place of 3- acetylphenylboronic acid in Example 3A (38 mg, 12% yield).
  • Example 12 4-(6- ⁇ 2-r(2S)-2-(hvdroxymethyl)-1-pyrrolidinvnethyl)-2-naphthyl)benzonitrile
  • the title compound was prepared by the method of Example 1 H, substituting (2S)-2-pyrrolidinylmethanol in place of (2R)-2-methylpyrrolidine.
  • Example 13 4-(6-f2-f(3R)-3-hvdroxy-1-pyrrolidinyllethyl)-2-naphthyl)benzonitrile
  • the title compound was prepared by the method of Example 1 H, substituting (3R)-3-pyrrolidinol in place of (2R)-2-methylpyrrolidine.
  • Example 15 4- ⁇ 6-r2-(2-isopropyl-1-pyrrolidinyl)ethyn-2-naphthyl)benzonitrile
  • the title compound was prepared by the method of Example 1 H, substituting 2-isopropylpyrrolidine in place of (2R)-2-methylpyrrolidine.
  • Example 21 4-(6-(2-r(2S)-2-methyl-1-pyrrolidinvnethyl ⁇ -2-naphthyl)benzonitrile
  • the title compound was prepared by the method of Example 1 H, substituting (2S)-2-methylpyrrolidine in place of (2R)-2-methylpyrrolidine.
  • Example 25 4-(6- ⁇ 2-r(2-hvdroxyethyl)(methyl)aminolethyl)-2-naphthyl)benzonitrile
  • the title compound was prepared by the method of Example 1 H, substituting 2-(methylamino)ethanol in place of (2R)-2-methylpyrrolidine.
  • Example 26B tert-butyl(dimethyl)(2-r6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- naphthynethoxyjsilane
  • a solution of the product from Example 26A (920 mg, 2.518 mmol), Pd(OAc) 2 , (28 mg, 0.126 mmol, 0.05 equiv.), 2-(dicyclohexylphosphino)biphenyl (176 mg, 0.504 mmol, 0.2 equiv.), and Et 3 N (1.4 mL, 10.07 mmol, 4 equiv.) in dioxane (15 mL) was stirred under a dry nitrogen atmosphere at room temperature.
  • Pinacolborane (1.1 mL, 7.553 mmol, 3 equiv.) was added dropwise to the reaction mixture. When the addition was complete, the reaction was stirred at 80 °C for 1 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between saturated aqueous NH 4 CI and Et 0. The organic layer was dried (MgSO ), and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (98:2 hexane/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to give the product as a yellow solid (660 mg, 64% yield).
  • Example 26D 2-r6-(5-pyrimidinyl)-2-naphthyllethanol
  • THF 3 mL
  • the mixture was then partitioned between ethyl acetate and saturated aqueous Na 2 CO 3 .
  • the organic layer was washed with brine then dried (MgSO 4 ) and filtered.
  • the filtrate was concentrated under reduced pressure to give the title compound as an off-white solid (32 mg, 83% yield) which was used in the next step without further purification.
  • the title compound was prepared by the method in Example 26D, substituting the product from Example 28A in place of the product from Example 26C.
  • Example 28D 2-(6- ⁇ 2-f(2R)-2-methyl-1-pyrrolidinvnethyl)-2-naphthyl)-1 ,3-thiazole
  • the title compound was prepared by the method of Example 3C substituting the product from Example 28C in place of the product from Example 3B (hydrochloride salt, 4 mg, 14% yield).
  • Example 30 (3-fluorophenyl)(6- 2-f(2R)-2-methyl-1-pyrrolidinyllethyl>-2-naphthyl)methanone
  • a mixture of the product from Example 10 (3.2 mg, 0.009 mmol) and manganese dioxide (5.4 mg, 0.062 mmol, 7 equiv.) in anhydrous dichloromethane (1 mL) was stirred at room temperature for 3.5 hr.
  • the reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure.
  • the residue was purified by preparative TLC (95:5:trace dichloromethane/methanol/NH 4 OH).
  • Example 31A (6-Bromo-naphthalen-2-yl)-methanol To a stirred 1.0 M solution of lithium aluminum hydride (108 mL, 108 mmol) was added dropwise over 20 min a solution of methyl 6-bromo-2-naphthoate (18.9 g, 71.3 mmol) in THF (180 mL), while maintaining the reaction temperature below -5 °C. When the addition was complete, the reaction mixture was stirred at -10 °C for 1 hr, then quenched by the sequential dropwise addition of distilled water (4 mL), 2 N aqueous Na 2 CO 3 (4 mL), and distilled water (12 mL). After stirring for 15 min at room temperature, the reaction mixture was filtered.
  • lithium aluminum hydride 108 mL, 108 mmol
  • Example 31 B 2-Bromo-6-chloromethyl-naphthalene A stirred solution of the product from Example 31A (30.5 g, 129 mmol) in dioxane (320 mL) under a dry nitrogen atmosphere was chilled to -10 °C. Solid anhydrous ZnCI 2 (514 mg, 3.77 mmol, 0.03 equiv.) was added in one lot, followed by the dropwise addition of thionyl chloride (19.3 mL, 264 mmol, 2.0 equiv.). The reaction mixture was allowed to warm to room temperature then stirred an additional 2 hr. This reaction mixture was then concentrated under reduced pressure and the residue was partitioned between dichloromethane and saturated aqueous NaHC0 3 (500 mL).
