Tri- and bi-cyclic heteroaryl histamine-3 receptor ligands (2025)

U.S. patent number 7,205,316 [Application Number 11/123,324] was granted by the patent office on 2007-04-17 for tri- and bi-cyclic heteroaryl histamine-3 receptor ligands. This patent grant is currently assigned to Abbott Laboratories. Invention is credited to Robert J. Altenbach, Lawrence A. Black, Marlon D. Cowart, Huaqing Liu.

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Tri- and bi-cyclic heteroaryl histamine-3 receptor ligands

Abstract

Compounds of formula (I) ##STR00001## wherein R.sub.1 or R.sub.2is a tricyclic or bicyclic ring, each of which contains at leasttwo heteroatoms, and R.sub.1, R.sub.2, R.sub.3, R.sub.3a, R.sub.3b,R.sub.4, R.sub.5, L, X, X', Y, Y', Z, and Z' are as defined herein,are useful in treating conditions or disorders prevented by orameliorated by histamine-3 receptor ligands. Also disclosed arepharmaceutical compositions comprising the histamine-3 receptorligands, methods for using such compounds and compositions, and aprocess for preparing compounds within the scope of formula(I).

Prior Publication Data

Related U.S. Patent Documents

References Cited [Referenced By]

U.S. Patent Documents

Foreign Patent Documents

Other References

Primary Examiner: McKane; Joseph K.
Assistant Examiner: Kosack; Joseph R.
Attorney, Agent or Firm: Chen; Portia

Parent Case Text

This application claims priority to U.S. Provisional ApplicationNo. 60/570,397 filed on May 12, 2004, the complete disclosure ofwhich is herein incorporated by reference.

Claims

What is claimed is:

1. A compound of the formula: ##STR00037## or a pharmaceuticallyacceptable salt, ester, amide, or prodrug thereof, wherein: Y' isCH or CF; X, X', Z, and Z' are each; R.sub.1 is L.sub.2R.sub.6;R.sub.2 is selected from the group consisting of hydrogen, alkyl,alkoxy, aryl, cycloalkyl, halogen, cyano, and thioalkoxy; R.sub.3is selected from the group consisting of hydrogen, alkyl, alkoxy,halogen, cyano, and thioalkoxy; R.sub.3a is selected from the groupconsisting of hydrogen, methyl, alkoxy, halogen, and cyano;R.sub.3b is selected from the group consisting of hydrogen, alkyl,alkoxy, halogen, hydroxy, cyano, and thioalkoxy; R.sub.4 andR.sub.5 are each independently selected from the group consistingof alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, and (NR.sub.AR.sub.B)alkyl, wherein R.sub.A andR.sub.B are each independently selected from the group consistingof hydrogen, alkyl, acyl, and formyl; or R.sub.4 and R.sub.5 takentogether with the nitrogen atom to which each is attached form anon-aromatic ring of the formula: ##STR00038## R.sub.6 is abicyclic or tricyclic ring, each containing at least twoheteroatoms; R.sub.7, R.sub.8, R.sub.9, and R.sub.10 at eachoccurrence are each independently selected from the groupconsisting of hydrogen, hydroxyalkyl, fluoroalkyl, and alkyl; orone of the pair R.sub.7 and R.sub.8 or the pair R.sub.9 andR.sub.10 is taken together to form a C.sub.3 C.sub.6 ring, wherein0, 1, or 2 heteroatoms selected from O, N, or S replace a carbonatom in the ring; R.sub.11, R.sub.12, R.sub.13, and R.sub.14 areeach independently selected from the group consisting of hydrogen,hydroxy, hydroxyalkyl, alkyl, and fluoro; Q is selected from thegroup consisting of a bond, O, S, and NR.sub.15; L is--[C(R.sub.16)(R.sub.17)].sub.n--; L.sub.2 is a bond; R.sub.15 isselected from the group consisting of hydrogen, alkyl, acyl,alkoxycarbonyl, amido, and formyl; R.sub.16 and R.sub.17 at eachoccurrence are independently selected from the group consisting ofhydrogen, alkyl, alkoxy, and fluoro; R.sub.18 and R.sub.19 at eachoccurrence are each independently selected from the groupconsisting of hydrogen, hydroxy, alkyl, alkoxy, and fluoro; R.sub.xand R.sub.y at each occurrence are independently selected from thegroup consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylamino,dialkylamino, and fluoro, or one of R.sub.x or R.sub.y represents acovalent bond when taken together with R.sub.x or R.sub.y on anadjacent carbon atom such that a double bond is represented betweenthe adjacent carbon atoms; m is an integer from 1 to 5; n is aninteger from 1 to 6; p is an integer from 2 to 6; and q is aninteger from 1 to 4.

2. The compound of claim 1, wherein R.sub.1 is L.sub.2R.sub.6,L.sub.2 is a bond, and R.sub.6 is an aromatic or non-aromatic 5- to6-membered ring fused to an aromatic or non-aromatic 5- to10-membered ring, provided that the fused ring system contains atleast two heteroatoms.

3. The compound of claim 1, wherein R.sub.1 is L.sub.2R.sub.6,L.sub.2 is a bond, and R.sub.6 is selected from the groupconsisting of 4H-thieno[3,2-b]pyrrolyl;benzo[4,5]imidazo[2,1-b]thiazolyl;2-methyl-imidazo[1,2-a]pyridinyl; 4H-benzo[1,3]dioxinyl;[1,2,4]triazolo[1,5-a]pyrimidinyl; benzothiazolyl; benzotriazolyl;[1,3]dioxolo[4,5-b]pyridinyl;6-methyl-thiazolo[3,2-b][1,2,4]triazolyl;2,3-dihydro-imidazo[2,1-b]thiazolyl;2,7-dimethyl-pyrazolo[1,5-a]pyrimidinyl; [1,8]naphthyridinyl; andquinoxalinyl.

4. The compound of claim 1, wherein R.sub.4 and R.sub.5 takentogether with the nitrogen atom to which each is attached form a 4-to 8-membered non-aromatic ring represented by formula (a).

5. The compound of claim 4, wherein at least one substituentrepresented by R.sub.7, R.sub.8, R.sub.9, and R.sub.10 is selectedfrom the group consisting of alkyl, fluoroalkyl, and hydroxyalkylor at least one substituent represented by R.sub.x or R.sub.y isselected from the group consisting of hydrogen, hydroxy, andfluoro.

6. The compound of claim 1, wherein R.sub.4 and R.sub.5 takentogether with the nitrogen atom to which each is attached to form2-methylpyrrolidine.

7. The compound of claim 1, selected from the group consisting of:6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-(4H-thieno[3,2-b]pyrrol-5-y-l)-quinoline;3-methyl-2-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-be-nzo[4,5]imidazo[2,1-b]thiazole;2-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1--yl)-ethyl]-quinoline;2-(4H-benzo[1,3]dioxin-6-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]--quinoline;6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-[1,2,4]triazolo[1-,5-a]pyrimidin-5-yl-quinoline;2-benzothiazol-2-yl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline-;2-[1,3]dioxolo[4,5-b]pyridin-6-yl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-e-thyl]-quinoline;6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-2-(6-methyl-thiazolo[3,2-b][1-,2,4]triazol-5-yl)-quinoline;2-(2,3-dihydro-imidazo[2,1-b]thiazol-6-yl)-6-{2-[(2R)-2-methyl-pyrrolidin--1-yl]-ethyl}-quinoline;2-(2,7-dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl)-6-{2-[(2R)-2-methyl-pyrrol-idin-1-yl]-ethyl}-quinoline;2-methyl-3-{6-[2-([2R]-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-[1-,8]naphthyridine; and6-{6-[2-([2R]-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-quinoxaline-.

8. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1 in combination with apharmaceutically acceptable carrier.

9. A method of treating Alzheimer's disease, attention-deficithyperactivity disorder, schizophrenia, or cognitive deficits ofschizophrenia comprising administering an effective amount of acompound of claim 1.

Description

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates to tricyclic and bicyclic heteroarylcompounds, compositions comprising such compounds, methods formaking the compounds, and methods of treating conditions anddisorders using such compounds and compositions.

2. Description of Related Technology

Histamine is a well-known modulator of neuronal activity. At leastfour types of histamine receptors have been reported in theliterature, typically referred to as histamine-1, histamine-2,histamine-3, and histamine-4. The class of histamine receptor knownas histamine-3 receptors is believed to play a role inneurotransmission in the central nervous system.

The histamine-3 (H.sub.3) receptor was first characterizedpharmacologically on histaminergic nerve terminals (Nature, 302:832837 (1983)), where it regulates the release of neurotransmitters inboth the central nervous system and peripheral organs, particularlythe lungs, cardiovascular system and gastrointestinal tract.H.sub.3 receptors are thought to be disposed presynaptically onhistaminergic nerve endings, and also on neurons possessing otheractivity, such as adrenergic, cholinergic, serotoninergic, anddopaminergic activity. The existence of H.sub.3 receptors has beenconfirmed by the development of selective H.sub.3 receptor agonistsand antagonists ((Nature, 327:117 123 (1987); Leurs and Timmerman,ed. "The History of H.sub.3 Receptor: a Target for New Drugs,"Elsevier (1998)).

The activity at the H.sub.3 receptors can be modified or regulatedby the administration of H.sub.3 receptor ligands. The ligands candemonstrate antagonist, agonist or partial agonist activity. Forexample, H.sub.3 receptors have been linked to conditions anddisorders related to memory and cognition processes, neurologicalprocesses, cardiovascular function, and regulation of blood sugar,among other systemic activities. Although various classes ofcompounds demonstrating H.sub.3 receptor-modulating activity exist,it would be beneficial to provide additional compoundsdemonstrating activity at the H.sub.3 receptors that can beincorporated into pharmaceutical compositions useful fortherapeutic methods.

SUMMARY OF THE INVENTION

One aspect of the invention relates to a compound of theformula:

##STR00002## or a pharmaceutically acceptable salt, ester, amide,or prodrug thereof, wherein:

Y, and Y' are each independently selected from the group consistingof CH, CF, and N;

X, X', Z, and Z' are each independently C or N;

one of R.sub.1 and R.sub.2 is selected from the group consisting ofL.sub.2R.sub.6;

the other of R.sub.1 and R.sub.2 is selected from the groupconsisting of hydrogen, alkyl, alkoxy, aryl, cycloalkyl, halogen,cyano, and thioalkoxy, provided that R.sub.2 is absent when Z' isN;

R.sub.3 is absent when X' is N or R.sub.3 is selected from thegroup consisting of hydrogen, alkyl, alkoxy, halogen, cyano, andthioalkoxy;

R.sub.3a is absent when Z is N or R.sub.3a is selected from thegroup consisting of hydrogen, methyl, alkoxy, halogen, andcyano;

R.sub.3b is absent when X is N or R.sub.3b is selected from thegroup consisting of hydrogen, alkyl, alkoxy, halogen, hydroxy,cyano, and thioalkoxy;

R.sub.4 and R.sub.5 are each independently selected from the groupconsisting of alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, and (NR.sub.AR.sub.B)alkyl, whereinR.sub.A and R.sub.B are each independently selected from the groupconsisting of hydrogen, alkyl, acyl, and formyl; or R.sub.4 andR.sub.5 taken together with the nitrogen atom to which each isattached form a non-aromatic ring of the formula:

##STR00003##

R.sub.6 is a bicyclic or tricyclic ring, each containing at leasttwo heteroatoms;

R.sub.7, R.sub.8, R.sub.9, and R.sub.10 at each occurrence are eachindependently selected from the group consisting of hydrogen,hydroxyalkyl, fluoroalkyl, and alkyl; or one of the pair R.sub.7and R.sub.8 or the pair R.sub.9 and R.sub.10 is taken together toform a C.sub.3 C.sub.6 ring, wherein 0, 1, or 2 heteroatomsselected from O, N, or S replace a carbon atom in the ring;

R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are each independentlyselected from the group consisting of hydrogen, hydroxy,hydroxyalkyl, alkyl, and fluoro;

Q is selected from the group consisting of a bond, O, S, andNR.sub.15;

L is --[C(R.sub.16)(R.sub.17)].sub.n-- or--[C(R.sub.16)(R.sub.17)].sub.pO--;

L.sub.2 is selected from the group consisting of a bond, --O--,--C(.dbd.O)--, --S--, --[C(R.sub.18)(R.sub.19)].sub.q--,--O--[C(R.sub.18)(R.sub.19)].sub.q--, --NH-- and --N(alkyl)--;

R.sub.15 is selected from the group consisting of hydrogen, alkyl,acyl, alkoxycarbonyl, amido, and formyl;

R.sub.16 and R.sub.17 at each occurrence are independently selectedfrom the group consisting of hydrogen, alkyl, alkoxy, andfluoro;

R.sub.18 and R.sub.19 at each occurrence are each independentlyselected from the group consisting of hydrogen, hydroxy, alkyl,alkoxy, and fluoro;

R.sub.x and R.sub.y at each occurrence are independently selectedfrom the group consisting of hydrogen, hydroxy, alkyl, alkoxy,alkylamino, dialkylamino, and fluoro, or one of R.sub.x or R.sub.yrepresents a covalent bond when taken together with R.sub.x orR.sub.y on an adjacent carbon atom such that a double bond isrepresented 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 1 or 2 of X, X', Y, Y', Z, and Z' is nitrogen; providedthat R.sub.3 is absent when X' is N; R.sub.3a is absent when Z isN; R.sub.2 is absent when Z' is N, and R.sub.3b is absent when X isN.

Another aspect of the invention relates to pharmaceuticalcompositions comprising compounds of the invention. Suchcompositions can be administered in accordance with a method of theinvention, typically as part of a therapeutic regimen for treatmentor prevention of conditions and disorders related to H.sub.3receptor activity.

Yet another aspect of the invention relates to a method ofselectively modulating H.sub.3 receptor activity. The method isuseful for treating and/or preventing conditions and disordersrelated to H.sub.3 receptor modulation in mammals. Moreparticularly, the method is useful for conditions and disordersrelated to memory and cognition processes, neurological processes,cardiovascular function, and body weight.

Processes for making compounds of the invention also arecontemplated.

The compounds, compositions comprising the compounds, methods formaking the compounds, and methods for treating or preventingconditions and disorders by administering the compounds are furtherdescribed herein.

DETAILED DESCRIPTION OF THE INVENTION

Definition of Terms

Certain terms as used in the specification are intended to refer tothe following definitions, as detailed below.

The term "acyl" as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, 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.

The term "acyloxy" as used herein, means an acyl group, as definedherein, appended to the parent molecular moiety through an oxygenatom. Representative examples of acyloxy include, but are notlimited to, acetyloxy, propionyloxy, and isobutyryloxy.

The term "alkenyl" as used herein, means a straight or branchedchain hydrocarbon containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of alkenyl include, but are notlimited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and3-decenyl.

The term "alkoxy" as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygenatom. Representative examples of alkoxy include, but are notlimited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, and hexyloxy.

The term "alkoxyalkoxy" as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety throughanother alkoxy group, as defined herein. Representative examples ofalkoxyalkoxy include, but are not limited to, tert-butoxymethoxy,2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.

The term "alkoxyalkyl" as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples ofalkoxyalkyl include, but are not limited to, tert-butoxymethyl,2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

The term "alkoxycarbonyl" as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term "alkoxyimino" as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through animino group, as defined herein. Representative examples ofalkoxyimino include, but are not limited to, ethoxy(imino)methyland methoxy(imino)methyl.

The term "alkoxysulfonyl" as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkoxysulfonyl include, but are not limited to, methoxysulfonyl,ethoxysulfonyl, and propoxysulfonyl.

The term "alkyl" as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,and n-decyl.

The term "alkylamino" as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through aNH group. Representative examples of alkylamino include, but arenot limited to, methylamino, ethylamino, isopropylamino, andbutylamino.

The term "alkylcarbonyl" as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, methylcarbonyl,ethylcarbonyl, isopropylcarbonyl, n-propylcarbonyl, and thelike.

The term "alkylsulfonyl" as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term "alkynyl" as used herein, means a straight or branchedchain hydrocarbon group containing from 2 to 10 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativeexamples of alkynyl include, but are not limited, to acetylenyl,1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term "amido" as used herein, means an amino, alkylamino, ordialkylamino group appended to the parent molecular moiety througha carbonyl group, as defined herein. Representative examples ofamido include, but are not limited to, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, andethylmethylaminocarbonyl.

The term "amino" as used herein, means a --NH.sub.2 group.

The term "aryl" as used herein, means a monocyclic aromatic ringsystem. Representative examples of aryl include, but are notlimited to, phenyl.

The 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.sub.AR.sub.B, and(NR.sub.AR.sub.B)sulfonyl.

The term "arylalkoxy" as used herein, means an aryl group, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples ofarylalkoxy include, but are not limited to, 2-phenylethoxy,3-naphth-2-ylpropoxy, and 5-phenylpentyloxy.

The term "arylalkoxycarbonyl" as used herein, means an arylalkoxygroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representativeexamples of arylalkoxycarbonyl include, but are not limited to,benzyloxycarbonyl.

The term "arylalkyl" as used herein, means an aryl group, asdefined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples ofarylalkyl include, but are not limited to, benzyl, 2-phenylethyland 3-phenylpropyl.

The term "carbonyl" as used herein, means a --C(.dbd.O)--group.

The term "carboxy" as used herein, means a --CO.sub.2H group, whichmay be protected as an ester group --CO.sub.2-alkyl.

The term "cyano" as used herein, means a --CN group.