  • Example 31 D (6-Bromo-naphthalen-2-yl)-acetic acid A stirred mixture of the product from Example 31 C (29.62 g, 120 mmol) in glacial acetic acid (300 mL) and distilled water (150 mL) under a dry nitrogen atmosphere was cooled to -15 °C. Concentrated sulfuric acid (120 mL, 4.32 mol, 36.0 equiv.) was added dropwise over 20 min while maintaining the reaction temperature below 10 °C. The reaction mixture was then stirred at reflux for 2 hr. After cooling to 35 °C, ice (500 g) was added to the mixture and stirring was continued for 45 min.
  • Example 31 F 2-r6-(2-Hvdroxy-ethyl)-naphthalen-2-yll-2H-pyridazin-3-one
  • a mixture of the product from Example 31 E (500 mg, 1.87 mmol), 2H- pyridazin-3-one (180 mg, 1.87 mmol), copper powder (120 mg, 1.87 mmol), and K 2 CO 3 (775 mg, 5.61 mmol, 3 equiv.) in pyridine (75 mL) was stirred at reflux under a dry nitrogen atmosphere for 20 hr. The reaction mixture was cooled to room temperature then concentrated under reduced pressure. Residual pyridine was removed by repeated evaporation with toluene.
  • Example 31 H 2-(6- 2-r(2R)-2-Methyl-1-pyrrolidin-1-yll-ethyll-2-naphthalen-2-yl)-2H-pyridazin-3- one
  • a mixture of the product from Example 31 G (0.30 g, 0.87 mmol) and (2R)- 2-methylpyrrolidine (0.37 g, 4.36 mmol, 5.0 equiv.) in anhydrous acetonitrile (3.5 mL) was stirred in a sealed tube at room temperature for 66 hours.
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was partitioned between ethyl acetate and saturated aqueous Na 2 CO 3 .
  • Example 35 4- ⁇ 6-r2-(1-pyrrolidinyl)ethvn-2-naphthyl)benzonitrile
  • the title compound was prepared by the method of Example 1 H, substituting pyrrolidine in place of (2R)-2-methylpyrrolidine.
  • Example 36 4-(6-(2-f(2R)-2-methyl-1-pyrrolidinyllethyl)-2-naphthyl)thiomorpholine
  • the title compound was prepared by the method of Example 27, substituting thiomorpholine in place of morpholine.
  • 2-bromo-6-(2-bromoethoxy)naphthalene A round-bottom flask containing 1.0 g (4.5 mmol) of 6-bromo-2-naphthol, 1,2-dibromoethane (135 mmol, 12 mL), potassium hydroxide (5 mL of a 40% solution) and tetrabutylammonium bromide (1.35 mmol, 0.43 g) was heated at 100°C for 3h.
  • Example 39 3-f6-f2-(1-pyrrolidinyl)ethoxyl-2-naphthyl ⁇ pyridine
  • the product from Example 37B and 3-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-pyridine were processed as described in Example 38, except that a second column chromatography was done to provide 10 mg of the title compound.
  • Example 40A (2R)-H2-f(6-bromo-2-naphthyl)oxylethyl>-2-methylpyrrolidine
  • (2R)-2-Methylpyrrolidine (L)-tartrate (541 mg, 2.3 mmol) was partitioned between aqueous 2 M NaOH (2.5 mL) and toluene (0.6 mL). The aqueous phase was separated, diluted with brine (0.3 mL), and extracted with toluene (2 x 0.3 mL). The combined organic phases were dried (Na 2 SO ) and carried on to the next step with a toluene rinse (0.3 mL).
  • Example 37A The product from Example 37A (495 mg, 1.5 mmol), potassium carbonate (207 mg, 1.5 mmol), and the above toluene solution were suspended into DMF (3 mL) and heated at 50 °C overnight.
  • the reaction mixture was brought to room temperature and partitioned between 0.2 M aqueous NaOH (20 mL) and dichloromethane (10 mL).
  • the aqueous phase was separated and extracted with dichloromethane, and the combined organic phases were washed with 0.2 M aqueous NaOH, dried (Na 2 SO ), and filtered quickly through a silica plug with a 0 to 10% methanol / dichloromethane gradient.
  • the filtrate was partitioned between water and 2:1 dichloromethane / hexanes.
  • aqueous phase was separated and extracted with 20% hexanes / dichloromethane, and the combined organic phases were concentrated and chromatographed through silica with a little hexanes / dichloromethane followed by a gradient of 0 to 10% methanol / dichloromethane. The appropriate fractions were combined and concentrated under high vacuum to provide 451 mg of a 6:1 mixture of title compound and starting dibromide which was used in the next step without further purification; MS (ESI APCI) m/z 334 / 336 (M+H) + .
  • Example 40B 3-(6-f2-r(2R)-2-methyl-1-pyrrolidinv ⁇ ethoxy 2-naphthyl)benzonitrile
  • a mixture of the product from Example 40A (147 mg, approximately 0.38 mmol), 3-cyanophenylboronic acid (96 mg, 0.65 mmol), PdCI 2 (PPh 3 ) 2 (28 mg, 0.04 mmol) and isopropanol (2.5 mL) was treated with 2 M aqueous sodium carbonate (700 ⁇ L) and heated at 55 °C overnight, then at 85 °C for two days. The mixture was cooled to room temperature and partitioned between 2 M aqueous NaOH (2 mL) and dichloromethane (10 mL).
  • the aqueous phase was separated and extracted with dichloromethane.
  • the combined organic phases were filtered through diatomaceous earth, concentrated, and chromatographed through silica once with a gradient of 0%/50%/50% to 10%/40%/50% methanol / ethyl acetate / dichloromethane, and a second time with a gradient of 0%/0%/100% to 0%/50%/50% to 5%/45%/50% methanol / ethyl acetate / dichloromethane to provide 28 mg of an orange gum;
  • 1 HNMR 300 MHz, CD 3 OD
  • Example 41 3-(6-(2-r(2R)-2-methyl-1-pyrrolidinv ⁇ ethoxy)-2-naphthyl)pyridine The product from Example 40A and 3-(4,4,5,5-tetramethyl-
  • [1 ,3,2]dioxaborolan-2-yl)-pyridine were processed as described for Example 40B, except that a single chromatography was conducted with a gradient of 0%/50%/50% to 10%/40%/50% methanol / ethyl acetate / dichloromethane followed by 8% methanol / dichloromethane to provide the title compound.
  • Example 42 4-(2-f2-f(2R)-2-methyl-1-pyrrolidinvnethyl)-6-quinolinyl)benzonitrile
  • Example 42A ethyl (6-bromo-2-quinolinyl)acetate
  • diisopropylamine (19.2 g, 0.19 mole) in diethyl ether (200 mL)
  • 2.5 M n-butyllithium in hexane 74 mL, 0.185 mole
  • the clear solution was mixed for 30 min, and followed by addition of 6-bromo-2- methyl-quinoline (13.32 g, 0.060 mole) in ether (200 mL) slowly at -78 °C.
  • the organic layer was concentrated, azeotroped with ethyl acetate (250 mL x 2) to a volume of -50 mL.
  • the resulting precipitate was diluted with heptane (50 mL), stirred at room temperature overnight, and then at 5 °C for 2 hours.
  • Example 42C 2-(6-bromo-2-quinolinyl)ethyl 4-methylbenzenesulfonate
  • a 500 mL round bottom flask was charged with the product from Example 42B (7.65 g, 0.030 mole), 4-N,N-dimethylaminopyridine (0.36 g, 0.003 mole), dichloromethane (100 mL) and triethylamine (9.3 g, 0.092 mmol).
  • Toluenesulfonyl chloride (11.5 g, 0.060 mole) was added in portions, and the solution was stirred at rt for 6 hours. The solution was stripped down to dryness, and the crude product was taken into ethyl acetate (150 mL) and 5% NaHCO 3 aq. solution (150 mL). The upper organic was washed with water (150 mL), concentrated, azeotroped with ethyl acetate (250 mL x2) to a volume of - 50 mL. The slurry was diluted with heptane (50 mL), stirred at room temperature overnight, and then at 5 °C for 8 hours.
  • Example 42D The product from Example 42D (160 mg, 0.5 mmol), 4-cyanophenylboronic acid (0.75 mmol), and dichlorobis(triphenylphosphine) palladium (II) (35.1 mg, 0.05 mmol) were combined in isopropyl alcohol (5.0 mL) and 0.2 M K 3 PO 4 aq. solution (5.0 mL, 1.0 mmol) and heated at 60 °C for 24 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (20 mL).
  • Example 49 6-(3,5-difluorophenyl)-2- ⁇ 2-r(2R)-2-methyl-1-pyrrolidinvnethyl)quinoline
  • the title compound was prepared using the procedure described in Example 42E substituting 3,5-difluorophenylboronic acid for 4-cyanophenylboronic acid.
  • Example 50 (3-fluorophenyl)(2- ⁇ 2-[(2R)-2-methyl-1-pyrrolidinv ⁇ ethyl)-6-quinolinyl)methanone
  • the product from Example 42D (320 mg, 1.0 mmol) in THF (10 mL) was treated with 2.5M n-butyllithium (0.5 mL, 1.25 mmol) at -78 °C.
  • the solution was mixed for 15 min, and treated with a solution of 3-fluoro-N-methoxy-N- methylbenzamide (2.0 mmol) in THF (5.0 mL) at -78 °C.
  • Tetrakis(triphenylphosphine) palladium (0) 28.8 mg, 0.025 mmol
  • 2- (dicyclohexylphosphino)biphenyl 35.0 mg, 0.10 mmol
  • 3-pyridinylboronic acid (0.375 mmol)
  • sodium carbonate 40.0 mg, 0.375 mmol
  • the mixture was then treated with the product from Example 42D (80 mg, 0.25 mmol) and heated at 80°C for 24 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (20 mL).