The term "cycloalkenyl" as used herein, means a monocyclichydrocarbon containing from 3 to 8 carbons and containing at leastone carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of cycloalkenyl include, but arenot limited to, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,2,4-cyclohexadien-1-yl and 3-cyclopenten-1-yl.

The term "cycloalkyl" as used herein, means a saturated cyclichydrocarbon group containing from 3 to 8 carbons. Examples ofcycloalkyl 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.sub.AR.sub.B.

The term "cycloalkylalkyl" as used herein, means a cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examplesof cycloalkylalkyl include, but are not limited to,cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl,cyclohexylmethyl, and 4-cycloheptylbutyl.

The term "cycloalkylcarbonyl" as used herein, means a cycloalkylgroup, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representativeexamples of cycloalkylcarbonyl include, but are not limited to,cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, andcycloheptylcarbonyl.

The term "dialkylamino" as used herein, means two independent alkylgroups, as defined herein, appended to the parent molecular moietythrough a nitrogen atom. Representative examples of dialkylaminoinclude, but are not limited to, dimethylamino, diethylamino,ethylmethylamino, butylmethylamino.

The term "ethylenedioxy" as used herein, means a--O(CH.sub.2).sub.2O-- group wherein the oxygen atoms of theethylenedioxy group are attached to the parent molecular moietythrough one carbon atom forming a five-membered ring or the oxygenatoms of the ethylenedioxy group are attached to the parentmolecular moiety through two adjacent carbon atoms forming asix-membered ring.

The term "fluoro" as used herein means --F.

The term "fluoroalkyl" as used herein, means at least one fluorogroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative exampleof fluoroalkyl include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, and2,2,2-trifluoroethyl.

The term "formyl" as used herein, means a --C(O)H group.

The term "halo" or "halogen" as used herein, means Cl, Br, I, orF.

The term "haloalkoxy" as used herein, means at least one halogen,as defined herein, appended to the parent molecular moiety throughan alkoxy group, as defined herein. Representative examples ofhaloalkoxy include, but are not limited to, chloromethoxy,2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.

The term "haloalkyl" as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Representative examples ofhaloalkyl include, but are not limited to, chloromethyl,2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and2-chloro-3-fluoropentyl.

The term "heteroaryl," as used herein, refers to an aromatic five-or six-membered ring wherein 1, 2, 3, or 4 heteroatoms areindependently selected from nitrogen, oxygen, or sulfur, or atautomer thereof. Examples of such rings include, but are notlimited to, a ring wherein one carbon is replaced with an O or Satom; one, two, or three N atoms arranged in a suitable manner toprovide an aromatic ring, or a ring wherein two carbon atoms in thering are replaced with one O or S atom and one N atom. Theheteroaryl groups are connected to the parent molecular moietythrough a carbon or nitrogen atom. Representative examples ofheteroaryl include, but are not limited to, furyl, imidazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridazinonyl, pyridinyl, pyridinonyl,pyrimidinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienylor thiophenyl, triazinyl, and triazolyl.

The 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.sub.AR.sub.B, (NR.sub.AR.sub.B)carbonyl, and(NR.sub.AR.sub.B)sulfonyl.

The term "heterocycle," as used herein, refers to a three-, four-,five-, six-, seven-, or eight-membered monocyclic ring containingone, two, or three heteroatoms independently selected from thegroup consisting of nitrogen, oxygen, and sulfur. Rings containingat least four members can be saturated or unsaturated. For example,the four- and five-membered ring has zero or one double bond. Thesix-membered ring has zero, one, or two double bonds. The seven-andeight-membered rings have zero, one, two, or three double bonds.The heterocycle groups of the invention can be attached to theparent molecular moiety through a carbon atom or a nitrogen atom.Representative examples of nitrogen-containing heterocyclesinclude, but are not limited to, azepanyl, azetidinyl, aziridinyl,azocanyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl,pyrrolinyl, dihydrothiazolyl, and thiomorpholinyl. Representativeexamples of non-nitrogen containing heterocycles include, but arenot limited to, tetrahydrofuryl and tetrahydropyranyl.

The 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.sub.AR.sub.B, and (NR.sub.AR.sub.B)sulfonyl.

The term "hydroxy" as used herein means a --OH group.

The term "hydroxyalkyl" as used herein, means at least one hydroxygroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examplesof hydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-methyl-2-hydroxyethyl, 3-hydroxypropyl,2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

The term "hydroxy-protecting group" means a substituent whichprotects hydroxyl groups against undesirable reactions duringsynthetic procedures. Examples of hydroxy-protecting groupsinclude, but are not limited to, methoxymethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl,triphenylmethyl, 2,2,2-trichloroethyl, t-butyl, trimethylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, methylene acetal,acetonide benzylidene acetal, cyclic ortho esters,methoxymethylene, cyclic carbonates, and cyclic boronates.Hydroxy-protecting groups are appended onto hydroxy groups byreaction of the compound that contains the hydroxy group with abase, such as triethylamine, and a reagent selected from an alkylhalide, alkyl trifilate, trialkylsilyl halide, trialkylsilyltriflate, aryldialkylsilyltriflate, or an alkylchloroformate,CH.sub.2I.sub.2, or a dihaloboronate ester, for example withmethyliodide, benzyl iodide, triethylsilyltriflate, acetylchloride, benzylchloride, or dimethylcarbonate. A protecting groupalso may be appended onto a hydroxy group by reaction of thecompound that contains the hydroxy group with acid and an alkylacetal.

The term "imino" as defined herein means a --C(.dbd.NH)--group.

The term "mercapto" as used herein, means a --SH group.

The term "methylenedioxy" as used herein, means a --OCH.sub.2O--group wherein the oxygen atoms of the methylenedioxy are attachedto the parent molecular moiety through two adjacent carbonatoms.

The term "--NR.sub.AR.sub.B" as used herein, means two groups,R.sub.A and R.sub.B, which are appended to the parent molecularmoiety through a nitrogen atom. R.sub.A and R.sub.B areindependently selected from hydrogen, alkyl, acyl and formyl.Representative examples of --NR.sub.AR.sub.B include, but are notlimited to, amino, dimethylamino, methylamino, acetylamino, andacetylmethylamino.

The term "(NR.sub.AR.sub.B)alkyl" as used herein, means an--NR.sub.AR.sub.B group, as defined herein, appended to the parentmolecular moiety through an alkyl group, as defined herein.Representative examples of (NR.sub.AR.sub.B)alkyl include, but arenot limited to, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl,2-(amino)ethyl, 2-(ethylmethylamino)ethyl, and the like.

The term "(NR.sub.AR.sub.B)carbonyl" as used herein, means an--NR.sub.AR.sub.B group, as defined herein, appended to the parentmolecular moiety through a carbonyl group, as defined herein.Representative examples of NR.sub.AR.sub.B)carbonyl include, butare not limited to, aminocarbonyl, (methylamino)carbonyl,(dimethylamino)carbonyl, (ethylmethylamino)carbonyl, and thelike.

The term "(NR.sub.AR.sub.B)sulfonyl" as used herein, means a--NR.sub.AR.sub.B group, as defined herein, appended to the parentmolecular moiety through a sulfonyl group, as defined herein.Representative examples of (NR.sub.AR.sub.B)sulfonyl include, butare not limited to, aminosulfonyl, (methylamino)sulfonyl,(dimethylamino)sulfonyl and (ethylmethylamino)sulfonyl.

The term "nitro" as used herein means a --NO.sub.2 group.

The term "nitrogen protecting group" as used herein, means thosegroups intended to protect a nitrogen atom against undesirablereactions during synthetic procedures. Nitrogen protecting groupscomprise carbamates, amides, N-benzyl derivatives, and iminederivatives. Preferred nitrogen protecting groups are acetyl,benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl,pivaloyl, tert-butoxycarbonyl (Boc), tert-butylacetyl,trifluoroacetyl, and triphenylmethyl (trityl). Nitrogen-protectinggroups are appended onto primary or secondary amino groups byreacting the compound that contains the amine group with base, suchas triethylamine, and a reagent selected from an alkyl halide, analkyl trifilate, a dialkyl anhydride, for example as represented by(alkyl-O).sub.2C.dbd.O, a diaryl anhydride, for example asrepresented by (aryl-O).sub.2C.dbd.O, an acyl halide, analkylchloroformate, or an alkylsulfonylhalide, anarylsulfonylhalide, or halo-CON(alkyl).sub.2, for exampleacetylchloride, benzoylchloride, benzylbromide,benzyloxycarbonylchloride, formylfluoride, phenylsulfonylchloride,pivaloylchloride, (tert-butyl-O--C.dbd.O).sub.2O, trifluoroaceticanhydride, and triphenylmethylchloride.

The term "oxo" as used herein means (.dbd.O).

The term "bicyclic ring" as used herein, refers to a bicyclic aryl,as defined herein, a bicyclic heteroaryl, as defined herein, or abicyclic heterocycle, as defined herein.

The term "tricyclic ring" as used herein, refers to a tricyclicheteroaryl, as defined herein, or a tricyclic heterocycle, asdefined herein.

The bicyclic and tricyclic ring systems of the present inventionare substituted with 0, 1, 2, 3, or 4 substituents independentlyselected 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.sub.AR.sub.B,and (NR.sub.AR.sub.B)sulfonyl.

It is also contemplated that the nitrogen heteroatoms in themonocyclic, bicyclic and tricyclic ring systems can be optionallyquaternized or oxidized to the N-oxide. Also, the nitrogencontaining heterocyclic rings can be optionally N-protected.

The term "bicyclic aryl" as used herein, refers to a bicyclic fusedring system wherein a phenyl group is fused to a monocyclicheterocycle group, as defined herein. Representative examples ofbicyclic aryl groups include, but are not limited to,benzo[1,3]dioxolyl, and benzo[1,3]dioxinyl. The bicyclic arylgroups are connected to the parent moiety through any substitutablecarbon or nitrogen atoms of the group.

The term "bicyclic heteroaryl" as used herein, refers to a bicyclicfused ring system where a heteroaryl ring, as defined herein isfused to a phenyl group, a monocyclic cycloalkyl group, as definedherein, a monocyclic cycloalkenyl group, as defined herein, aheterocycle group, as defined herein, or an additional heteroarylgroup. The bicyclic heteroaryl groups are connected to the parentmolecular moiety through any substitutable carbon or nitrogen atomof the groups. Examples of bicyclic heteroaryl groups include, butare not limited to, benzothiazolyl, benzoxadiazolyl,benzotriazolyl, indazolyl, isothiazolyl, 4H-thieno[3,2,b]pyrrolyl,imidazo[1,2-a]pyridin-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-5-yl,[1,3]dioxolo[4,5-b]pyridin-6-yl,thiazolo[3,2-b][1,2,4]triazol-5-yl,2,3-dihydro-imidazo[2,1-b]thiazol-6-yl,pyrazolo[1,5-a]pyrimidin-6-yl, and naphthyridinyl.

The term "tricyclic heteroaryl" as used herein, refers to atricyclic fused ring system where a bicyclic heteroaryl, as definedherein, is fused to a phenyl group, a monocyclic cycloalkenylgroup, as defined herein, a monocyclic cycloalkyl group, as definedherein, a heterocycle group, as defined herein, or an additionalheteroaryl group. The tricyclic heteroaryl groups are connected tothe parent molecular moiety through any substitutable carbon ornitrogen atom of the groups. Examples of tricyclic heteroarylgroups include, but are not limited to,benzo[4,5]imidazo[2,1-b]thiazolyl.

The term "bicyclic heterocyle" as used herein, refers to a bicyclicfused ring system where a heterocycle ring is fused to a monocycliccycloalkenyl group, as defined herein, a monocyclic cycloalkylgroup, as defined herein, or an additional monocyclic heterocyclegroup, as defined herein. The bicyclic heterocycle groups areconnected to the parent molecular moiety through any substitutablecarbon or nitrogen atom of the groups. Representative examples ofbicyclic heterocycles include, but are not limited to,octahydro-pyrrolo[3,4-c]pyrrolyl; octahydro-pyrido[1,2-a]pyrazinyl;3-thioxo-hexahydro-pyrrolo[1,2-c]imidazol-1-one;tetrahydro-imidazo[4,5-d]imidazole-2,5-dione;hexahydro-pyrrolo[1,2-a]pyrazine-1,4-dione;hexahydro-pyrano[3,4-c]pyrrol-4-one;3-thioxo-hexahydro-pyrrolo[1,2-c]imidazol-1-one;decahydro-pyrazino[2,3-b]pyraziinyl;hexahydro-pyrido[1,2-a]pyrazin-1-one;hexahydro-furo[3,4-c]pyrrol-1-one;hexahydro-thieno[3,4-c]pyrrol-1-one; octahydro-benzoimidazol-2-one;hexahydro-pyrrolo[1,2-a]pyrazine-1,4-dione;octahydro-pyrrolo[3,4-b]pyridinyl;tetrahydro-[1,4]dithiino[2,3-c]pyrrole-5,7-dione;hexahydro-pyrrolo[1,2-c]imidazole-3-thione;hexahydro-pyrrolo[1,2-c]imidazole-3-thione;tetrahydro-thieno[3,4-d]imidazol-2-one; andoctahydro-pyrrolo[1,2-a]pyrazinyl.

The term "tricyclic heterocycle" as defined herein, refers to atricyclic fused ring system where a bicyclic heterocycle, asdefined herein, is fused to a monocyclic cycloalkenyl group, asdefined herein, a monocyclic cycloalkyl group, as defined herein,or an additional monocyclic heterocycle group, as defined herein.The tricyclic heterocycle groups are connected to the parentmolecular moiety through any substitutable carbon or nitrogen atomin the groups. Representative examples of tricyclic heterocyclesinclude, but are not limited to,hexahydro-1-oxa-2a,3-diaza-cyclopenta[cd]pentalen-2-one anddodecahydro-1,4,7,9b-tetraaza-phenalene.

The term "sulfonyl" as used herein means a --S(O).sub.2--group.

The term "thioalkoxy" as used herein means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfur atom. Representative examples of thioalkoxy include, but areno limited to, methylthio, ethylthio, and propylthio.

As used herein, the term "antagonist" encompasses and describescompounds that prevent receptor activation by an H.sub.3 receptoragonist alone, such as histamine, and also encompasses compoundsknown as "inverse agonists". Inverse agonists are compounds thatnot only prevent receptor activation by an H.sub.3 receptoragonist, such as histamine, but also inhibit intrinsic H.sub.3receptor activity.

Compounds of the Invention

Compounds of the invention can have the general formula (I) asdescribed above.

The invention also includes compounds having the formula (I)wherein Y and Y' are CH; X, X', and Z' are C; R.sub.2, R.sub.3, andR.sub.3b are hydrogen; Z is N; and R.sub.3a is absent.

In another embodiment, compounds of the invention can have formula(I) wherein Y is CH; X, X', Z, and Z' are C; R.sub.2, R.sub.3,R.sub.3a, and R.sub.3b are hydrogen; and Y' is N.

In yet another embodiment, compounds of the invention have formula(I) wherein Y and Y' are CH; X and Z' are C; R.sub.2 and R.sub.3bare hydrogen; X' is N; Z is N; and R.sub.3 and R.sub.3a areabsent.

Yet another embodiment relates to compounds of the invention havingthe formula (I) wherein X, X', Z, and Z' are C; R.sub.2, R.sub.3,R.sub.3a, and R.sub.3b are hydrogen; Y is N; and Y' is N.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y' is CH; X, X', and Z are C;R.sub.3, R.sub.3a, and R.sub.3b are hydrogen; Y is N; Z' is N; andR.sub.2 is absent.

Another embodiment relates to compounds of the invention having theformula (I) wherein Y' is CH; X, Z, and Z' are C; R.sub.2,R.sub.3a, and R.sub.3b are hydrogen; Y is N; X' is N; and R.sub.3is absent.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y' is CH; X, X', and Z' are C;R.sub.2, R.sub.3, and R.sub.3b are hydrogen; Y is N; Z is N; andR.sub.3a is absent.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y is CH; X, X', and Z are C;R.sub.3, R.sub.3a, and R.sub.3b are hydrogen; Y' is N; Z' is N; andR.sub.2 is absent.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y and Y' are CH; Z' and Z are C;R.sub.2 and R.sub.3a are hydrogen; X' is N; X is N; and R.sub.3 andR.sub.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.sub.2, R.sub.3, R.sub.3a, andR.sub.3b are hydrogen; and Y is N.

In yet another embodiment, compounds of the invention have formula(I) wherein Y and Y' are CH; X' and Z' are C; R.sub.2 and R.sub.3are hydrogen; X is N; Z is N; and R.sub.3a and R.sub.3b areabsent.

Still yet another embodiment relates to compounds of the inventionhaving the formula (I) wherein Y is CH; X, Z', and Z are C;R.sub.2, R.sub.3a, and R.sub.3b are hydrogen; Y' is N; X' is N; andR.sub.3 is absent.

Preferred compounds of the invention are those compounds of formula(I) wherein Y' is CH; X, X', Z and Z' are C; R.sub.2, R.sub.3,R.sub.3a, and R.sub.3b are hydrogen; and Y is N.

R.sub.1 can be any tricyclic or bicyclic ring attached eitherdirectly to the heteroaryl core or via a linker as defined byL.sub.2, wherein L.sub.2 is a bond, --O--, --C(.dbd.O)--, --S--,--[C(R.sub.18)(R.sub.19)].sub.q--,--O--[C(R.sub.18)(R.sub.19)].sub.q--, --NH-- and --N(alkyl)--.Suitably tricyclic and bicyclic rings contain at least twoheteroatoms. Preferred tricyclic and bicyclic rings have from twoto four heteroatoms. Preferably, compounds of the invention arethose wherein R.sub.1 is L.sub.2R.sub.6, L.sub.2 is --CH.sub.2-- ora bond, and R.sub.6 is an aromatic or non-aromatic 5- to 6-memberedring fused to an aromatic or non-aromatic 5- to 10-membered ring,provided that the fused system contains at least two heteroatoms.It is preferred that L.sub.2 is a bond.