  • Example 52A ethyl (6-bromo-1 -oxo-2, 3-dihydro-1 /-/-inden-2-yl)acetate
  • n-Butyllithium 14 mL, 2 M in pentane
  • diisopropylamine 2.86 g, 28 mmol
  • tetrahydrofuran 60 mL
  • 6-bromo-1- indanone 4.8 g, 22.7 mmol
  • Example 52B (6-bromo-1 -hydroxy-2, 3-dihydro-1 -/-inden-2-yl)acetic acid
  • Example 52A The product from Example 52A in THF was treated with tert- butylaminoborane (1.18 g, 13.5 mmol) and heated at 40-45 °C for 2.5 hours.
  • the mixture was treated with sodium hydroxide solution (1.8 g in water, 40 mL) and heating was continued for 30 minutes.
  • the mixture was allowed to cool to room temperature and the aqueous layer was separated.
  • the organic layer was diluted with isopropyl acetate (40 mL) and water (40 mL) and combined with the aqueous layer.
  • the solution was cooled to 0 °C and the pH was adjusted to 2 by addition of concentrated hydrochloric acid.
  • the mixture was filtered and the fitler cake dried at room temperature.
  • the solid was slurried in dichloromethane (6 mL), refiltered, and redried to provide the title compound.
  • Example 52C methyl (5-bromo-1 H-inden-2-yl)acetate
  • the product from Example 52B (1.35 g, 5 mmol) in methanol (12 mL) was treated with concentrated sulfuric acid (2 mL) and heated to gentle reflux. After 2 hours, additional sulfuric acid was added (1 mL) and heating was continued for another 2 hours. The mixture was concentrated under vacuum and the residue was diluted with water (15 mL). The mixture was cooled to 10 °C, filtered, and the filter cake washed with water (5 mL) and dried to provide the title compound.
  • Example 52D 2-(5-bromo-1r-7-inden-2-yl)ethanol
  • the product from Example 52C (1.1 g, 4.1 mmol) in diethyl ether (5 mL) was added dropwise to a suspension of lithium aluminum hydride (0.125 g, 3.3 mmol) in diethyl ether (10 mL) maintaining the internal temperature below 10 °C.
  • the reaction mixture was diluted with diethyl ether (10 mL), cooled to 0 °C, and treated with saturated aqueous sodium sulfate dropwise.
  • Example 52E 2-(7-bromo-3-isoquinolinyl)ethanol The product from Example 52D (0.85 g, 3.5 mmol) in methanol (15 mL) at -
  • Example 52F 2-(7-bromo-3-isoquinolinyl)ethyl 4-methylbenzenesulfonate
  • the product from Example 52E (0.51 g, 2.0 mmol), tosyl chloride (0.68 g,
  • Example 52G 7-bromo-3- ⁇ 2-f(2R)-2-methyl-1-pyrrolidinyl1ethyl)isoquinoline
  • the product from Example 52F was dissolved in a solution of (2R)-2- methylpyrrolidine (0.26 g, 3.0 mmol) in acetonitrile (20 mL).
  • the solution was treated with potassium carbonate (0.5 g, 3.6 mmol) and heated at 50-55 °C for 20 hours in a sealed flask.
  • the mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated in vacuo.
  • the residue was diluted with MTBE (20 mL) and water (20 mL) and the pH was adjusted to 3-3.5 with concentrated HCI.
  • Example 52H 4-(3- ⁇ 2-[(2R)-2-methyl-1-pyrrolidinyllethyl>-7-isoquinolinyl)benzonitrile
  • the product from Example 52G (0.2 g, 0.6 mmol), 4-cyanophenylboronic acid (0.22 g, 1.5 mmol), bis(triphenylphosphine)palladium dichloride (55 mg, 0.08 mmol), and potassium phosphate (7 mL, 0.2 M in water) were combined in isopropanol (7 mL) and heated at 60-65 °C for 7 hours in a sealed flask.
  • the mixture was filtered through diatomaceous earth, the filtrate was concentrated in vacuo, and then partitioned between MTBE (10 mL) and water (10 mL).
  • the organic layer was separated, washed with aqueous sodium bicarbonate solution (5 %,10 mL), and then extracted with a solution of 2M HCI (15 mL).
  • the pH of the acidic aqueous layer was adjusted with base using potassium carbonate and extracted with isopropyl acetate (15 mL).
  • the organic layer was evaporated in vacuo and the residue was chased with heptane (10 mL) to provide the title compound.
  • (2R)-2-methyl-1-[2-(4-nitrophenyl)ethyllpyrrolidine (2R)-2-Methylpyrrolidine L-tartrate (4.0 g, 17.0 mmol), 1 -(2-bromoethyl)-4- nitrobenzene (9.8 g, 43 mmol), and potassium carbonate (12 g, 85 mmol), were combined in DMF (20 mL) in a sealed tube at 50°C and stirred vigorously for 16 hours. The mixture was allowed to cool to room temperature, diluted with diethyl ether (100 mL), washed with water (2 times, 100 mL and then 50 mL), and extracted with 1 M HCI (2 times, 50 mL and 25 mL).
  • aqueous acidic extractions were combined, washed with diethyl ether (50 mL), cooled to 0°C, adjusted to pH 14 with 50% NaOH solution, and extracted with dichloromethane (3 times, 50 mL). The dichloromethane extractions were combined, dried
  • Example 54C 2,2-dimethyl-N-(4-(2-[(2R)-2-methyl-1-pyrrolidinvnethyl ⁇ phenyl)propanamide
  • the product from Example 54B (2.77 g, 14 mmol) was dissolved in anhydrous dichloromethane (70 mL) under nitrogen, treated with triethylamine (2.3 mL, 16 mmol), cooled to 0°C, treated with trimethylacetyl chloride (1.9 mL, 15 mmol), stirred at ambient temperature for 60 hours and treated with 1 M NaOH (40 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 times, 40 mL).
  • Example 54E 2-amino-5- ⁇ 2-f(2R)-2-methyl-1-pyrrolidinv ⁇ ethyl)benzaldehvde
  • 3M HCI 40 mL
  • the product from Example 54D (2.46 g, 7.8 mmol) in 3M HCI (40 mL) was heated at 80°C for 4 hours, allowed to cool to room temperature, and carefully poured into a mixture of 1M NaOH (250 mL) and dichloromethane (75 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 times, 75 mL). The combined dichloromethane layers were dried (MgSO ), filtered, and the filtrate was concentrated.
  • Example 54F 6- ⁇ 2-r(2R)-2-methyl-1-pyrrolidinv ⁇ ethyl)-2-(3-pyridinyl)quinoline
  • the product from Example 54E (32.5 mg, 0.14 mmol) and 3-acetylpyridine (17 mg, 0.14 mmol) were combined in ethanol (2 mL) and treated with one drop of a saturated solution of potassium hydroxide in ethanol and heated at 80 °C for 16 hours. The mixture was allowed to cool to room temperature and concentrated. The residue was purified by chromatography on silica gel eluting with a gradient 10:1 :1 to 6:1 :1 to 4:1:1 ethyl acetate:formic acid:water.
  • Example 55 6-(2-[(2R)-2-methyl-1-pyrrolidinvnethyl)-2-(4-pyridinyl)quinoline
  • the title compound was prepared using the procedure described in Example 54F substituting 4-acetylpyridine acid for 3-acetylpyridine.
  • Example 56 6- ⁇ 2-r(2R)-2-methyl-1-pyrrolidinyllethyl)-2-(2-pyridinyl)quinoline
  • the title compound was prepared using the procedure described in Example 54F substituting 2-acetylpyridine acid for 3-acetylpyridine.
  • Example 57 6- ⁇ 2-r(2R)-2-methyl-1-pyrrolidinyllethyl)-2-(1 ,3-thiazol-2-yl)quinoline
  • the product from Example 54E (46 mg, 0.20 mmol) and 1-(1 ,3-thiazol-2- yl)ethanone (52 mg, 0.41 mmol) were combined in ethanol 0.4 mLand treated with one drop of a saturated solution of potassium hydroxide in ethanol and heated at 80 °C for 16 hours. The mixture was allowed to cool to room temperature and concentrated.
  • Example 60 1-r6-(6- ⁇ 2-r(2R)-2-methyl-1-pyrrolidinyllethyl)-2-quinolinyl)-2-pyridinyllethanone
  • the title compound was prepared using the procedure described in Example 57 substituting 2,6-diacetylpyridine for 1-(1 ,3-thiazol-2-yl)ethanone.
  • Example 61 4-(2- ⁇ 2-[(2R)-2-methyl-1-pyrrolidinv ⁇ ethyl ⁇ -6-quinoxalinyl)benzonitrile and 4-(3-(2-[(2R)-2-methyl-1-pyrrolidinyllethyl ⁇ -6-quinoxalinyl)benzonitrile
  • Example 61A 4-bromo-1 ,2-benzenediamine 4-Bromo-2-nitroaniline (10 g, 46 mmol) in THF (120 mL) was treated with 1% Pt/C (1.0 g) and hydrogenated at room temperature under 40 psi of H 2 pressure. After 2 hours, the reaction was filtered and the filtrate concentrated to provide the title compound which was used without further purification in the next step.
  • MS 188 (M+H) + ; 1 H NMR (400 MHz, CDCI 3 ) ⁇ 6.77-6.81 (m, 2H), 6.54 (d, J 8.4Hz, 1 H), 3.28 (br, 4H).
  • Example 61 B 7-bromo-2-methylquinoxaline and 6-bromo-2-methylquinoxaline
  • the product from Example 61 A (9.4g, 50 mmol) in acetonitrile (100 mL) was treated with 40% aqueous pyruvic aldehyde (11.0 mL, 60 mmol) dropwise. After stirring at room temperature for 2 hours, the mixture was concentrated and the residue was suspended in IPAc (100 mL) and filtered. The filtrate was washed with 20% brine, dried with Na 2 SO 4 , filtered, and the filtrate was concentrated.
  • (2R)-2-Methylpyrrolidine hydrochloride 5 (973 mg, 8.0 mmol) and 37% aqueous solution of formaldehyde (0.57 mL, 7.0 mmol) were combined in EtOH (20 mL) ' and heated in a sealed tube at 85 °C for 1 hour. The mixture was allowed to cool to room temperature, treated with the products from Example 61 C (500 mg, 2.0 mmol), and heated at 85 °C overnight. The mixture was allowed to cool to room and concentrated to dryness under vacuum. The residue was partitioned between IPAc (50 mL) and 20% brine (40 mL). The organic layer was separated, dried with Na 2 S0 , filtered, and the filtrate was concentrated under vacuum.