Specific examples of R.sub.6 include, but are not limited to,4H-thieno[3,2-b]pyrrolyl; benzo[4,5]imidazo[2,1-b]thiazolyl;2-methyl-imidazo[1,2-a]pyridinyl; 4H-benzo[1,3]dioxinyl;[1,2,4]triazolo[1,5-a]pyrimidinyl; benzothiazolyl; benzotriazolyl;[1,3]dioxolo[4,5-b]pyridinyl;6-methyl-thiazolo[3,2-b][1,2,4]triazolyl;2,3-dihydro-imidazo[2,1-b]thiazolyl;2,7-dimethyl-pyrazolo[1,5-a]pyrimidinyl; [1,8]naphthyridinyl; andquinoxalinyl.

Other bicyclic and tricyclic rings suitable for R.sub.6 are:

##STR00004## ##STR00005## and the like. Such rings can be attachedto the parent molecular moiety through a group L.sub.2, aspreviously described, via any suitable carbon atom.

Preferably, R.sub.4 and R.sub.5 are taken together with thenitrogen atom to which each is attached form a 4- to 8-memberednon-aromatic ring represented by formula (a). The preferredcompounds of the invention are those wherein at least onesubstituent represented by R.sub.7, R.sub.8, R.sub.9, and R.sub.10is selected from the group consisting of alkyl, halogen,fluoroalkyl, and hydroxyalkyl or at least one substituentrepresented by R.sub.x or R.sub.y is selected from the groupconsisting of hydrogen, hydroxy, and fluoro. More preferably,R.sub.4 and R.sub.5 taken together with the nitrogen atom to whicheach is attached to form 2-methylpyrrolidine and, morespecifically, (2R)-methylpyrrolidine.

Specific compounds contemplated as part of the invention include,but are not limited to, for example:6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-(4H-thieno[3,2-b]pyrrol-5-y-l)-quinoline;3-methyl-2-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-be-nzo[4,5]imidazo[2,1-b]thiazole;2-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1--yl)-ethyl]-quinoline;2-(4H-benzo[1,3]dioxin-6-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]--quinoline;6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-2-[1,2,4]triazolo[1-,5-a]pyrimidin-5-yl-quinoline;2-benzothiazol-2-yl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline-;3-benzotriazol-1-ylmethyl-2-methyl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)--ethyl]-quinoline;2-[1,3]dioxolo[4,5-b]pyridin-6-yl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-et-hyl]-quinoline;6-{2-[(2R)-2-methyl-pyrrolidin-1-yl]-ethyl}-2-(6-methyl-thiazolo[3,2-b][1-,2,4]triazol-5-yl)-quinoline;2-(2,3-dihydro-imidazo[2,1-b]thiazol-6-yl)-6-{2-[(2R)-2-methyl-pyrrolidin--1-yl]-ethyl}-quinoline;2-(2,7-dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl)-6-{2-[(2R)-2-methyl-pyrrol-idin-1-yl]-ethyl}-quinoline;2-methyl-3-{6-[2-([2R]-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-[1-,8]naphthyridine;6-{6-[2-([2R]-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-quinoxaline-;6-(2-methyl-benzothiazol-5-yl)-2-[2-(2R-methyl-pyrrolidin-1-yl)-ethyl]-q-uinoline; and7-(2-methyl-benzothiazol-5-yl)-3-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-iso-quinoline.

Compounds of the invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are"R" or "S" depending on the configuration of substituents aroundthe chiral carbon atom. The terms "R" and "S" used herein areconfigurations as defined in IUPAC 1974 Recommendations for SectionE, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13 30.The invention contemplates various stereoisomers and mixturesthereof and these are specifically included within the scope ofthis invention. Stereoisomers include enantiomers anddiastereomers, and mixtures of enantiomers or diastereomers.Individual stereoisomers of compounds of the invention may beprepared synthetically from commercially available startingmaterials which contain asymmetric or chiral centers or bypreparation of racemic mixtures followed by resolution well-knownto those of ordinary skill in the art. These methods of resolutionare exemplified by (1) attachment of a mixture of enantiomers to achiral auxiliary, separation of the resulting mixture ofdiastereomers by recrystallization or chromatography and optionalliberation of the optically pure product from the auxiliary asdescribed in Furniss, Hannaford, Smith, and Tatchell, "Vogel'sTextbook 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 chiralchromatographic columns or (3) fractional recrystallizationmethods.

Methods for Preparing Compounds of the Invention

The compounds of the invention can be better understood inconnection with the following synthetic schemes and methods whichillustrate a means by which the compounds can be prepared.

Abbreviations which have been used in the descriptions of theschemes and the examples that follow are: Ac for acetyl; atm foratmosphere(s); BINAP for2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Boc forbutyloxycarbonyl; Bu for butyl; dba for dibenzylidene acetone; DCMfor dichloromethane; DMAP for 4-(N,N-dimethylamino)pyridine; DMFfor N,N-dimethylformamide; DMSO for dimethylsulfoxide; dppf for1,1'-bis(diphenylphosphino)ferrocene; Et for ethyl; EtOH forethanol; EtOAc for ethyl acetate; HPLC for high pressure liquidchromatography; IPA for isopropyl alcohol; IPAC or IPAc forisopropyl acetate; LAH for lithium aluminum hydride; LDA forlithium diisopropylamide; NBS for N-bromosuccinimide; NIS forN-iodosuccinimide; Me for methyl; MeOH for methanol; Ms formethanesulfonyl; MTBE for tert-butyl methyl ether; Pd forpalladium; tBu for tert-butyl; TBDMSCl for t-butyldimethylsilylchloride; TBDMSO for t-butyldimethylsilyl-O; TEA for triethylamine;TFA for trifluoroacetic acid; THF for tetrahydrofuran; TMEDA forN,N,N',N'-tetramethylethylenediamine; TfO for CF.sub.3S(O).sub.3--;and Ts for p-MePhS(O).sub.2--.

The compounds of this invention can be prepared by a variety ofsynthetic procedures. Representative procedures are shown in, butare not limited to, Schemes 1 27.

##STR00006##

Compounds of formula (7) and (9), wherein X, X', Y, Y', Z, Z',R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, and L.sub.2 are asdefined in formula (I), can be prepared as described in Scheme 1.Compounds of formula (1), wherein W is OH, Br, Cl, or I, purchasedor prepared using methodolgy known to those of ordinary skill inthe art, can be treated with lithium diisopropylamine and achloroformate such as, but not limited to, ethyl chloroformate toprovide esters of formula (2). Esters of formula (2) can be treatedwith a reducing agent such as, but not limited to, lithiumborohydride to provide alcohols of formula (3). Alcohols of formula(3) wherein W is Br, Cl, or I can be treated with a base such as,but not limited to, triethylamine and a sulfonating agent such as,but not limited to, methanesulfonyl chloride or p-toluensulfonylchloride to provide sulfonates of formula (4). Compounds of formula(3) wherein W is --OH can be converted to compounds of formula (4a)wherein W is triflate by reaction with triflic anhydride and a basesuch as, but not limited to, pyridine or triethylamine. Sulfonatesor triflates of formula (4) or (4a) can be treated with an optionalbase such as, but not limited to, potassium carbonate or sodiumcarbonate and an amine of formula (5) with or without heat toprovide amines of formula (6), wherein W is triflate, Br, Cl, orI.

The Suzuki reaction can be used to produce compounds of formula(7), wherein L.sub.2 is a bond, and X, X', Y, Y', Z, Z', R.sub.2,R.sub.3, R.sub.4, R.sub.6 and R.sub.5 are as defined for formula(I). In such a Suzuki reaction, compounds of formula (6) wherein Wis triflate, Br, Cl, or I are reacted with boronic acids of formula(14), as shown in Scheme 4 herein, wherein R.sub.94 is hydrogen, ametal catalyst, a base, and optionally with a Pd ligand added. Thereaction can be performed in a solvent such as, but is not limitedto, tetrahydrofuran, DMF, 1,4-dioxane and the like, at atemperature from about 20.degree. C. to about 120.degree. C.Examples of metal catalysts include, but are not limited to,palladium diacetate, Pd(PPh.sub.3).sub.4, Pd.sub.2(dba).sub.3,dichloro(di-tert-butylphosphinous acid) palladium (II) dimmer, andPdCl.sub.2(dppf). Examples of bases include, but are not limitedto, 0.2 M K.sub.3PO.sub.4, Cs.sub.2CO.sub.3, CsF, KF, andNa.sub.2CO.sub.3. Examples of palladium ligands include, but arenot limited to, (dicyclohexylphosphinyl)biphenyl,trifurylphosphine, tris(tert-butyl) phosphine, andtriphenylphosphine. Boronic acid esters of formula (14) whereinR.sub.94 is alkyl, and L.sub.2 is a bond can be used in place ofboronic acids in the aforesaid reaction. Boronic acids can beesterified to the corresponding boronic acid esters with alcoholssuch as methanol or with diols such as pinacol.

There are many aryl or heteroaryl boronic acids and boronic acidesters that are available commercially or that can be prepared asdescribed in the scientific literature of synthetic organicchemistry.

Alternatively, using the Stille coupling, compounds of formula (7)wherein L.sub.2 is a bond, and X, X', Y, Y', Z, Z', R.sub.2,R.sub.3, R.sub.4, R and R.sub.5, are as defined for formula (I),may be prepared from compounds of formula (6) wherein W istriflate, Cl, Br, or I, by treatment with aryl or heteroarylstannanes of formula (13), as shown in Scheme 4 herein, a palladiumsource such as tris(dibenzylidineacetone)dipalladium (CAS #52409-22-0) or palladium diacetate, and a ligand such astri(2-furyl)phosphine (CAS # 5518-52-5) or triphenyl arsine in asolvent, for example in DMF at a temperature from about 25.degree.C. to about 150.degree. C. While many organotin reagents for theStille coupling are commercially available or described in theliterature, new organotin reagents can be prepared fromarylhalides, aryltriflates, heteroarylhalides, heteroaryltriflatesby reaction with distannanes like (Me.sub.3Sn).sub.2 (hexamethyldistannane) in the presence of a palladium source likePd(Ph.sub.3P).sub.4. Such methods are described, for instance, inKrische, et. al., Helvetica Chimica Acta 81(11):1909 1920 (1998),and in Benaglia, et al., Tetrahedron Letters 38:4737 4740 (1997).These reagents can be reacted with (6) wherein W is triflate, Cl,Br, or I, to give (7) wherein L.sub.2 is a bond, and X, X', Y, Y',Z, Z', R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are asdefined in formula (I), as described under Stille conditions, orfor example under the conditions reported by Littke, Schwartz, andFu, Journal of the American Chemical Society 124:6343 6348(2002).

Alternatively, compounds of formula (7) wherein L.sub.2 is a bondor --[C(R.sub.18)(R.sub.19)].sub.q--, and X, X', Y, Y', Z, Z',R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined forformula (I), can be prepared according to the so called Negishicoupling by reaction of a compound of formula (6) wherein W is ahalide or triflate, with a compound of the formulahalide-zinc-L.sub.2R.sub.6. The catalyst may be selected from thosetypically employed for the reaction (for example,tetrakis(triphenylphosphine)palladium,tetrakis(triphenylphosphine)nickel,dichlorobis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium/n-butyl lithium,dichlorobis(1,1-bis(diphenylphosphino)ferrocene)palladium anddichlorobis(1,4-bis(diphenylphosphino)butane)palladium). Suitablesolvents include tetrahydrofuran, diethylether and dimethoxyethane.The reaction is typically carried out at a temperature from about20.degree. C. to about 160.degree. C., usually 20.degree. C. to130.degree. C. for 10 minutes to about 5 days, usually 30 minutesto about 15 hours. Alternatively, one skilled in the art willappreciate that the reactive groups of the reagents can bereversed. Thus one skilled in the art will appreciate that W in theaforesaid reaction can be the zinc halide coupled to anR.sub.6L.sub.2-halide or triflate. (Knochel, P. and Singer, R. D.Chem. Rev., 93, pages 2117 2188, 1993).

Compounds of formula (7) wherein L.sub.2 is a bond, R.sub.6 is aheterocycle, and X, X', Y, Y', Z, Z', R.sub.2, R.sub.3, R.sub.4 andR.sub.5 are as defined for formula (I), can be prepared by treatingcompounds of formula (6) wherein W is Br, or I, with anorganolithium reagent such as, but not limited to, n-butyllithium,sec-butyllithium or tert-butyllithium to provide a lithiumintermediate. This lithium intermediate can then be treated with aheterocycle that is substituted with --C(.dbd.O), such astropinone, to provide an alcohol. An example of this transformationcan be found in (Appell, M. et al. Bioorg. Med. Chem. 2002, 10,1197 1206). Alternatively, compounds of formula (6) wherein W isBr, or I, can be converted into a Grignard reagent and reacted witha heterocycle that is substituted with --C(.dbd.O), such astropinone, to provide an alcohol. The resulting alcohol can beoptionally eliminated to the corresponding alkene via methods knownto those of ordinary skill in the art to provide the correspondingalkene. The double bond of the alkene can be optionally reduced tothe saturated bond by methods known to those of ordinary skill inthe art.

Compounds of formula (7) wherein L.sub.2 is a bond, R.sub.6 is anitrogen-containing heteroaryl or heterocycle ring linked to thebicyclic core group through a nitrogen, and X, X', Y, Y', Z, Z',R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined for formula(I), may be prepared by heating compounds of formula (6) wherein Wis triflate or halogen, with a compound of the formula H--R.sub.6wherein H is a hydrogen on a nitrogen atom, with a base such as,but not limited to, sodium t-butoxide or cesium carbonate, in thepresence of a metal catalyst such as, but not limited to, coppermetal or CuI, palladium diacetate, and also optionally with aligand such as, but not limited to, BINAP, tri-tertbutylphosphinein a solvent such as dioxane, toluene, N,N-dimethylformamide (DMF),N,N-dimethylacetamide, N-methylpyrrolidinone (NMP) or pyridine.References that describe these methodologies may be found in thefollowing references: J. Hartwig et al., Angew. Chem. Int. Ed.37:2046 2067 (1998); J. P. Wolfe et al., Acc. Chem. Res., 13:805818 (1998); M. Sugahara et al., Chem. Pharm. Bull., 45:719 721(1997); J. P. Wolfe et al., J. Org. Chem., 65:1158 1174, (2000); F.Y. Kwong et al., Org. Lett., 4:581 584, (2002); A. Klapars et al.,J. Amer. Chem. Soc., 123:7727 7729 (2001); B. H. Yang et al., J.Organomet. Chem., 576:125 146 (1999); A. Kiyomori et al., Tet.Lett., 40:2657 2640 (1999); and Hartwig, J. Org. Chem., 64(15):55755580 (1999).

Compounds of formula (6) wherein W is Br, or I, can also be treatedwith an organolithium reagent such as, but not limited to,n-butyllithium, sec-butyllithium or tert-butyllithium to provide anintermediate anion which is then reacted with an amide of formula(8) to provide compounds of formula (9) wherein X, X', Y, Y', Z,Z', R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as definedfor formula (I). Compound (8) is prepared from the correspondingcarboxylic acid of formula R.sub.6--COOH via activation (withSOCl.sub.2, oxalyl chloride, N,N'-carbonyl diimidazole (CDI),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), or EtOCCI)and subsequent reaction with N,O-dimethylhydroxylamine in thepresence of a non-nucleophilic base.

Compounds of formula (7) wherein L.sub.2 is --NH-- or--N(alkyl)--and X, X', Y, Y', Z, Z', R.sub.2, R.sub.3, R.sub.4,R.sub.5, and R.sub.6 are as defined for formula (I) can be preparedby heating compounds of formula (6) wherein W is triflate orhalogen, with compounds of formula H.sub.2N--R.sub.6, orHN(alkyl)--R.sub.6, with a base such as, but not limited to sodiumtert-butoxide or cesium carbonate, in the presence of a metalcatalyst such as, but not limited to, copper metal or CuI,palladium diacetate, and also optionally with a ligand such as, butnot limited to, BINAP, tri-tertbutylphosphine in solvents such asdioxane, toluene, pyridine. References that describe thesemethodologies may be found in the following references: J. Hartwig,et al., Angew. Chem. Int. Ed., 37:2046 2067 (1998); J. P. Wolfe etal., Acc. Chem. Res., 13:805 818 (1998); J. P. Wolfe et al., J.Org. Chem., 65:1158 1174 (2000); F. Y. Kwong et al., Org. Lett.,4:581 584, (2002); B. H. Yang et al., J. Organomet. Chem., 576:125146 (1999); and Hartwig, J. Org. Chem., 64(15):5575 5580(1999).