  • Example 62A methyl 5-bromo-2-iodobenzoate To a stirred slurry of methyl 2-iodo-benzoate ( 5.0 g, 0.019 mol) and N- bromosuccinimide (3.74 g, 0.021 mol) in acetic acid (10 mL) was added concentrated H 2 SO 4 (10 mL) dropwise, keeping the temperature at 20-40 °C. The mixture was stirred at room temperature for 88 hours and then heated at 50 °C for 4 hours. The mixture was cooled to 10 °C, treated with 40 g of ice water, and extracted with 50 mL of CH 2 CI 2 .
  • Example 62B (5-bromo-2-iodophenyl)methanol To a stirred mixture of NaBH 4 (11.18 g, 0.296 mol) in EtOH (200 mL) at 5
  • Example 62A was added the product from Example 62A (50.4 g, 0.148 mol) in THF (100 mL). The mixture was alowed to warm to room temperature and stirred for 18 hours. The mixture was treated with additional NaBH 4 (8.4 g, 0.222 mol) and was stirred for 22 hours. The mixture was cooled to 0 °C, treated with 100 mL of 15 % aqueous citric acid slowly, and extracted with 600 mL of CH 2 CI 2 . The organic phase was washed with 200 mL of 15 % NaCI and concentrated to provide the title compound.
  • Example 62C 5-bromo-2-iodobenzaldehyde A solution of oxalyl chloride (1.53 g, 0.012 mol) in CH 2 CI 2 (15 mL) was cooled to -70 °C, and DMSO (1.41 g, 0.018 mol) in CH 2 CI 2 (15 mL) was added at -65 to -70 °C. The mixture was stirred under nitrogen for 10 minutes at -70 °C and then treated with the product from Example 62B (2.35 g, 7.5 mmol) in 60 mL CH 2 CI 2 .
  • Example 62C The product from Example 62C (2.28 g, 7.3 mmol) in THF (10 mL) was treated with t-butylamine (1.61 g, 22.0 mmol) and stirred under nitrogen at room temperature for 40 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in 30 mL of methylene chloride. The methylene chloride was washed with 10 mL water and concentrated to provide the title compound which was used in the next step without further purification.
  • Example 62F 7-bromo-3-(2-r(2R)-2-methyl-1-pyrrolidinyllethyl ⁇ isoquinoline
  • the product from Example 62E 0.5 g, 2.0 mmol
  • triethylamine 0.5 g, 4.9 mmol
  • the mixture was treated with methanesulfonyl chloride (0.24 g, 2.1 mmol) and stirred at 0-10 °C for 2 hours.
  • the mixture was treated with additional methanesulfonyl chloride (0.2 mmol) and stirred at room temperature for 16 hours.
  • the mixture was treated with a solution of Na 2 C0 3 (0.15 g, 1.4 mmol, in 5 mL water) and heated at 65 °C for 16 hours. After cooling to room temperature, the mixture was diluted with 20 mL of CH 2 CI 2 and filtered. The filtrate was washed with 10 mL of 15% NaCI and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10:90:1 MeOH:CHCI 3 :Et 3 N) to provide the title compound.
  • Example 62E The product from Example 62E (0.3 g, 1.2 mmol), 3-pyridineboronic acid (0.22 g, 1.8 mmol), 2-(dicyclohexylphosphino)biphenyl (80 mg, 0.2 mmol), and PdCl 2 (PPh3)2 (80 mg, 0.1 mmol) were combined in isopropanol (15 mL) and treated with a solution of Na 2 C ⁇ 3 (0.19 g, 1.8 mmol) in water (5 mL) and heated at 65 °C for 16 hours. After cooling to room temperature, the mixture was diluted with 20 mL of CH 2 CI 2 and filtered. The filtrate was washed with 10 ml 15% NaCI and concentrated under reduced pressure.
  • Example 57 substituting 1-(benzyloxy)acetone for 1-(1 ,3-thiazol-2-yl)ethanone.
  • Example 65 2-cvclopropyl-6- ⁇ 2-f(2R)-2-methyl-1-pyrrolidinvnethyl)quinoline The title compound was prepared using the procedure described in Example 57 substituting 1-cyclopropylethanone for 1-(1 ,3-thiazol-2-yl)ethanone.
  • Example 66 4-(6-(2-r(2R)-2-methyl-1-pyrrolidinyllethyl ⁇ -2-quinolinyl)benzonitrile The title compound was prepared using the procedure described in Example 57 substituting 4-acetylbenzonitrile for 1-(1 ,3-thiazol-2-yl)ethanone.
  • Example 67 2,6-dimethyl-5-(6- ⁇ 2-r(2R)-2-methyl-1-pyrrolidinvnethyl)-2-quinolinyl)nicotinonitrile
  • the title compound was prepared using the procedure described in Example 57 substituting 5-acetyl-2,6-dimethylnicotinonitrile for 1-(1 ,3-thiazol-2- yl)ethanone.
  • Example 69 ethyl 5-(6-(2-r(2R)-2-methyl-1-pyrrolidinyllethyl ⁇ -2-quinolinyl)-3- isoxazolecarboxylate
  • the title compound was prepared using the procedure described in Example 57 substituting ethyl 5-acetyl-3-isoxazolecarboxylate for 1-(1 ,3-thiazol-2- yl)ethanone.