Compounds of formula (7), wherein L.sub.2 is oxygen, and X, X', Y,Y', Z, Z', R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are asdefined for formula (I) can be prepared by heating compounds offormula (6) wherein W is triflate or halogen, with a compound offormula HOR.sub.6 wherein R.sub.6 is as defined in formula (I),using a base such as but not limited to sodium hydride in a solventsuch as toluene or N,N-dimethylformamide, in the presence of ametal containing catalyst such as CuI or palladium diacetate.References that describe these methodologies may be found in thefollowing references: J. Hartwig et al., Angew. Chem. Int. Ed.,37:2046 2067 (1998); J.-F. Marcoux et al., J. Am. Chem. Soc.,119:10539 10540 (1997); A. Aranyos et al., J. Amer. Chem. Soc.,121:4369 4378 (1999); M. Palucki et al., J. Amer. Chem. Soc.,119:3395 3396 (1997); and T. Yamamoto et al., Can. J. Chem., 61:8691 (1983). Additional methodologies useful for the synthesis ofcompounds of formula (7), wherein L.sub.2 is oxygen and R.sub.6 isas defined in formula (1) can be found in the following references:A. Aranyos et al., J. Amer. Chem. Soc., 121:4369 4378 (1999); E.Baston et al., Synth. Commun., 28:2725 2730 (1998); and A.Toshimitsu et al., Het. Chem., 12:392 397 (2001).

Compounds of formula (7), wherein L.sub.2 is sulfur and X, X', Y,Y', Z, Z', R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are asdefined for formula (I) can be prepared by heating compounds offormula (6) wherein W is halogen with a compound of formulaHSR.sub.6, wherein R.sub.6 is as defined for formula (I), using abase with or without a metal catalyst such as CuI or palladiumdiacetate, in the presence of a base in a solvent such asdimethylformamide or toluene. References that describe thesemethodologies may be found in the following references: G. Y. Li etal., J. Org. Chem., 66:8677 8681 (2001); G. Y. Li et al., Angew.Chem. Int. Ed., 40:1513 1516 (2001); U. Schopfer et al.,Tetrahedron, 57:3069 3074 (2001); and C. Palomo et al., Tet. Lett.,41:1283 1286(2000).

Compounds of formula (7), wherein L.sub.2 is--O[C(R.sub.18)(R.sub.19)].sub.q--, and X, X', Y, Y', Z, Z',R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, q, R.sub.18, andR.sub.19 are as defined for formula (I) can be prepared by treatingcompounds of formula (6) wherein W is OH with a compounds offormula HO[C(R.sub.18)(R.sub.19)].sub.qR.sub.6 wherein R.sub.6, q,R.sub.18, and R.sub.19 are as defined for formula (I), in thepresence of diethyl azodicarboxylate and triphenylphosphine usingthe conditions of the Mitsunobu reaction which is well known to oneskilled in the art of organic chemistry. Compounds of formula (6)wherein W is OH can be generated from compounds of formula (6)wherein W is Cl, Br or I as described in Mann, G.; et. al. J. Amer.Chem. Soc. 1999, 121, 3224 3225. Alternatively, compounds offormula (7), wherein L.sub.2 is --O[C(R.sub.18)(R.sub.19)].sub.q--,and X, X', Y, Y', Z, Z', R.sub.2, R.sub.3, R.sub.4, R.sub.5,R.sub.6, q, R.sub.18, and R.sub.19, are as defined for formula (I)can be prepared by heating compounds of formula (6) wherein W isCl, Br or I with compounds of formulaHO[C(R.sub.18)(R.sub.19)].sub.qR.sub.6 wherein R.sub.6, q,R.sub.18, and R.sub.19 are as defined in formula (I), in thepresence of a base such as Cs.sub.2CO.sub.3 and a catalyst such asPd(OAc).sub.2 in a solvent such as toluene or DMF (Torraca, K. E.;et. al. J. Amer. Chem. Soc. 123, 2001, 10770 10771.)

Compounds of formula (7), wherein L.sub.2 is--[C(R.sub.18)(R.sub.19)].sub.q--, q is 1, and X, X', Y, Y', Z, Z',R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.18 and R.sub.19are as defined for formula (I), can be prepared from compounds offormula (9). Compounds of formula (9) can be manipulated byreactions well known to those skilled in the art of organicchemistry such as the Grignard reaction, catalytic hydrogenation,metal hydride reduction, alkylation of alcohols, fluorination with(diethylamino)sulfur trifluoride, fluorination with[bis(2-methoxyethyl)amino]sulfur trifluoride to provide compoundsof formula (7), wherein L.sub.2 is--[C(R.sub.18)(R.sub.19)].sub.q--, q is 1, and X, X', Y, Y', Z, Z',R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.18, andR.sub.19, are defined for formula (I).

Compounds of formula (7), wherein L.sub.2 is--[C(R.sub.18)(R.sub.19)].sub.q-- and X, X', Y, Y', Z, Z', R.sub.2,R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.18, R.sub.19 and q are asdefined for formula (I) can be prepared by cross-coupling reactionsknown to those skilled in the art. Examples of these reactions arethe Kumada, Suzuki, Heck, Stille, Suzuki-Miyaaura, Tamao-Kamuda andSonogashira reaction. Suitable reagents, for example, alkylGrignard reagents, boronic acids or ester, tin intermediates,alkenes and alkynes can be coupled with compounds of formulas (6)wherein W is triflate or halogen, in the presence of a metalcatalyst such as palladium, nickel, silver or indium, to preparecompounds of formula (7), wherein L.sub.2 is a substituted orunsubstituted alkyl, alkenyl or alkynyl chain. Compounds of formula(7) wherein L.sub.2 is an alkenyl or alkynyl chain can be reducedto compounds of formula (7) wherein L.sub.2 is an alkyl chain bymethods known to those skilled in the art such as catalytichydrogenation. References that describe these methodologies are: G.A. Molander et al., Tetrahedron, 58:1465 1470 (2002); W. Dohle et.al., Org. Lett., 3:2871 2873 (2001); G. Zou et al., Tet. Lett.,42:7213 7216 (2001); A. J. Suzuki, Organomet. Chem., 576:147 168(1999); A. F. Littke, J. Amer. Chem. Soc., 122:4020 4028 (2000); N.Miyaura et al., Chem. Rev., 95:2457 2483 (1995); H. Horie et al.,J. Mater. Chem., 11:1063 1071 (2001); C. Dai et al., J. Amer. Chem.Soc., 123:2719 2724 (2001); F. Diederich et al., Metal-catalyzedCross-Coupling Reactions, Wiley-VCH; Weinheim, 1998; A.Mohanakrishnan et al., Syn. Lett., 7:1097 1099 (1999); B. H.Lipshutz et al., Org. Lett., 3:1869 1872 (2001); B. H. Lipshutz etal., Tet. Lett., 40:197 200 (1999); and J. Tsuji, PalladiumReagents and Catalysts-innovations in Organic Synthesis, John Wiley& Sons: New York, 1995.

##STR00007##

Compounds of formula (7), wherein L.sub.2 is a bond, and X, X', Y,Y', Z, Z', R.sub.2, R.sub.3, R.sub.4, R.sub.6 and R.sub.5 are asdefined in formula (I) can be prepared as described in Scheme 2.Halides of formula (6) wherein W is Br, Cl, or I, can be treatedwith a distannane such as hexamethylditin (CAS # 661-69-8) in thepresence of a catalyst such as Pd(PPh.sub.3).sub.4 in a solventsuch as dioxane with heating to provide tin intermediates ofstructure (6a), wherein R.sub.91 is lower alkyl (Li, D. et. al., J.Org. Chem., 65:2802 2805 (2000)). Alternatively, compounds offormula (6) wherein W is Br or I can be treated with analkyllithium reagent such as sec-BuLi in a solvent such as THF ordiethyl ether at -78.degree. C. to provide an intermediate lithiumspecies via a lithium-halogen exchange reaction followed byreaction with trialkyltin chloride such as tri-n-butyltin chlorideto provide tin intermediates of structure (6a). Using the Stillecoupling reaction conditions as described in Scheme 1, tinintermediates of structure (6a) can be reacted with halides offormula (10) or triflates of structure (11) to provide compounds offormula (7) wherein L.sub.2 is a bond, and X, X', Y, Y', Z, Z',R.sub.2, R.sub.3, R.sub.4, R.sub.6 and R.sub.5 are as defined informula (I).

##STR00008##

Alternatively, compounds of formula (7), wherein L.sub.2 is a bond,and X, X', Y, Y', Z, Z', R.sub.2, R.sub.3, R.sub.4, R.sub.6 andR.sub.5 are as defined in formula (I) can be prepared as describedin Scheme 3. Compounds of formula (6) wherein W is Br or I can betreated with an alkyllithium reagent such as sec-BuLi in a solventsuch as THF or diethyl ether at -78.degree. C. to provide anintermediate lithium species via a lithium-halogen exchangereaction followed by a trialkoxyborate such as triiosopropyl borateto provide a borate intermediate of formula (12) wherein R.sub.92is hydrogen. Alternatively, compounds of formula (6) wherein W istriflate, Br, Cl or I, can be treated with bis-(pinacolato)diboronin the presence of a catalyst such as PdCl.sub.2(dppf) as describedin Ishiyama, T.; et. al. J. Org. Chem. 1995, 60, 7508 7510 toprovide borates of general structure (12) whereinB(OR.sub.92).sub.2 is boronpinacolate. Using the Suzuki couplingreaction as described in Scheme 1, a reaction well known to thoseskilled in the art of organic chemistry, borate intermediates ofstructure (12) can be reacted with halides of structure (10) ortriflates of structure (11) to provide compounds of generalstructure (7) wherein L.sub.2 is a bond, and X, X', Y, Y', Z, Z',R.sub.2, R.sub.3, R.sub.4, R.sub.6 and R.sub.5 are as defined forformula (I).

##STR00009##

Tin intermediates of formula (13) wherein R.sub.93 is lower alkyl,L.sub.2 is a bond, and R.sub.6 is defined as in formula (I), can beprepared as described in Scheme 4 from the corresponding halides offormula (10), wherein L.sub.2 is a bond, by treatment with adistannane such as hexamethylditin (CAS # 661-69-8) in the presenceof a catalyst such as Pd(PPh.sub.3).sub.4 in a solvent such asdioxane with heating to provide tin intermediates of structure(13), wherein R.sub.93 is lower alkyl. Alternatively, halideintermediates of structure (10) can be reacted with an alkyllithium reagent such as sec-BuLi to provide an intermediate lithiumspecies which can then be treated with a tri-alkyltin chloride suchas trimethyltin chloride. An example of this transformation can befound in Balle, T. et. al., Synthesis, 11:1509 1512 (2002).

Boronic acid ester intermediates of formula (14), wherein R.sub.94is H or lower alkyl, L.sub.2 is a bond, and R.sub.6 is as definedin formula (I), can be prepared by the reaction of halides offormula (10), wherein L.sub.2 is a bond and n is 0 or 1, with analkyllithium reagent such as sec-BuLi in a solvent such as THF orether at -78.degree. C. to provide an intermediate lithium speciesvia a lithium-halogen exchange reaction followed by atrialkoxyborate such as triiosopropyl borate. Halides of structure(10) can be also treated with bis-(pinacolato)diboron in thepresence of a catalyst such as PdCl.sub.2(dppf) as described inIshiyama, T. et. al., J. Org. Chem. 60:7508 7510 (1995) to provideborates of general structure (14), wherein B(OR.sub.94).sub.2 isboronpinacolate, L.sub.2 is a bond and n is 0 or 1.

##STR00010## ##STR00011##

Alternatively, compounds of formula (7), wherein X, X', Y, Y', Z,Z', L.sub.2, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are asdefined in formula (I), can be prepared as described in Scheme 5.Esters of formula (15) can be treated with a reducing agent suchas, but not limited to, lithium aluminum hydride to providealcohols of formula (16). Alcohols of formula (16) can be treatedwith thionyl chloride to provide chlorides of formula (17).Chlorides of formula (17) can be treated with sodium cyanide orpotassium cyanide to provide the nitrile which can be treated withaqueous acid to provide acids of formula (18). Acids of formula(18) can be treated with a reducing agent such as, but not limitedto, diborane or borane THF complex to provide alcohols of formula(19). Alcohols of formula (19) can be used in place of compound (3)in Scheme 1. Alternatively, alcohols of formula (19) can be treatedwith a hydroxy-protecting reagent such as, but not limited to,tert-butyldimethylsilyl chloride. The protected compounds offormula (20) can be processed as described in Schemes 1 3 toprovide compounds of formula (21). Compounds of formula (21) can bedeprotected using methods known to those of ordinary skill in theart and then treated with a sulfonating agent such as, but notlimited to, methanesulfonyl chloride or p-toluensulfonyl chlorideto provide sulfonates of formula (22). Sulfonates of formula (22)can be treated with an amine of formula (5) to provide compounds offormula (7).

##STR00012##

Compounds of formula (26), wherein X, X', Y, Y', Z, Z', L.sub.2,R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined informula (I), can be prepared as described in Scheme 6. Hydroxycompounds of formula (23), purchased or prepared using methodsknown to those of ordinary skill in the art, can be treated with1,2-dibromoethane to provide bromides of formula (24). Bromides offormula (24) can be treated with amines of formula (5) to providecompounds of formula (25). Compounds of formula (25) can beprocessed as described in Scheme 1 4 to provide compounds offormula (26).

##STR00013##

Compounds of formula (34), wherein Y, Y', Z', L.sub.2, R.sub.2,R.sub.4, R.sub.5 and R.sub.6 are as defined in formula (I), can beprepared as described in Scheme 7. Indanones of formula (28) can betreated with a base such as, but not limited to, lithiumdiisopropylamide and ethyl bromoacetate to provide esters offormula (29). Esters of formula (29) can be treated withborane-tert-butylamine complex and then an aqueous basic solutionsuch as, but not limited to, sodium hydroxide in water to providehydroxyacids of formula (30). Hydroxyacids of formula (30) can betreated with a strong acid such as, but not limited to,concentrated sulfuric acid with heat in a solvent such as methanolto provide esters of formula (31). Esters of formula (31) can betreated with a reducing agent such as, but not limited to, lithiumaluminum hydride to provide alcohols of formula (32). Alcohols offormula (32) can be treated with ozone followed by dimethylsulfideand ammonium hydroxide to provide isoquinolines of formula (33).Isoquinolines of formula (33) can be processed as described inSchemes 1 3 and 5 to provide compounds of formula (34).

##STR00014##

Compounds of formula (42), wherein R.sub.2, R.sub.4, R.sub.5 andR.sub.6 are as defined in formula (I) and L.sub.2 is--[C(R.sub.18)(R.sub.19)].sub.q-- or a bond can be prepared asdescribed in Scheme 8. 1-(2-Bromoethyl)-4-nitrobenzene can betreated with amines of formula (5) to provide amines of formula(37). Amines of formula (37) can be treated with palladium oncarbon under a hydrogen atmosphere to provide anilines which canthen be treated with a nitrogen protecting reagent such as, but notlimited to, trimethylacetyl chloride to provide protected anilinesof formula (38). Protected anilines of formula (38) can be treatedwith an organolithium reagent such as, but not limited to,n-butyllithium, sec-butyllithium, or tert-butyllithium andN,N-dimethylformamide to provide aldehydes of formula (39). Theaniline of aldehydes of formula (39) can be deprotected usingmethods well-known to those skilled in the art such as, but notlimited to, heating in aqueous hydrochloric acid to providealdehydes of formula (40). Aldehydes of formula (40) can be treatedwith ketones of formula (41) and a base such as, but not limitedto, potassium ethoxide to provide compounds of formula (42).

Compounds of formula (44), wherein R.sub.1, R.sub.4, R.sub.5 andR.sub.6 are as defined in formula (I) and L.sub.2 is--[C(R.sub.18)(R.sub.19)].sub.q-- or a bond also can be prepared asdescribed in Scheme 8. Aldehydes of formula (40) can be treatedwith ketones of formula (43) and a base such as, but not limitedto, potassium ethoxide to provide compounds of formula (44).

Compounds of formula (41) or (43) can be purchased commercially orsynthesized from procedures which are known to those skilled in theart. One example of such a synthesis as described in Chikashita, H.et al., Bull. Chem. Soc. Jpn. 61:3637 3648 (1988) involves thedeprotonation of a fused polycyclic compound such as benzothiazoleusing a base such as n-butyllitium providing an intermediatelithium anion which is reacted with an electrophile such asN,N-dimethyl acetamide to provide compounds of formula (41) whereinL.sub.2 is a bond.

Alternatively, a polycyclic compound that is substituted with Cl,Br, I or triflate can be converted to the corresponding acetate ofgeneral structure (41) wherein L.sub.2 is a bond, by severalmethods that are known to those skilled in the art. In the reactioncommonly known as metal-halide exchange, a polycyclic compound thatis substituted with Br or I, can be treated with an alkyl lithiumsuch as n-butyl lithium to provide an intermediate lithium anionwhich is with an electrophile such as N-methoxy-N-methylacetamide.An example of this transformation can be found in Wai, J. S. et.al., J. Med. Chem. (43)26:4923 4926 (2000). In the reactioncommonly known as the Heck reaction, a polycyclic compound that issubstituted with Cl, Br, I or triflate, can be reacted with a vinylether such as N-butyl vinyl ether in the presence of a catalystsuch as palladium acetate to provide acetates of general structure(41), wherein L.sub.2 is a bond. An example of such atransformation can be found in Viaud, M. et al., Heterocycles,(41)12: 2799 2810 (1995). In the reaction commonly known as theStille reaction, a polycyclic compound that is substituted with Cl,Br, I or triflate, can be coupled with a tin-vinyl ether such as1-ethoxyvinyltri-n-butyltin in the presence of a catalyst such astetrakis(triphenylphosphine)palladium(0) to provide acetates ofgeneral structure (41) wherein L.sub.2 is a bond. An example ofsuch a transformation can be found in Viaud, M. et. al.,Tetrahedron 53(14): 5159 5168 (1997).

Compounds of formula (41) wherein L.sub.2 is a bond can also beobtained by the cyclization of a dicarbonyl intermediate with anappropriate reagent. Examples of such cyclization reactions areillustrated in the following references: Badr, M. Z. A. et. al.,Bull. Chem. Soc. Jpn. 61:1339 1344 (1988); Kaugars, G. et. al.,Heterocycles (38)12:2593 2604 (1994); Bruni, F. et. al.,Heterocycles, 31(6): 1141 1149 (1990); and Reddy, K. V. et. al., J.Indian Chem. Soc., 63: 443 445 (1986).

##STR00015## ##STR00016##

Compounds of formula (50), wherein L.sub.2, R.sub.4, R.sub.5 andR.sub.6 are as defined in formula (I), can be prepared as describedin Scheme 9. Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can beprepared using the procedures described in Synthetic Comm., 17(14):1647 1653 (1987). Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylatecan 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 achlorinating reagent, such as, but not limited to, thionyl chlorideto provide 3-(chloromethyl)-7-methoxy-2-methylquinoline.3-(Chloromethyl)-7-methoxy-2-methylquinoline can be treated withsodium cyanide or potassium cyanide to provide(7-methoxy-2-methyl-3-quinolinyl)acetonitrile.(7-Methoxy-2-methyl-3-quinolinyl)acetonitrile can be treated withacid, such as, but not limited to, glacial acetic acid andconcentrated sulfuric acid, in water and 1,4-dioxane with heat toprovide (7-methoxy-2-methyl-3-quinolinyl)acetic acid.(7-Methoxy-2-methyl-3-quinolinyl)acetic acid can be treated with areducing agent, such as, but not limited to, B.sub.2H.sub.6,borane-THF complex, or borane-pyridine complex, to provide2-(7-methoxy-2-methyl-3-quinolinyl)ethanol.2-(7-Methoxy-2-methyl-3-quinolinyl)ethanol can be treated withmethanesulfonyl chloride and a base, such as, but not limited to,triethylamine or diisopropylamine to provide2-(7-methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate.2-(7-Methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate can betreated with an amine of formula (5) to provide amines of formula(47). Amines of formula (47) can be treated with BBr.sub.3 toprovide hydroxy compounds of formula (48). Hydroxy compounds offormula (48) can be treated with trifluoromethanesulfonic anhydrideor trifluoromethanesulfonyl chloride to provide triflates offormula (49). Triflates of formula (49) can be processed asdescribed in Schemes 1 3 to provide compounds of formula (50).

##STR00017##

1,5-Naphthyridines of formula (53), wherein L.sub.2, R.sub.4,R.sub.5 and R.sub.6 are as defined in formula (I), can be preparedas described in Scheme 10. 3,7-Dibromo-[1,5]naphthyridine, preparedas described by W. W. Paudler, J. Org. Chem., 33:1384 (1968), canbe treated with (2-ethoxyvinyl)tributylstannane, a halide source,such as, but not limited to, tetraethylammonium chloride, and apalladium source, such as, but not limited to,dichlorobis(triphenylphosphine)palladium (II) in a solvent, suchas, but not limited to, N,N-dimethylformamide with heat (about50.degree. C. to about 150.degree. C.) to provide3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine.3-Bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine can be treated with anacid, such as, but not limited to, formic acid at about 0.degree.C. to about 60.degree. C. in a solvent, such as, but not limitedto, 1,2-dichloroethane to provide(7-bromo-1,5-naphthyridin-3-yl)acetaldehyde. Alternatively,3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine in a solvent, such as,but not limited to, tetrahydrofuran can be treated with an aqueousacid, such as, but not limited to, hydrochloric acid at about0.degree. C. to about 60.degree. C. to provide(7-bromo-1,5-naphthyridin-3-yl)acetaldehyde.(7-Bromo-1,5-naphthyridin-3-yl)acetaldehyde can be treated with anamine of formula (5) under reductive amination conditions, such as,but not limited to, sodium triacetoxyborohydride and an acid, suchas, but not limited to, acetic acid in a solvent, such as, but notlimited to, 1,2-dichloroethane at about 0.degree. C. to about50.degree. C. to provide amines of formula (52). Amines of formula(52) can be processed as described in Schemes 1 3 to provide1,5-naphthyridines of formula (53).

##STR00018##

Cinnolines of formula (60), wherein L.sub.2, R.sub.4, R.sub.5 andR.sub.6 are as defined in formula (I), can be prepared as describedin Scheme 11. Amines of formula (5) can be treated with 3-butynylmethanesulfonate at room temperature with stirring for about 1 hourand then heated at about 50.degree. C. for about 24 hours. Themixture is allowed to cool to room temperature, and filtered. Thefiltrate is diluted with acetonitrile to provide a 0.1 M solutionof alkynes of formula (55) for use in subsequent steps.5-Bromo-2-iodophenylamine, prepared as described by Sakamoto inChem. Pharm. Bull. 35:1823 (1987), can be treated with alkynes offormula (55), a source of palladium (II), such as, but not limitedto, Pd(Ph.sub.3P).sub.2Cl.sub.2, CuI, and a base, such as, but notlimited to, triethylamine in an organic solvent, such as, but notlimited to, DMF at about 50.degree. C. to about 80.degree. C. toprovide alkynes of formula (56). Alkynes of formula (56) can betreated with aqueous acid, such as but not limited to aqueous HClin the presence of sodium nitrite at about 0.degree. C. to about100.degree. C. to provide hydroxy cinnolines of formula (57).Hydroxy cinnolines of formula (57) can be processed as described inSchemes 1 3 to provide hydroxy cinnolines of formula (58). Hydroxycinnolines of formula (58) can be treated withN-phenylbis(trifluoromethanesulfonimide) and a base, such as, butnot limited to, diisopropylethylamine in an organic solvent, suchas, but not limited to, 1,2-dichloroethane at about 25.degree. C.to about 40.degree. C. to provide triflates of formula (59).Triflates of formula (59) can be treated with a catalytic palladiumsource, such as, but not limited to, palladium (II) acetate and ahydrogen donor, such as, but not limited to, formic acid at about25.degree. C. to about 50.degree. C. to provide cinnolines offormula (60).

##STR00019##

Cinnolines of formula (60), wherein L.sub.2, R.sub.4, R.sub.5 andR.sub.6 are as defined in formula (I), also can be prepared asdescribed in Scheme 12. 7-Chloro-3-cinnolinol, prepared asdescribed by H. E. Baumgarten, J. Het. Chem., 6:333 (1969), can betreated with trifluoromethanesulfonyl chloride ortrifluoromethanesulfonic anhydride and a base, such as, but notlimited to, triethylamine or pyridine in a solvent, such as, butnot limited to, dichloromethane at about 0.degree. C. or roomtemperature to provide 7-chloro-3-cinnolinyltrifluoromethanesulfonate. 7-Chloro-3-cinnolinyltrifluoromethanesulfonate can be treated with(2-ethoxyvinyl)tributylstannane, a halide source, such as, but notlimited to, tetraethylammonium chloride, and a palladium source,such as, but not limited to,dichlorobis(triphenylphosphine)palladium (II) in a solvent, suchas, but not limited to, N,N-dimethylformamide at about 50.degree.C. to about 150.degree. C. to provide7-chloro-3-(2-ethoxyvinyl)cinnoline.7-Chloro-3-(2-ethoxyvinyl)cinnoline can be processed as describedin Scheme 10 to provide amines of formula (62). Amines of formula(62) can be processed as described in Schemes 1 3 to providecinnolines of formula (60).

##STR00020##

Cinnolines of formula (67), wherein L.sub.2, R.sub.4, R.sub.5 andR.sub.6 are as defined in formula (I), can be prepared as describedin Scheme 13. 7-Chloro-3-cinnolinyl trifluoromethanesulfonate,prepared as described in Scheme 12, can be processed as describedin Schemes 1 3 to provide chlorides of formula (64). Chlorides offormula (64) can be treated with2-(2-ethoxy-vinyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane,prepared as described by C. M. Vogels in Chem. Commun. 1: 51 (2000)a palladium source, such as, but not limited to,tris(dibenzylideneacetone)dipalladium (0), tri(tert-butyl)phosphineor dichloro(di-tert-butylphosphinous acid)palladium (II) dimer anda base such as cesium fluoride, in a solvent, such as, but notlimited to, 1,4-dioxane at about 30.degree. C. to about 120.degree.C. to provide ethers of formula (65). Ethers of formula (65) can beprocessed as described in Scheme 10 to provide cinnolines offormula (67).

##STR00021##

Quinolines of formula (73), wherein L.sub.2, R.sub.4, R.sub.5 andR.sub.6 are as defined in formula (I), can be prepared as describedin Scheme 14. 2-(3-Nitrophenyl)ethanol, CAS #100-27-6, can betreated with methanesulfonyl chloride (or toluenesulfonylchloride), and a base, such as, but not limited to, triethylaminein a solvent, such as, but not limited to, methylene chloride toprovide 2-(3-nitrophenyl)ethyl methanesulfonate.2-(3-Nitrophenyl)ethyl methanesulfonate can be treated with aminesof formula (5) and a base, such as, but not limited to, potassiumcarbonate in a solvent, such as, but not limited to, acetonitrileto provide amines of formula (70). Amines of formula (70) can betreated with hydrogen with a palladium source, such as but notlimited to palladium on carbon in a solvent, such as, but notlimited to, methanol, ethanol, or ethyl acetate to provide anilinesof formula (71). Anilines of formula (71) can be treated with2,2,3-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 processed as described inSchemes 1 3 to provide quinolines of formula (73).

##STR00022##

Naphthyridines of formula (80), wherein L.sub.2, R.sub.4, R.sub.5and R.sub.6 are as defined in formula (I), can be prepared asdescribed in Scheme 15. 5-Bromo-2-iodopyridine (CAS# 223463-13-6)can be processed as described in Schemes 1 3 to provide pyridinesof formula (76). Compounds of formula (76) can be treated with abase, such as, but not limited to, lithium diisopropylamide andN,N-dimethylformamide, as described in Numata et al., Synthesis,306 311 (1999), to provide compounds of formula (77). Compounds offormula (77) can be treated with 3-butyn-1-ol, CuI, a base such as,but not limited to, triethylamine, and palladium source, such as,but not limited to, Pd(PPh.sub.3).sub.2Cl.sub.2 in a solvent, suchas but not limited to N,N-dimethylformamide to provide alkynes offormula (78). Alkynes of formula (78) can be treated with ammoniaat about 80.degree. C. in a solvent, such as, but not limited to,ethanol to provide naphthyridines of formula (79). Naphthyridinesof formula (79) can be processed as described in Scheme 1 toprovide naphthyridines of formula (80).

##STR00023##

Naphthyridines of formula (86), wherein L.sub.2, R.sub.4, R.sub.5and R.sub.6 are as defined in formula (I), can be prepared asdescribed in Scheme 16. 6-Bromo-2-pyridinecarbaldehyde can betreated with N-iodosuccinimide in sulfuric acid and acetic acid toprovide 6-bromo-3-iodo-2-pyridinecarbaldehyde and6-bromo-5-iodo-2-pyridinecarbaldehyde.6-Bromo-3-iodo-2-pyridinecarbaldehyde can be treated withtert-butylamine in a solvent, such as, but not limited to, THF toprovide imine (84). Imine (84) can be treated with 3-butyn-1-ol,CuI, a base, such as, but not limited to, triethylamine ordiisopropylamine, and a palladium source, such as, but not limitedto, Pd(PPh.sub.3).sub.2Cl.sub.2 in a solvent, such as but notlimited to N,N-dimethylformamide to provide alcohols of formula(85). Alcohols of formula (85) can be processed as described inSchemes 1 3 to provide naphthyridines of formula (86).

##STR00024##

Naphthyridines of formula (91), wherein R.sub.4, R.sub.5 andR.sub.6 are as defined in formula (I), can be prepared as describedin Scheme 17. Imines of formula (84), prepared as described inScheme 16, can be treated with alkynes of formula (88), CuI, abase, such as, but not limited to, triethylamine ordiisopropylamine, and a palladium source, such as, but not limitedto, Pd(PPh.sub.3).sub.2Cl.sub.2 in a solvent, such as but notlimited to N,N-dimethylformamide to provide naphthyridines offormula (89). Naphthyridines of formula (89) can be treated with analkyllithium reagent, such as, but not limited to, methyllithium,n-butyllithium, sec-butyllithium, or t-butyllithium, and ethyleneoxide in a solvent, such as, but not limited to, THF or diethylether to provide alcohols of formula (90). Alcohols of formula (90)can be treated as described in Schemes 1 3 to providenaphthyridines of formula (91).

##STR00025##

Isoquinolines of formula (95), wherein R.sub.4, R.sub.5 and R.sub.6are as defined in formula (I), can be prepared as described inScheme 18. Methyl 2-iodobenzoate can be treated withN-bromosuccinimide in acetic acid and sufuric acid to providemethyl 5-bromo-2-iodobenzoate. Methyl 5-bromo-2-iodobenzoate can betreated with a reducing agent, such as, but not limited to, sodiumborohydride or lithium aluminum hydride in a solvent, such as, butnot limited to, THF, ethanol, or a mixture thereof, to provide(5-bromo-2-iodophenyl)methanol. (5-Bromo-2-iodophenyl)methanol canbe treated with an oxidizing agent, such as, but not limited to,pyridinium chlorochromate, pyridinium dichromate, MnO.sub.2, aperacid such as meta-chloroperoxybenzoic acid, or Swern conditions(DMSO/Cl(CO).sub.2Cl/TEA) to provide 5-bromo-2-iodobenzaldehyde.5-Bromo-2-iodobenzaldehyde can be treated with tert-butylamine in asolvent, such as, but not limited to, THF to provideN-[(5-bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine.N-[(5-Bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine can betreated with alkynes of formula (88), CuI, a base, such as, but notlimited to, triethylamine or diisopropylamine, and a palladiumsource, such as, but not limited to, Pd(PPh.sub.3).sub.2Cl.sub.2 ina solvent, such as but not limited to N,N-dimethylformamide toprovide isoquinolines of formula (93). Isoquinolines of formula(93) can be treated with an alkyllithium reagent, such as, but notlimited to, methyllithium, n-butyllithium, sec-butyllithium, ort-butyllithium, and ethylene oxide in a solvent, such as, but notlimited to, THF or diethyl ether to provide alcohols of formula(94). Alcohols of formula (94) can be treated as described inSchemes 1 3 to provide isoquinolines of formula (95).

##STR00026##

Isoquinolines of formula (34a) are a subgenus of compounds (34),wherein X, Y', and Z' are all carbon atoms, for instance CH, andL.sub.2, R.sub.4, R.sub.5 and R.sub.6 are as defined in formula(I), and the compounds of the subgenus (34a) can be prepared asdescribed in Scheme 19. Methyl 2-iodobenzoate can be treated withN-bromosuccinimide in acetic acid and sufuric acid to provde methyl5-bromo-2-iodobenzoate. Methyl 5-bromo-2-iodobenzoate can betreated with a reducing agent, such as, but not limited to, sodiumborohydride or lithium aluminum hydride in a solvent, such as, butnot limited to, THF, ethanol, or a mixture thereof, to provide(5-bromo-2-iodophenyl)methanol. (5-Bromo-2-iodophenyl)methanol canbe treated with an oxidizing agent, such as, but not limited to,pyridinium chlorochromate, pyridinium dichromate, MnO.sub.2, aperacid such as meta-chloroperoxybenzoic acid, or Swern conditions(DMSO/Cl(CO).sub.2Cl/TEA) to provide 5-bromo-2-iodobenzaldehyde.5-Bromo-2-iodobenzaldehyde can be treated with tert-butylamine in asolvent, such as, but not limited to, THF to provideN-[(5-bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine.N-[(5-Bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine can betreated with the alkyne but-3-yn-1-ol, CuI, a base, such as, butnot limited to, triethylamine or diisopropylamine, and a palladiumsource, such as, but not limited to, Pd(PPh.sub.3).sub.2Cl.sub.2 ina solvent, such as, but not limited to, N,N-dimethylformamide toprovide an isoquinoline. The 2-hydroxyethylisoquinoline can betreated as described in Schemes 1 3, and 5 to provide isoquinolinesof formula (34a).

##STR00027## ##STR00028##

Quinoxalines of formula (105), wherein L.sub.2, R.sub.6, R.sub.4and R.sub.5 are as defined for formula (I), can be prepared asdescribed in Scheme 20. Amines of formula (37), prepared asdescribed in Scheme 8, can be treated with palladium on carbonunder a hydrogen atmosphere to provide anilines that can then betreated with acetic anhydride in a solvent such as a mixture ofsulfuric acid and water to provide acetamides of formula (100).Acetamides of formula (100) can be nitrated using conditions wellknown to those skilled in the art. One example of such a nitrationreaction utilizes nitric acid in sulfuric acid in the presence ofacetic anhydride to provide acetamides of formula (101). Acetamidesof formula (101) can be converted to Boc protected nitroanilinesusing a procedure described in Grehen, L, et. al, Acta Chem. Scand.Ser B. 41(1):18 23, in which the acetamide is reacted withdi-tert-butyldicarbonate in the presence of 4-dimethylaminopyridinefollowed by treatment with 2-diethylaminodiethylamine to provide aBoc-protected nitroaniline which can be treated with palladium oncarbon under a hydrogen atmosphere to provide anilines of formula(102). Anilines of formula (102) can be reacted with a bromoacetateto provide anilines of formula (110) wherein R.sub.95 is alkyl.Anilines of formula (110) can be treated with an acid such as, butnot limited to, trifluoroacetic acid with heating to providedihydroquinoxalinones of formula (111). Dihydroquinoxalinones offormula (111) can be oxidized using an oxidizing agent such as, butnot limited to, silver nitrate to provide quinoxalinones of formula(112). Quinoxalinones of formula (112) can be treated withtriflouroacetic anhydride in the presence of a base such as2,6-lutidine in a solvent such as dichloromethane to providecompounds of structure (113) wherein W is triflate. Alternatively,quinoxalinones of formula (112) can be treated with POCl.sub.3 toprovide compounds of structure (113) wherein W is Cl. Compounds offormula (113) can be processed as described in Schemes 1 3 toprovide quinoxalines of formula (105).