  • Example 70 5-(6- ⁇ 2-[(2R)-2-methyl-1-pyrrolidinvnethyl ⁇ -2-quinolinyl)-2-thiophenecarbonitrile The title compound was prepared as the major product using the procedure described in Example 57 substituting 5-acetyl-2-thiophenecarbonitrile for 1-(1 ,3- thiazol-2-yl)ethanone.
  • Example 72 2-(2,4-dimethyl-1 ,3-oxazol-5-yl)-6-(2-r(2R)-2-methyl-1-pyrrolidinvilethyl)quinoline
  • the title compound was prepared using the procedure described in Example 57 substituting 1-(2,4-dimethyl-1 ,3-oxazol-5-yl)ethanone for 1-(1 ,3- thiazol-2-yl)ethanone.
  • Example 57 substituting ethyl 5-acetyl-3-methyl-4-isoxazolecarboxylate for 1-(1 ,3- thiazol-2-yl)ethanone.
  • 1 H NMR 300 MHz, CD 3 OD
  • Example 74A 4-(7-bromo-3-isoquinolinyl)benzonitrile
  • the product from Example 62D (3.6 mmol), 4-cyanophenylacetylene (4.3 mmol), Cul (0.2 mmol), PdCI 2 (PPh 3 ) 2 (0.1 mmol), and diisopropylamine (5.3 mmol) can be combined in toluene (15 mL) and processed as described in Example 62E to provide the title compound.
  • Example 74B The product from Example 74B, methanesulfonyl chloride, and (2R)-2- methylpyrrolidine hydrochloride are processed as described in Example 62F to provide the title compound.
  • Example 75A The product from Example 75A (0.58 g, 2.4 mmol) in acetic anhydride (2.2 mL) and concentrated sulfuric acid (0.16 mL) was cooled to 0 °C and treated dropwise with 90 % nitric acid (0.115 mL, 2.4 mmol). After stirring at ambient temperature for 16 hours, the mixture was diluted with water, cooled to 0 °C, the
  • Example 75C 4- ⁇ 2-[(2R)-2-methyl-1-pyrrolidinyllethyl)-2-nitroaniline
  • the product from Example 75B (0.60 g, 2.1 mmol) in 3M HCI (12 mL) was heated at 80 °C for 2 hours, cooled to 0 °C, the pH was adjusted by the slow addition of 1 M NaOH, and extracted with dichloromethane (4 times). The combined dichloromethane layers were dried (MgS0 ), filtered, and the filtrate was concentrated to provide the title compound.
  • Example 75D 4-(2-[(2R)-2-methyl-1 -pyrrolidinyllethylj-l ,2-benzenediamine The title compound was prepared using the procedure described in
  • Example 54B substituting the product from Example 75C for the product from Example 54A to provide the title compound.
  • Example 75D The product from Example 75D (14.6 mg, 0.067 mmol) was treated with 0.075 mL of a 1 M solution of glyoxal in ethanol (made by diluting 0.4 g of a 40 % weight solution of glyoxal in water with ethanol to a total volume of 6.9 mL) and heated at 80 °C for 16 hours. The mixture was allowed to cool to room temperature and concentrated. The residue was chromatographed on silica gel eluting with a gradient of 2% and 3.5% (9:1 MeOH:conc NH 4 OH) in dichloromethane to provide the title compound.
  • Example 75E 7-f2-f(2R)-2-Methyl-1-pyrrolidinyllethyl)-2-(4-methoxyphenyl)quinoxaline
  • the product from Example 75D and oxo(4-methoxyphenyl)acetaldehyde (chemical abstracts number 16208-17-6) is processed as described in Example 75E to provide the title compounds.
  • Example 75D The product from Example 75D and oxo(phenyl)acetaldehyde is processed as described in Example 75E to provide the title compounds.
  • Example 77 6- ⁇ 2-r(2R)-2-methyl-1-pyrrolidinvnethyl)-2-(3-pyridinyl)quinazoline
  • N-(2-formyl-4-(2-f(2R)-2-methyl-1-pyrrolidinv ⁇ ethyl)phenyl)nicotinamide The product from Example 54E (35 mg, 0.15 mmol) and triethylamine (0.051 rtiL, 0.36 mmol) were combined in dichloromethane (0.5 mL) and treated with nicotinoyl chloride hydrochloride (30 mg, 0.17 mmol). After stirring at ambient temperature for 16 hours, the mixture was concentrated and the residue purified by chromatography on silica gel eluting with a gradient of 2% and 3.5% (9:1 MeOH:conc NH 4 OH) in dichloromethane to provide the title compound.
  • Example 77A The product from Example 77A (25 mg, 0.074 mmol) in saturated aqueous ammonium chloride (3 mL) was heated at 80 °C for 16 hours. The mixture was allowed to cool to room temperature, adjusted to pH 14 with 1 M NaOH, and extracted with dichloromethane (3 times). The combined dichloromethane layers were dried (MgSO4), filtered, and the filtrate was concentrated. The residue was purified by chromatography on silica gel eluting with a gradient of 2% and 3.5% (9:1 MeOH onc NH 4 OH) in dichloromethane to provide the title compound.