##STR00029##

Quinoxalines of formula (105), wherein L.sub.2, R.sub.6, R.sub.4and R.sub.5 are as defined in formula (I), can be prepared asdescribed in Scheme 21. 2-Chloro-quinoxaline-6-carboxylic acid(Wolf et al., J. Amer. Chem. Soc. 71: 6 10 (1949)) can be reducedto (2-chloro-quinoxalin-6-yl)-methanol using a reducing agent suchas, but not limited to, borane-THF complex.(2-Chloro-quinoxalin-6-yl)-methanol can be processed as describedin Scheme 5 to provide quinoxalines of formula (105).

##STR00030##

Quinazolines of formula (123), wherein R.sub.4, R.sub.5 and R.sub.6are as defined in formula (I), can be prepared as described inScheme 22. Anilines of formula (40) prepared as described in Scheme8, can be treated with acid chlorides of formula (121) in thepresence of a base such as pyridine in a solvent such asdichloromethane to provide amides of formula (122). Amides offormula (122) can be treated with a source of ammonia, such asaqueous ammonium hydroxide, and heated to provide quinazolines offormula (123).

##STR00031##

Quinazolines of formula (123), wherein L.sub.2, R.sub.4, R.sub.5and R.sub.6 are as defined in formula (I) is aryl or heteroaryl canalso be prepared as described in Scheme 23. Anilines of formula(40), prepared as described in Scheme 8, can be treated with ureaand heated as described in Troeger, et. al., .Prakt. Chem. 117:181(1927), to provide quinazolinones of formula (130). Quinazolinonesof formula (130) can be treated with triflic anhydride in thepresence of a base such as 2,6-lutidine in a solvent such asdichloromethane to provide triflates of general structure (131).Triflates of formula (131) can be treated as described in Schemes 13 to provide quinoxalines of formula (123).

##STR00032##

Compounds of formula (144) and (145), wherein Y, Y', Z', L.sub.2,R.sub.2, R.sub.4, R.sub.5 and R.sub.6 are as defined in formula(I), can be prepared as described in Scheme 24. Nitrobenzenes offormula (138) can be treated with a reducing agent such as, but notlimited to, platinum on carbon under a hydrogen atmosphere toprovide diaminobenzenes of formula (139). Diaminobenzenes offormula (139) can be treated with 2-oxopropanal to provide amixture of bromides of formula (140) and (141). Bromides of formula(140) and (141) can be treated with formaldehyde and amines offormula (5) to provide a mixture of aminobromides of formula (142)and (143). Aminobromides of formula (142) and (143) can beprocessed as described in Schemes 1 3 to provide compounds offormula (144) and (145).

##STR00033##

Compounds of formula (154), wherein Y, Y', Z', L.sub.2, R.sub.2,R.sub.4, R.sub.5 and R.sub.6 are as defined in formula (I), can beprepared as described in Scheme 25. Compounds of formula (138),purchased or prepared using known methods in the art, can betreated with NaNO.sub.2 and acid, such as, but not limited to,concentrated sulfuric acid followed by treatment with Kl to provideiodo compounds of formula (148). Iodo compounds of formula (148)can be treated with SnCl.sub.2 and an acid such as, but notlimited, concentrated HCl 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 toPdCl.sub.2(PPh.sub.3).sub.2 to provide alkynes of formula (150).Alkynes of formula (150) can be treated with NaNO.sub.2 and an acidsuch as, but not limited to, 6M HCl to provide compounds of formula(151). Compounds of formula (151) can be treated with POCl.sub.3 toprovide chlorides of formula (152). Chlorides of formula (152) canbe treated as described in Schemes 1 3 to provide compounds offormula (153). Compounds of formula (153) can be treated withamines of formula (5) to provide compounds of formula (154).

##STR00034##

Compounds of formula (159 161), wherein Y, Y', Z', L.sub.2,R.sub.2, R.sub.4, R.sub.5 and R.sub.6 are as defined in formula(I), can be prepared as described in Scheme 26. Compounds offormula (149), can be treated with amines of formula (55), copper(I) iodide, a base such as, but not limited to triethylamine, and ametal catalyst such as, but not limited to,PdCl.sub.2(PPh.sub.3).sub.2 to provide alkynes of formula (157).Alkynes of formula (157) can be treated with NaNO.sub.2 and an acidsuch as, but not limited to, 6 M HCl to provide compounds offormula (158). Compounds of formula (158) can be converted tocompounds of formula (159) using reaction conditions as describedin Schemes 1 3 to provide compounds of formula (159). Compounds offormula (159) can be treated with an alkyl halide such as, but notlimited to, iodomethane or iodoethane and a base such as, but notlimited to, triethylamine or sodium hydride to provide compounds offormula (160). Compounds of formula (159) can be treated withphosphorus oxychloride to provide chlorides of formula (161).Phosphorous oxybromide may also be used to generate thecorresponding bromides.

##STR00035## ##STR00036##

An alternative method for preparing compounds of formula (160 161)and methods for preparation of compounds of formula (167 169),wherein Y, Y', Z', L.sub.2, R.sub.2, R.sub.4, R.sub.5 and R.sub.6are as defined in formula (I) is described in Scheme 27. Compoundsof general formula (151), can be treated with a reagent forprotecting a hydroxy group known to those of skill in the art suchas, but not limited to, tert-butyldimethylsilyl chloride or benzylbromide, and a base such as, but not limited to, sodium bicarbonateor imidazole to provide compounds of formula (163) wherein PG isthe hydroxy protecting group. Compounds of formula (163) can betreated with methanesulfonyl chloride (or toluenesulfonyl chloride)and a base such as, but not limited to, diisopropylamine ortriethylamine to provide sulfonates of formula (164). Sulfonates offormula (164) can be treated with amines of formula (5) to providecompounds of formula (165). Compounds of formula (165) can betreated as described in Schemes 1 3 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, butnot limited to, treatment with fluoride ion, acid, or hydrogenationin the presence of a metal catalyst (H.sub.2 and Pd/C) followed bytreatment with phosphorus oxychloride to provide chlorides offormula (161). Phosphorous oxybromide may also be used to generatethe corresponding bromides. Chlorides of formula (161) can betreated with nucleophiles such as, but not limited to, alkoxides,alkyl mercaptans, alkyl Grignards, or sodium cyanide to providecompounds of formula (160, 167 169).

The compounds and intermediates of the invention may be isolatedand purified by methods well-known to those skilled in the art oforganic synthesis. Examples of conventional methods for isolatingand purifying compounds can include, but are not limited to,chromatography on solid supports such as silica gel, alumina, orsilica derivatized with alkylsilane groups, by recrystallization athigh or low temperature with an optional pretreatment withactivated carbon, thin-layer chromatography, distillation atvarious pressures, sublimation under vacuum, and trituration, asdescribed for instance in "Vogel's Textbook of Practical OrganicChemistry", 5th edition (1989), by Furniss, Hannaford, Smith, andTatchell, pub. Longman Scientific & Technical, Essex CM20 2JE,England.

The compounds of the invention have at least one basic nitrogenwhereby the compound can be treated with an acid to form a desiredsalt. For example, a compound may be reacted with an acid at orabove room temperature to provide the desired salt, which isdeposited, and collected by filtration after cooling. Examples ofacids suitable for the reaction include, but are not limited totartaric 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 hydroxybutyric acid, camphorsulfonic, malic,phenylacetic, aspartic, glutamic, and the like.

Compositions of the Invention

The invention also provides pharmaceutical compositions comprisinga therapeutically effective amount of a compound of formula (I) incombination with a pharmaceutically acceptable carrier. Thecompositions comprise compounds of the invention formulatedtogether with one or more non-toxic pharmaceutically acceptablecarriers. The pharmaceutical compositions can be formulated fororal administration in solid or liquid form, for parenteralinjection or for rectal administration.

The term "pharmaceutically acceptable carrier," as used herein,means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of anytype. Some examples of materials which can serve aspharmaceutically acceptable carriers are sugars such as lactose,glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil,sesame oil, olive oil, corn oil and soybean oil; glycols; such apropylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions,as well as other non-toxic compatible lubricants such as sodiumlauryl sulfate and magnesium stearate, as well as coloring agents,releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also bepresent in the composition, according to the judgment of oneskilled in the art of formulations.

The pharmaceutical compositions of this invention can beadministered to humans and other mammals orally, rectally,parenterally, intracisternally, intravaginally, intraperitoneally,topically (as by powders, ointments or drops), bucally or as anoral or nasal spray. The term "parenterally," as used herein,refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous,intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions and sterilepowders for reconstitution into sterile injectable solutions ordispersions. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols(propylene glycol, polyethylene glycol, glycerol, and the like, andsuitable mixtures thereof), vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate, or suitablemixtures thereof. Suitable fluidity of the composition may bemaintained, for example, by the use of a coating such as lecithin,by the maintenance of the required particle size in the case ofdispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms may be ensured byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the use of agentsdelaying absorption, for example, aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it isoften desirable to slow the absorption of the drug fromsubcutaneous or intramuscular injection. This may be accomplishedby the use of a liquid suspension of crystalline or amorphousmaterial with poor water solubility. The rate of absorption of thedrug then depends upon its rate of dissolution which, in turn, maydepend upon crystal size and crystalline form. Alternatively,delayed absorption of a parenterally administered drug form isaccomplished by dissolving or suspending the drug in an oilvehicle.

Suspensions, in addition to the active compounds, may containsuspending agents, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar,tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds ofthe invention can be incorporated into slow-release ortargeted-delivery systems such as polymer matrices, liposomes, andmicrospheres. They may be sterilized, for example, by filtrationthrough a bacteria-retaining filter or by incorporation ofsterilizing agents in the form of sterile solid compositions, whichmay be dissolved in sterile water or some other sterile injectablemedium immediately before use.

Injectable depot forms are made by forming microencapsulatedmatrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug topolymer and the nature of the particular polymer employed, the rateof drug release can be controlled. Examples of other biodegradablepolymers include poly(orthoesters) and poly(anhydrides) Depotinjectable formulations also are prepared by entrapping the drug inliposomes or microemulsions which are compatible with bodytissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions whichcan be dissolved or dispersed in sterile water or other sterileinjectable medium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterallyacceptable diluent or solvent such as a solution in 1,3-butanediol.Among the acceptable vehicles and solvents that may be employed arewater, Ringer's solution, U.S.P. and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose anybland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid are usedin the preparation of injectables.

Solid dosage forms for oral administration include capsules,tablets, pills, powders, and granules. In such solid dosage forms,one or more compounds of the invention is mixed with at least oneinert pharmaceutically acceptable carrier such as sodium citrate ordicalcium phosphate and/or a) fillers or extenders such asstarches, lactose, sucrose, glucose, mannitol, and salicylic acid;b) binders such as carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such asglycerol; d) disintegrating agents such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certainsilicates, and sodium carbonate; e) solution retarding agents suchas paraffin; f) absorption accelerators such as quaternary ammoniumcompounds; g) wetting agents such as cetyl alcohol and glycerolmonostearate; h) absorbents such as kaolin and bentonite clay; andi) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixturesthereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using lactose ormilk sugar as well as high molecular weight polyethyleneglycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceuticalformulating art. They may optionally contain opacifying agents andcan also be of a composition that they release the activeingredient(s) only, or preferentially, in a certain part of theintestinal tract in a delayed manner. Examples of materials whichcan be useful for delaying release of the active agent can includepolymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoabutter, polyethylene glycol or a suppository wax which are solid atambient temperature but liquid at body temperature and thereforemelt in the rectum or vaginal cavity and release the activecompound.

Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the activecompounds, the liquid dosage forms may contain inert diluentscommonly used in the art such as, for example, water or othersolvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, 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 acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also includeadjuvants such as wetting agents, emulsifying and suspendingagents, sweetening, flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of acompound of this invention include ointments, pastes, creams,lotions, gels, powders, solutions, sprays, inhalants or patches. Adesired compound of the invention is admixed under sterileconditions with a pharmaceutically acceptable carrier and anyneeded preservatives or buffers as may be required. Ophthalmicformulation, ear drops, eye ointments, powders and solutions arealso contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition toan active compound of this invention, animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc andzinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds ofthis invention, lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellantssuch as chlorofluorohydrocarbons.

Compounds of the invention may also be administered in the form ofliposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formedby mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes maybe used. The present compositions in liposome form may contain, inaddition to the compounds of the invention, stabilizers,preservatives, and the like. The preferred lipids are the naturaland synthetic phospholipids and phosphatidylcholines (lecithins)used separately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press,New York, N.Y., (1976), p 33 et seq.

Dosage forms for topical administration of a compound of thisinvention include powders, sprays, ointments and inhalants. Theactive compound is mixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives,buffers or propellants, which can be required. Opthalmicformulations, eye ointments, powders and solutions are contemplatedas being within the scope of this invention. Aqueous liquidcompositions comprising compounds of the invention also arecontemplated.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts, esters, or amides derived frominorganic or organic acids. The term "pharmaceutically acceptablesalts, esters and amides," as used herein, refer to carboxylatesalts, amino acid addition salts, zwitterions, esters and amides ofcompounds of formula (I) which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation,allergic response, and the like, are commensurate with a reasonablebenefit/risk ratio, and are effective for their intended use.

The term "pharmaceutically acceptable salt" refers to those saltswhich are, within the scope of sound medical judgment, suitable foruse in contact with the tissues of humans and lower animals withoutundue toxicity, irritation, allergic response, and the like, andare commensurate with a reasonable benefit/risk ratio.Pharmaceutically acceptable salts are well-known in the art. Thesalts can be prepared in situ during the final isolation andpurification of the compounds of the invention or separately byreacting a free base function with a suitable organic acid.

Representative acid addition salts include, but are not limited toacetate, 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 andundecanoate. Preferred salts of the compounds of the invention arethe tartrate and hydrochloride salts.

Also, the basic nitrogen-containing groups can be quaternized withsuch agents as lower alkyl halides such as methyl, ethyl, propyl,and butyl chlorides, bromides and iodides; dialkyl sulfates such asdimethyl, diethyl, dibutyl and diamyl sulfates; long chain halidessuch as decyl, lauryl, myristyl and stearyl chlorides, bromides andiodides; arylalkyl halides such as benzyl and phenethyl bromidesand others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which can be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulphuric acid and phosphoricacid and such organic acids as oxalic acid, maleic acid, succinicacid, and citric acid.

Basic addition salts can be prepared in situ during the finalisolation and purification of compounds of this invention byreacting a carboxylic acid-containing moiety with a suitable basesuch as the hydroxide, carbonate or bicarbonate of apharmaceutically acceptable metal cation or with ammonia or anorganic primary, secondary or tertiary amine. Pharmaceuticallyacceptable salts include, but are not limited to, cations based onalkali 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 includingammonium, tetramethylammonium, tetraethylammonium, methylamine,dimethylamine, trimethylamine, triethylamine, diethylamine,ethylamine and the such as. Other representative organic aminesuseful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

The term "pharmaceutically acceptable ester," as used herein,refers to esters of compounds of the invention which hydrolyze invivo and include those that break down readily in the human body toleave the parent compound or a salt thereof. Examples ofpharmaceutically acceptable, non-toxic esters of the inventioninclude C.sub.1-to-C.sub.6 alkyl esters and C.sub.5-to-C.sub.7cycloalkyl esters, although C.sub.1-to-C.sub.4 alkyl esters arepreferred. Esters of the compounds of formula (I) may be preparedaccording to conventional methods. For example, such esters may beappended onto hydroxy groups by reaction of the compound thatcontains the hydroxy group with acid and an alkylcarboxylic acidsuch as acetic acid, or with acid and an arylcarboxylic acid suchas benzoic acid. In the case of compounds containing carboxylicacid groups, the pharmaceutically acceptable esters are preparedfrom compounds containing the carboxylic acid groups by reaction ofthe 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 thecompound with an acid such as hydrochloric acid and analkylcarboxylic acid such as acetic acid, or with acid and anarylcarboxylic acid such as benzoic acid.

The term "pharmaceutically acceptable amide," as used herein,refers to non-toxic amides of the invention derived from ammonia,primary C.sub.1-to-C.sub.6 alkyl amines and secondaryC.sub.1-to-C.sub.6 dialkyl amines. In the case of secondary amines,the amine may also be in the form of a 5- or 6-membered heterocyclecontaining one nitrogen atom. Amides derived from ammonia,C.sub.1-to-C.sub.3 alkyl primary amides and C.sub.1-to-C.sub.2dialkyl secondary amides are preferred. Amides of the compounds offormula (I) may be prepared according to conventional methods.Pharmaceutically acceptable amides are prepared from compoundscontaining primary or secondary amine groups by reaction of thecompound that contains the amino group with an alkyl anhydride,aryl anhydride, acyl halide, or aryl halide. In the case ofcompounds containing carboxylic acid groups, the pharmaceuticallyacceptable esters are prepared from compounds containing thecarboxylic acid groups by reaction of the compound with base suchas triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine,dialkylamine, for example with methylamine, diethylamine,piperidine. They also may be prepared by reaction of the compoundwith an acid such as sulfuric acid and an alkylcarboxylic acid suchas acetic acid, or with acid and an arylcarboxylic acid such asbenzoic acid under dehydrating conditions as with molecular sievesadded. The composition can contain a compound of the invention inthe form of a pharmaceutically acceptable prodrug.