  • Example 78 6-Methyl-2- ⁇ 6-r2-((2R)-2-methyl-pyrrolidin-1-yl)-ethvn-naphthalen-2-yl)-2H- pyridazin-3-one
  • the title compound was prepared by the method of Example 31 F, substituting 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-(2R)-2-methyl-pyrrolidine (Example 2B, 60 mg, 0.19 mmol) in place of 2-(6-bromo-naphthalen-2-yl)-ethanol (Example 31 E) and substituting 6-methyl-2H-pyridazin-3-one (41.5 mg, 0.38 mmol, 2 equiv.) in place of 2H-pyridazin-3-one.
  • Example 79C 5-[6-(2-Hvdroxy-ethyl)-naphthalen-2-yll-pyrimidine-2-carbonitrile A mixture of 5-trimethylstannanyl-pyrimidine-2-carbonitrile (Example 79B,
  • Example 79D 5- ⁇ 6-f2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethvn-naphthalen-2-ylVpyrimidine-2- carbonitrile
  • the title compound was prepared by the methods of Examples 3B and 3C substituting 5-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-pyrimidine-2-carbonitrile (Example 79C, 35.5 mg, 0.13 mmol) in place of 1- ⁇ 3-[6-(2-hydroxyethyl)-2- naphthyl]phenyl ⁇ ethanone (Example 3A) for the mesylate formation and substituting the crude mesylate thus formed (-45 mg, 0.13 mmol) in place of 2-[6- (3-acetylphenyl)-2-naphthyl]ethyl methanesulfonate (Example 3B).
  • Example 80A 1 -r6-(2-Hvdroxy-ethyl)-naphthalen-2-v ⁇ -1 /- -pyridin-2-one A mixture of 2-(6-bromo-naphthalen-2-yl)-ethanol (Example 31 E, 100 mg,
  • Example 80B 1-f6-T2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyll-naphthalen-2-yl>-1H-pyridin-2-one Methanesulfonyl chloride (0. 01 mL, 0.136 mmol, 1.2 equiv.) was added dropwise via a syringe to a stirred, -30 °C solution of 1-[6-(2-hydroxy-ethyl)- na ⁇ hthalen-2-yl]-1H-pyridin-2-one (Example 80A, 30 mg, 0.113 mmol) and Et 3 N (0.024 mL, 0.17 mmol, 1.5 equiv.).
  • Example 81 B Methanesulfonic acid 2-f6-(5-cyano-pyridin-3-yl)-naphthalen-2-yl]-ethyl ester Methanesulfonyl chloride (0.056 mL, 0.726 mmol, 1.2 equiv.) was added to a stirred, -30 °C solution of 5-[6-(2-hydroxy-ethyl)-naphthalen-2-yl]-nicotinonitrile (Example 81 A, 190 mg, 0.539 mmol) under a dry nitrogen atmosphere.
  • Triethylamine (0.13 mL, 0.908 mmol, 1.5 equiv.) was added dropwise to the chilled solution, then the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous Na 2 C0 3 . The organic layer was dried (MgS ⁇ 4) and filtered. The filtrate was concentrated under reduced pressure to give the title intermediate (192 mg, 90% yield).
  • Methanesulfonic acid 2-[6-(5-cyano-pyridin-3-yl)-naphthalen-2-yl]-ethyl ester (Example 81 B, 190 mg, 0.54 mmol), (2R)-2-methylpyrrolidine (138 mg, 1.62 mmol, 3.0 equiv.), and cesium carbonate (176 mg, 0.54 mmol) in anhydrous acetonitrile (6 mL) were stirred in a sealed tube at 50 °C for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous Na 2 C0 3 .

Abstract

Les composés correspondant à la formule (I) sont utiles pour traiter des états ou troubles dont la prévention ou l'amélioration est possible grâce aux ligands des récepteurs de l'histamine-3. Elle concerne aussi des compositions pharmaceutiques comprenant des ligands des récepteurs de l'histamine-3, des procédés pour utiliser ces composés et compositions et un procédé pour préparer ces composés dans le cadre de la formule (I).
EP03768721A 2002-11-12 2003-11-05 Amines bicycliques substituees utilisees comme ligands des recepteurs de l'histamine-3 Withdrawn EP1569637A1 (fr)

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US292422 1999-04-15
US10/292,422 US20040092521A1 (en) 2002-11-12 2002-11-12 Bicyclic-substituted amines as histamine-3 receptor ligands
US689735 2003-10-22
US10/689,735 US7153889B2 (en) 2002-11-12 2003-10-22 Bicyclic-substituted amines as histamine-3 receptor ligands
PCT/US2003/035365 WO2004043458A1 (fr) 2002-11-12 2003-11-05 Amines bicycliques substituees utilisees comme ligands des recepteurs de l'histamine-3

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JP4820094B2 (ja) 2011-11-24
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TW200418454A (en) 2004-10-01
PL376751A1 (pl) 2006-01-09
AU2003291329A1 (en) 2004-06-03
CA2505427C (fr) 2012-04-03
JP2011063594A (ja) 2011-03-31
MXPA05005116A (es) 2005-07-01
CA2765093A1 (fr) 2004-05-27
JP2006514926A (ja) 2006-05-18
WO2004043458A1 (fr) 2004-05-27

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