The term "pharmaceutically acceptable prodrug" or "prodrug," asused herein, represents those prodrugs of the compounds of theinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and loweranimals without undue toxicity, irritation, allergic response, andthe like, commensurate with a reasonable benefit/risk ratio, andeffective for their intended use. Prodrugs of the invention may berapidly transformed in vivo to a parent compound of formula (I),for example, by hydrolysis in blood. A thorough discussion isprovided in T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems, V. 14 of the A.C.S. Symposium Series, and in Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987), herebyincorporated by reference.

The invention contemplates pharmaceutically active compounds eitherchemically synthesized or formed by in vivo biotransformation tocompounds of formula (I).

Methods of the Invention

Compounds and compositions of the invention are useful formodulating the effects of histamine-3 receptors. In particular, thecompounds and compositions of the invention can be used fortreating and preventing disorders modulated by the histamine-3receptors. Typically, such disorders can be ameliorated byselectively modulating the histamine-3 receptors in a mammal,preferably by administering a compound or composition of theinvention, either alone or in combination with another active agentas part of a therapeutic regimen.

The compounds of the invention, including but not limited to thosespecified in the examples, possess an affinity for the histamine-3receptors. As histamine-3 receptor ligands, the compounds of theinvention may be useful for the treatment and prevention ofdiseases or conditions such as acute myocardial infarction,Alzheimer's disease, asthma, attention-deficit hyperactivitydisorder, bipolar disorder, cognitive dysfunction, cognitivedeficits in psychiatric disorders, deficits of memory, deficits oflearning, dementia, cutaneous carcinoma, drug abuse, diabetes, typeII diabetes, depression, epilepsy, gastrointestinal disorders,inflammation, insulin resistance syndrome, jet lag, medullarythyroid 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 ofschizophrenia, seizures, septic shock, Syndrome X, Tourette'ssyndrome, vertigo, and sleep disorders.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat septic shockand cardiovascular disorders, in particular, acute myocardialinfarction may be demonstrated by Imamura et al., Circ. Res.,78:475 481 (1996); Imamura et. al., Circ. Res., 78:863 869 (1996);R. Levi and N. C. E. Smith, "Histamine H.sub.3-receptors: A newfrontier in myocardial ischemia", J. Pharm. Exp. Ther., 292:825 830(2000); and Hatta, E., K. Yasuda and R. Levi, "Activation ofhistamine H.sub.3 receptors inhibits carrier-mediatednorepinephrine release in a human model of protracted myocradialischemia", J. Pharm. Exp. Ther., 283:494 500 (1997).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat sleepdisorders, in particular, narcolepsy may be demonstrated by Lin etal., Brain Res., 523:325 330 (1990); Monti, et al.,Neuropsychopharmacology 15:31 35 (1996); Sakai, et al., Life Sci.,48:2397 2404 (1991); Mazurkiewicz-Kwilecki and Nsonwah, Can. J.Physiol. Pharmacol., 67:75 78 (1989); P. Panula, et al.,Neuroscience 44:465 481 (1998); Wada, et al., Trends inNeuroscience 14:415 (1991); and Monti, et al., Eur. J. Pharmacol.205:283 (1991).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat cognition andmemory process disorders may be demonstrated byMazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol.,67:75 78 (1989); P. Panula, et al., Neuroscience, 82:993 997(1997); Haas, et al., Behav. Brain Res., 66:41 44 (1995); DeAlmeida and Izquierdo, Arch. Int. Pharmacodyn., 283:193 198 (1986);Kamei et al., Psychopharmacology, 102:312 318 (1990); Kamei andSakata, Jpn. J. Pharmacol., 57:437 482 (1991); Schwartz et al.,Psychopharmacology, The fourth Generation of Progress. Bloom andKupfer (eds). Raven Press, New York, (1995) 397; and Wada, et al.,Trends in Neurosci., 14:415 (1991).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treatattention-deficit hyperactivity disorder (ADHD) may be demonstratedby Shaywitz et al., Psychopharmacology, 82:73 77 (1984); Dumery andBlozovski, Exp. Brain Res., 67:61 69 (1987); Tedford et al., J.Pharmacol. Exp. Ther., 275:598 604 (1995); Tedford et al., Soc.Neurosci. Abstr., 22:22 (1996); and Fox, et al., Behav. Brain Res.,131:151 161 (2002).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat seizures, inparticular, epilepsy may be demonstrated by Yokoyama, et al., Eur.J. Pharmacol., 234:129 (1993); Yokoyama and linuma, CNS Drugs 5:321(1996); Onodera et al., Prog. Neurobiol., 42:685 (1994); R. Leurs,R. C. Vollinga and H. Timmerman, "The medicinal chemistry andtherapeutic potential of ligands of the histamine H.sub.3receptor", Progress in Drug Research 45:170 165, (1995); Leurs andTimmerman, Prog. Drug Res., 39:127 (1992); The Histamine H.sub.3Receptor, Leurs and Timmerman (eds), Elsevier Science, Amsterdam,The Netherlands (1998); and H. Yokoyama and K. Iinuma, "Histamineand Seizures: Implications for the treatment of epilepsy", CNSDrugs, 5(5):321 330 (1995).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat motionsickness, Alzheimer's disease, and Parkinson's disease may bedemonstrated by Onodera, et al., Prog. Neurobiol., 42:685 (1994);Leurs and Timmerman, Prog. Drug Res., 39:127 (1992); and TheHistamine H.sub.3 Receptor, Leurs and Timmerman (eds), ElsevierScience, Amsterdam, The Netherlands (1998).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat narcolepsy,schizophrenia, depression, and dementia may be demonstrated by R.Leurs, R. C. Vollinga and H. Timmerman, "The medicinal chemistryand therapeutic potential of ligands of the histamine H.sub.3receptor", Progress in Drug Research 45:170 165 (1995); TheHistamine H.sub.3 Receptor, Leurs and Timmerman (eds), ElsevierScience, Amsterdam, The Netherlands (1998); and Perez-Garcia C, et.al., and Psychopharmacology (Berl) 142(2):215 20 (February,1999).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat sleepdisorders, cognitive dysfunction, mood and attention alteration,vertigo and motion sickness, and treatment of cognitive deficits inpsychiatric disorders may be demonstrated by Schwartz, Physiol.Review 71:1 51 (1991).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat mildcognitive impairment, deficits of memory, deficits of learning anddementia may be demonstrated by C. E. Tedford, in "The HistamineH.sub.3 Receptor: a target for new drugs", the PharmacochemistryLibrary, vol. 30 (1998) edited by R. Leurs and H. Timmerman,Elsevier (New York). p. 269 and references also containedtherein.

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat obesity maybe demonstrated by Leurs, et al., Trends in Pharm. Sci., 19:177 183(1998); E. Itoh, M. Fujimiay, and A. Inui, "Thioperamide, Ahistamine H.sub.3 receptor antagonist, powerfully suppressespeptide YY-induced food intake in rats," Biol. Psych., 45(4):475481 (1999); S. I. Yates, et al., "Effects of a novel histamineH.sub.3 receptor antagonist, GT-2394, on food intake and weightgain in Sprague-Dawley rats," Abstracts, Society for Neuroscience,102.10:219 (November, 2000); and C. Bjenning, et al., "Peripherallyadministered ciproxifan elevates hypothalamic histamine levels andpotently reduces food intake in the Sprague Dawley rat," Abstracts,International Sendai Histamine Symposium, Sendai, Japan, #P39(November, 2000).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat inflammationand pain may be demonstrated by Phillips, et al., Annual Reports inMedicinal Chemistry 33:31 40 (1998).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat migraine maybe demonstrated by R. Leurs, R. C. Vollinga and H. Timmerman, "Themedicinal chemistry and therapeutic potential of ligands of thehistamine H.sub.3 receptor," Progress in Drug Research 45:170 165(1995); Matsubara, et al., Eur. J. Pharmacol., 224:145 (1992); andRouleau, et al., J. Pharmacol. Exp. Ther., 281:1085 (1997).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat cancer, inparticular, melanoma, cutaneous carcinoma and medullary thyroidcarcinoma may be demonstrated by Adam Szelag, "Role of histamineH.sub.3-receptors in the proliferation of neoplastic cells invitro," Med. Sci. Monit., 4(5):747 755 (1998); and C. H.Fitzsimons, et al., "Histamine receptors signalling in epidermaltumor cell lines with H-ras gene alterations," Inflammation Res.,47 (Suppl 1):S50 S51 (1998).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat vestibulardysfunctions, in particular, Meniere's disease may be demonstratedby R. Leurs, R. C. Vollinga and H. Timmerman, "The medicinalchemistry and therapeutic potential of ligands of the histamineH.sub.3 receptor," Progress in Drug Research 45:170 165 (1995), andPan, et al., Methods and Findings in Experimental and ChemicalPharmacology 21:771 777 (1998).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat asthma may bedemonstrated by A. Delaunois A., et al., "Modulation ofacetylcholine, capsaicin and substance P effects by histamineH.sub.3 receptors in isolated perfused rabbit lungs," EuropeanJournal of Pharmacology 277(2 3):243 250 (1995); and Dimitriadou,et al., "Functional relationship between mast cells and C-sensitivenerve fibres evidenced by histamine H.sub.3-receptor modulation inrat lung and spleen," Clinical Science 87(2):151 163 (1994).

The ability of the compounds of the invention, including, but notlimited to, those specified in the examples, to treat allergicrhinitis may be demonstrated by McLeod, et al., Progress in Resp.Research 31:133 (2001).

Compounds of the invention are particularly useful for treating andpreventing a condition or disorder affecting the memory orcognition, for example Alzheimer's disease, attention-deficithyperactivity disorder, schizophrenia, or the cognitive deficits ofschizophrenia.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain anamount of the active compound(s) which is effective to achieve thedesired therapeutic response for a particular patient, compositionsand mode of administration. The selected dosage level will dependupon the activity of the particular compound, the route ofadministration, the severity of the condition being treated and thecondition and prior medical history of the patient being treated.However, it is within the skill of the art to start doses of thecompound at levels lower than required to achieve the desiredtherapeutic effect and to gradually increase the dosage until thedesired effect is achieved.

When used in the above or other treatments, a therapeuticallyeffective amount of one of the compounds of the invention can beemployed in pure form or, where such forms exist, inpharmaceutically acceptable salt, ester, amide or prodrug form.Alternatively, the compound can be administered as a pharmaceuticalcomposition containing the compound of interest in combination withone or more pharmaceutically acceptable carriers. The phrase"therapeutically effective amount" of the compound of the inventionmeans a sufficient amount of the compound to treat disorders, at areasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particularpatient will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; activityof the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the durationof the treatment; drugs used in combination or coincidental withthe specific compound employed; and like factors well known in themedical arts. For example, it is well within the skill of the artto start doses of the compound at levels lower than required toachieve the desired therapeutic effect and to gradually increasethe dosage until the desired effect is achieved.

The total daily dose of the compounds of this inventionadministered to a human or lower animal may range from about 0.0003to about 30 mg/kg/day. For purposes of oral administration, morepreferable doses can be in the range of from about 0.01 to about0.1 mg/kg/day. If desired, the effective daily dose can be dividedinto multiple doses for purposes of administration; consequently,single dose compositions may contain such amounts or submultiplesthereof to make up the daily dose.

The compounds and processes of the invention will be betterunderstood by reference to the following examples, which areintended as an illustration of and not a limitation upon the scopeof the invention.

REFERENCE EXAMPLES

Reference Example 1

Preparation of (2R)-2-methylpyrrolidine

and

(2S)-2-methylpyrrolidine

(2R)-2-Methylpyrrolidine tartrate was prepared via resolution of2-methylpyrrolidine with D-tartaric acid using procedures describedby William Gaffield, et al. in Tetrahedron, 37:1861 1869 (1981) or,alternatively, prepared from L-prolinol by methods described byKarrer and Ehrhardt in Helv. Chim. Acta, 34: 2202, 2208 (1951).(2R)-2-methylpyrrolidine hydrobromide also is a suitable source of(2R)-2-methylpyrrolidine, and was prepared using the proceduredescribed 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); andElworthy, 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 providedherein. The (2S)-2-methylpyrrolidine can be prepared by proceduresdescribed in Kim, Mahn-Joo, et al., Bioorg. Med. Chem. Lett.6(1):71 76 (1996).

Reference Example 2

Preparation of Boronic Acid and Ester Reagents

There are many bicyclic and tricyclic boronic acids and boronicacid esters that are available commercially or that can be preparedas described in the scientific literature of synthetic organicchemistry. Non-exhaustive examples of boronic acid and boronic acidester reagents for the synthesis of compounds of formula (I) areprovided in Table 1, below, and the following description.

TABLE-US-00001 TABLE 1 Examples of Boronic Acid and Boronic AcidEster Reagents Commercial Source, Chemical Abstracts Boronic Acidor Boronic Acid Ester Number or Literature ReferenceThianthrene-1-boronic acid Aldrich Chemical Company, Inc.Benzoxazole-5-boronic acid Cat # 110831, Asymchem Laboratories,Inc. Benzothiazole-5-boronic acid Cat # 1464, Digital SpecialtyChemicals, Inc. 4-Methyl-7-(4,4,5,5-tetramethyl-1,3,2- Cat #CC13539CB, dioxaborolan-2-yl)-3,4-dihydro-2h-1,4- Acros OrganicsUSA benzoxazine 10-Methyl-3-(4,4,5,5-tetramethyl- Kraemer, C. S.;et. al. [1,3,2]dioxaborolan-2-yl)-10H- Synthesis 2002, 9, 11631170. phenothiazine (1,4-Dihydro-4,4-dimethyl-2-oxo-2H- Zhang, P.;et. al. J. Med. 3,1-benzoxazin-6-yl)boronic acid Chem. 2002, 45,4379 4382.

Boronic acid esters of formula (14),(R.sub.94O).sub.2B-L.sub.2R.sub.6 (14), wherein L.sub.2 is a bond,and wherein R.sub.94 is lower alkyl or wherein R.sub.94 can betaken together to form a ring which may itself be substituted withalkyl or aryl groups, may serve as synthetic replacements forboronic acids of formula (14), wherein R.sub.94 is hydrogen.Boronic acids of formula (14) and boronic acid esters of formula(14) are commercially available or can be prepared by methods wellknown 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 usingheteroaromatic compounds and reaction with bis(pinacolborane) inthe presence of an iridium catalysis ofIrCl[COD]2-(4,4'-di-t-butyl-2,2'-bipyridine in octane. Othermethods have been described wherein aryl halides and heteroarylhalides are transmetallated with alkyl lithiums or Grignardreagents, then treated with trialkylborate esters, then treatedwith acid to produce boronic acids and boronic acid esters (B. T.O'Neill, et al., Organic Letters, 2:4201 (2000); M. D. Sindkhedkar,et al., Tetrahedron, 57:2991 (2001); W. C. Black, et al., Journalof Medicinal Chemistry, 42:1274 (1999); Letsinger; Dandegaonker, J.Amer. Chem. Soc., 81:498 501 (1959); Carroll, F. Ivy, et al. J.Med. Chem., 2229 2237 (2001). Another method is the Miyaurareaction described in Ishiyama, Tatsuo; Ishida, Kousaku, Miyaura,Norio, Tetrahedron, 9813 9816 (2001) in which aryl and heteroarylhalides are reacted with bis(pinacolborane), KOAc, andPd.sub.2dba.sub.3 and tris-cyclohexylphosphine or PdCl.sub.2dppf(Ishiyama, et al. Tetrahedron, 9813 9816 (2001)). Another methodfor preparation of boronic acids and boronic acid esters is thereaction described in O. Baudoin, et al., J. Org. Chem., 65:92689271 (2000), in which aryl and heteroaryl halides or triflates arereacted with a dialkoxyborane such as pinacolborane, in thepresence of Et.sub.3N and Pd(OAc).sub.2 in dioxane. Methodologiesfor preparing compounds of formula (14) wherein one of the rings ofR.sub.6 is a cycloalkyl ring can be prepared, for example, frombicyclic or polycyclic compounds wherein one of the rings is acycloalkene (for example, see H. C. Brown, et al., J. Amer. Chem.Soc., 95:2396 2397 (1973) and H. C. Brown, et al., J. Amer. Chem.Soc., 98:1798 1806 (1976)) or cycloalkyl Grignard or cycloalkyllithium intermediates (see, for example, Graf et al., Tetrahedron,55:8801 8814 (1999) and Michailow, et al., Izv. Akad. Nauk SSSRSer. Khim, 76:78 (1959)).

Reference Example 3

Preparation of Stannane-Type Reagents

Reagents such Bu.sub.3SnR.sub.6 are suitable for reactions underStille conditions in Scheme 1 and are commercially available.However, where the reagents such as Me.sub.3SnR.sub.6,Bu.sub.3SnR.sub.6, and R.sub.6ZnCl wherein R.sub.6 is bicyclic ortricyclic are not commercially available, they may be prepared bymethods available to one with skill in the art. Examples of suchmethods include lithium halogen-metal exchange of heteroaryl,heterocyclic or aryl halides, followed by treatment withMe.sub.3SnCl (Li, et al. J. Med. Chem. 1996, 39, 1846),Bu.sub.3SnCl, ZnCl.sub.2, or B(OCH.sub.3).sub.3 (O'Neill, et al.Org. Lett. 2000, 2, 4201; Sindkhedkar, et al. Tet. 2001, 57, 2991)and magnesium halogen-metal exchange with isopropylmagnesiumchloride as described in Knochel, et al. J. Org. Chem. 2000, 65,4618 4634, followed by treatment with Me.sub.3SnCl, Bu.sub.3SnCl,or ZnCl.sub.2. Heteroaryl halides and triflates can be treated withtrimethylstannyl sodium as described in A. O. Koren, et al. J. Med.Chem. 1998, 41, 3690, to give Me.sub.3SnR.sub.6. Heteroaryl halidesand triflates can be treated wtih hexamethyldistannane as describedin W. C. Black, et al. J. Med. Chem. 1999, 42, 1274, to giveMe.sub.3SnR.sub.6.

EXAMPLES

Example 1

6-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-2-(4H-thieno[3,2-b]pyrrol-5-yl-)-quinoline

Example 1A

(2R)-2-Methylpyrrolidine

A flask containing 20 mL (20 mmol) of a 1M solution of LiAlH.sub.4in THF was cooled to 0.degree. C. To this well stirred solution wasadded 1.35 g (5.0 mmol) of [(2S)-5-oxopyrrolidin-2-yl]methyl4-methylbenzenesulfonate (CAS #51693-17-5) in 50 mL of THF. Thereaction was allowed to warm to 23.degree. C., and stirred for 60hours, then quenched by slow addition of 3 grams of powdered sodiumsulfate decahydrate. After one hour, the solids were removed byfiltration, and washed with isopropyl ether. Some loss of solventto evaporation occurred, so the filtrate and washings were combinedand diluted with isopropanol to 50 mL total volume. 40 mL of thesolution was treated with 600 mg (4.0 mmol) of L-tartaric acid inmethanol. After concentration under vacuum, a syrup was obtainedwhich solidified on standing, to give a quantitative yield (960 mg)of (2R)-methylpyrrolidine L-tartrate as a white powder.

Example 1B

(2R)-2-Methyl-1-[2-(4-nitrophenyl)ethyl]pyrrolidine

Example 1A (4.0 g, 17.0 mmol), 1-(2-bromoethyl)-4-nitrobenzene (9.8g, 43 mmol), and potassium carbonate (12 g, 85 mmol), were combinedin DMF (20 mL) in a sealed tube at 50.degree. C. and stirredvigorously for 16 hours. The mixture was allowed to cool to roomtemperature, diluted with diethyl ether (100 mL), washed with water(2 times, 100 mL and then 50 mL), and extracted with 1M HCl (2times, 50 mL and 25 mL). The aqueous acidic extractions werecombined, washed with diethyl ether (50 mL), cooled to 0.degree.C., adjusted to pH 14 with 50% NaOH solution, and extracted withdichloromethane (3 times, 50 mL). The dichloromethane extractionswere combined, dried (MgSO.sub.4), filtered, and the filtrateconcentrated to provide the title compound. .sup.1H NMR (300 MHz,CDCl.sub.3) .delta. 1.08 (d, J=6 Hz, 3 H), 1.43 (m, 1 H), 1.75 (m,2 H), 1.93 (m, 1 H), 2.19 (q, J=9 Hz, 1 H), 2.34 (m, 2 H), 2.91 (m,2 H), 3.03 (m, 1 H), 3.22 (td, J=8, 3 Hz, 1 H), 7.38 (d, J=9 Hz, 2H), 8.15 (d, J=9 Hz, 2 H); MS (DCl/NH.sub.3) m/z 235(M+H).sup.+.

Example 1C

4-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}aniline

The product from Example 1B (3.85 g, 16.4 mmol) was hydrogenatedusing 10% Pd/C (0.39 g) in methanol (20 mL) under 1 atm H.sub.2 for16 hours. After the H.sub.2 was replaced with N.sub.2, the mixturewas diluted with methanol (150 mL), stirred for 15 minutes,filtered, and the filtrate was concentrated to provide the titlecompound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.11 (d, J=6Hz, 3 H), 1.43 (m, 1 H), 1.74 (m, 2 H), 1.90 (m, 1 H), 2.25 (m, 3H), 2.70 (m, 2 H), 2.97 (m, 1 H), 3.24 (td, J=9, 3 Hz, 1 H), 3.55(s, 2 H), 6.63 (d, J=8 Hz, 2 H), 7.01 (d, J=8 Hz, 2 H); MS(DCl/NH.sub.3) m/z 205 (M+H).sup.+.

Example 1D

2,2-Dimethyl-N-(4-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}phenyl)propanamid-e

The product from Example 1C (2.77 g, 14 mmol) was dissolved inanhydrous dichloromethane (70 mL) under nitrogen, treated withtriethylamine (2.3 mL, 16 mmol), cooled to 0.degree. C., treatedwith trimethylacetyl chloride (1.9 mL, 15 mmol), stirred at ambienttemperature for 60 hours and treated with 1M NaOH (40 mL). Thelayers were separated and the aqueous layer was extracted withdichloromethane (2 times, 40 mL). The combined dichloromethanelayers were dried (MgSO.sub.4), filtered, and the filtrate wasconcentrated to provide 4.0 g of the title compound. .sup.1H NMR(300 MHz, CDCl.sub.3) .delta. 1.10 (d, J=6 Hz, 3 H), 1.31 (s, 9 H),1.44 (m, 1 H), 1.76 (m, 2 H), 1.92 (m, 1 H), 2.18 (q, J=9 Hz, 1 H),2.27 (m, 2 H), 2.78 (m, 2 H), 2.99 (m, 1 H), 3.23 (td, J=9, 3 Hz, 1H), 7.17 (d, J=8 Hz, 2 H), 7.44 (d, J=8 Hz, 2 H); MS (DCl/NH.sub.3)m/z 289 (M+H).sup.+.

Example 1E

N-(2-Formyl-4-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}phenyl)-2,2-dimethylp-ropanamide

The product from Example 1D (4.0 g, 13.9 mmol) under nitrogen inanhydrous diethyl ether (140 mL) was treated withN,N,N'N'-tetramethylethylenediamine (6.5 mL, 43 mmol), cooled to-5.degree. C., treated with n-butyllithium (16.7 mL of a 2.5 Msolution in hexanes) over 10 minutes, stirred for 4 hours atambient temperature, cooled to -5.degree. C., treated all at oncewith anhydrous N,N-dimethylformamide (6.5 mL, 83 mmol), stirred for16 hours at ambient temperature, diluted with diethyl ether (100mL), washed with water (75 mL), washed with brine, dried(MgSO.sub.4), filtered, and the filtrate was concentrated. Theresidue was purified by chromatography on silica gel eluting with agradient of 2%, 3.5%, 5%, and 7.5% (9:1 MeOH:conc NH.sub.4OH) indichloromethane to provide the title compound. .sup.1H NMR (300MHz, CDCl.sub.3) .delta. 1.10 (d, J=6 Hz, 3 H), 1.35 (s, 9 H), 1.44(m, 1 H), 1.75 (m, 2 H), 1.93 (m, 1 H), 2.19 (q, J=9 Hz, 1 H), 2.31(m, 2 H), 2.85 (m, 2 H), 3.01 (m, 1 H), 3.23 (td, J=8, 3 Hz, 1 H),7.47 (dd, J=8, 2 Hz, 1 H), 7.51 (d, J=2 Hz, 1 H), 8.71 (d, J=8 Hz,1 H), 9.92 (s, 1 H), 11.31 (s, 1 H); MS (DCl/NH.sub.3) m/z 317(M+H).sup.+.

Example 1F

2-Amino-5-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}benzaldehyde

The product from Example 1E (2.46 g, 7.8 mmol) in 3M HCl (40 mL)was heated at 80.degree. C. for 4 hours, allowed to cool to roomtemperature, and carefully poured into a mixture of 1M NaOH (250mL) and dichloromethane (75 mL). The layers were separated and theaqueous layer was extracted with dichloromethane (2 times, 75 mL).The combined dichloromethane layers were dried (MgSO.sub.4),filtered, and the filtrate was concentrated. The residue waspurified by chromatography on silica gel eluting with a gradient of2%, 3.5% and 5% (9:1 MeOH:conc NH.sub.4OH) in dichloromethane toprovide the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3).delta. 1.12 (d, J=6 Hz, 3 H), 1.50 (m, 1 H), 1.76 (m, 2 H), 1.93(m, 1 H), 2.25 (m, 3 H), 2.76 (m, 2 H), 2.99 (m, 1 H), 3.25 (td,J=9, 3 Hz, 1 H), 5.99 (s, 2 H), 6.60 (d, J=8 Hz, 1 H), 7.19 (dd,J=8, 2 Hz, 1 H), 7.31 (d, J=2 Hz, 1 H), 9.85 (s, 1 H); MS(DCl/NH.sub.3) m/z 233 (M+H).sup.+.

Example 1G

6-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-2-(4H-thieno[3,2-b]pyrrol-5-yl-)-quinoline

The product from Example 1F (23 mg, 0.1 mmol) and1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone (Maybridge ChemicalCompany Ltd., catalog number SEW 02099) (10 mg, -0.06 mmol) werecombined in ethanol 0.2 mL and treated with one drop of a saturatedsolution of potassium hydroxide in ethanol and heated at 80.degree.C. for 16 hours. The mixture was allowed to cool to roomtemperature and concentrated. The residue was purified bychromatography on silica gel eluting with a gradient of 2% and 3.5%of (9:1 MeOH:conc NH.sub.4OH) in dichloromethane to provide thetitle compound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.13 (d,J=6.10 Hz, 3 H), 1.46 (m, 1 H), 1.77 (m, 2 H), 1.94 (m, 1 H), 2.24(q, J=8.82 Hz, 1 H), 2.37 (m, 2 H), 2.98 (m, 2 H), 3.12 (m, 1 H),3.29 (td, J=8.48, 2.71 Hz, 1 H), 6.98 (dd, J=5.76, 0.68 Hz, 1 H),7.06 (s, 1 H), 7.18 (d, J=5.43 Hz, 1 H), 7.56 (m, 2 H), 7.72 (d,J=8.82 Hz, 1 H), 7.92 (d, J=8.14 Hz, 1 H), 8.03 (d, J=8.82 Hz, 1H), 9.89 (br. s, 1 H); MS (DCl/NH.sub.3) [M+H].sup.+ at 362.

Example 2

3-Methyl-2-{6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-ben-zo[4,5]imidazo[2,1-b]thiazole

The title compound was prepared using the procedure described inExample 1G substituting1-(3-methyl-benzo[4,5]imidazo[2,1-b]thiazol-2-yl)-ethanone (KeyOrganics Limited/Bionet Research, catalog number 1r-1190) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. .sup.1H NMR (300 MHz,CDCl.sub.3) .delta. 1.14 (d, J=6.10 Hz, 3 H), 1.47 (m, 1 H), 1.78(m, 2 H), 1.95 (m, 1 H), 2.25 (q, J=8.59 Hz, 1 H), 2.39 (m, 2 H),3.02 (m, 2 H), 3.13 (m, 1 H), 3.20 (s, 3 H), 3.29 (td, J=8.48, 2.71Hz, 1 H), 7.28 (m, 1 H), 7.40 (td, J=7.71, 1.19 Hz, 1 H), 7.66 (m,3 H), 7.82 (d, J=7.80 Hz, 1H), 7.90 (d, J=8.14 Hz, 1 H), 8.05 (d,J=9.16 Hz, 1 H), 8.18 (d, J=8.48 Hz, 1 H); MS (DCl/NH.sub.3)[M+H].sup.+ at 427.

Example 3

2-(2-Methyl-imidazo[1,2-a]pyridin-3-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-y-l)-ethyl]-quinoline

The title compound was prepared using the procedure described inExample 1G substituting1-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-ethanone (Key OrganicsLimited/Bionet Research, catalog number 1j-043) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. .sup.1H NMR (300 MHz,CDCl.sub.3) .delta. 1.16 (d, J=6.10 Hz, 3 H), 1.49 (m, 1 H), 1.79(m, 2 H), 1.96 (m, 1 H), 2.27 (m, 1 H), 2.43 (m, 2 H), 2.78 (s, 3H), 3.05 (m, 2 H), 3.15 (m, 1 H), 3.32 (m, 1 H), 6.90 (td, J=6.95,1.36 Hz, 1 H), 7.29 (m, 1 H), 7.63 (m, 3 H), 7.71 (d, J=8.48 Hz, 1H), 8.05 (d, J=8.48 Hz, 1 H), 8.19 (d, J=8.82 Hz, 1 H), 9.69 (dt,J=7.04, 1.06 Hz, 1 H); MS (DCl/NH.sub.3) [M+H].sup.+ at 371.

Example 4

2-(4H-Benzo[1,3]dioxin-6-yl)-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-q-uinoline

The title compound was prepared using the procedure described inExample 1G substituting 1-(4H-benzo[1,3]dioxin-6-yl)-ethanone(Goswami, J., et. al. J. Indian Chem. Soc., 2002, 79(5), 469 471)for 1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. .sup.1H NMR (300 MHz,CDCl.sub.3) .delta. 1.14 (d, J=6.10 Hz, 3 H), 1.47 (m, 1 H), 1.78(m, 2 H), 1.95 (m, 1 H), 2.25 (m, 1 H), 2.40 (m, 2 H), 3.03 (m, 2H), 3.13 (m, 1 H), 3.30 (m, 1 H), 5.03 (s, 2 H), 5.31 (s, 2 H),7.01 (d, J=8.48 Hz, 1 H), 7.60 (dd, J=8.48, 2.03 Hz, 1 H), 7.62 (s,1 H), 7.78 (d, J=8.48 Hz, 1 H), 7.88 (d, J=2.03 Hz, 1 H), 7.92 (dd,J=8.65, 2.20 Hz, 1 H), 8.04 (d, J=8.48 Hz, 1 H), 8.13 (d, J=8.48Hz, 1 H); MS (DCl/NH.sub.3) [M+H].sup.+ at 375.

Example 5

6-[2-((2R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-2-[1,2,4]triazolo[1,5-a]pyrimi-din-5-yl-quinoline

The title compound was prepared using the procedure described inExample 1G substituting1-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl-ethanone for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. .sup.1H NMR (300 MHz,CDCl.sub.3) .delta. 1.15 (d, J=6.10 Hz, 3 H), 1.49 (m, 1 H), 1.79(m, 2 H), 1.96 (m, 1 H), 2.27 (m, 1 H), 2.43 (m, 2 H), 3.05 (m, 2H), 3.15 (m, 1 H), 3.32 (m, 1 H), 7.68 (dd, J=8.48, 2.03 Hz, 1 H),7.73 (d, J=1.70 Hz, 1 H), 8.13 (d, J=8.48 Hz, 1 H), 8.30 (d, J=8.48Hz, 1 H), 8.56 (s, 1 H), 8.65 (d, J=7.12 Hz, 1 H), 8.79 (d, J=8.48Hz, 1 H), 8.94 (d, J=7.12 Hz, 1 H); MS (DCl/NH.sub.3) [M+H].sup.+at 359.

Example 6

2-Benzothiazol-2-yl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-ethyl]-quinoline

The title compound was prepared using the procedure described inExample 1G substituting 1-benzothiazol-2-yl-ethanone (OakwoodProducts, Inc., catalog number 9660) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. .sup.1H NMR (300 MHz,CDCl.sub.3) .delta. 1.15 (d, J=6.10 Hz, 3 H), 1.48 (m, 1 H), 1.77(m, 2 H), 1.96 (m, 1 H), 2.27 (q, J=8.48 Hz, 1 H), 2.42 (m, 2 H),3.06 (m, 2 H), 3.15 (m, 1 H), 3.31 (m, 1 H), 7.44 (td, J=7.63, 1.36Hz, 1 H), 7.52 (td, J=7.63, 1.36 Hz, 1 H), 7.66 (dd, J=8.48, 2.03Hz, 1 H), 7.69 (s, 1 H), 7.99 (d, J=7.12 Hz, 1 H), 8.13 (m, 2 H),8.24 (d, J=8.48 Hz, 1 H), 8.47 (d, J=8.82 Hz, 1 H); MS(DCl-NH.sub.3) [M+H].sup.+ at 374.

Example 7

3-Benzotriazol-1-ylmethyl-2-methyl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-et-hyl]-quinoline

The title compound was prepared using the procedure described inExample 1G substituting 4-benzotriazol-1-yl-butan-2-one (Katritzky,A. R., et. al. J. Org. Chem., 2001, 66(16), 5606 5612) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. .sup.1H NMR (300 MHz,CDCl.sub.3) .delta. 1.11 (d, J=5.76 Hz, 3 H), 1.45 (m, 1 H), 1.76(m, 2 H), 1.93 (m, 1 H), 2.21 (m, 1 H), 2.35 (m, 2 H), 2.77 (s, 3H), 2.96 (m, 2 H), 3.07 (m, 1 H), 3.26 (m, 1 H), 6.01 (s, 2 H),7.32 7.47 (m, 4 H), 7.57 (m, 2 H), 7.94 (d, J=8.48 Hz, 1 H), 8.13(m, 1 H); MS (DCl/NH.sub.3) [M+H].sup.+ at 386.

Example 8

2-[1,3]Dioxolo[4,5-b]pyridin-6-yl-6-[2-((2R)-2-methyl-pyrrolidin-1-yl)-eth-yl]-quinoline

The title compound was prepared using the procedure described inExample 1G substituting 1-[1,3]dioxolo[4,5-b]pyridin-6-yl-ethanone(Dallacker et al., Z. Naturforsch. B Anorg. Chem. Org. Chem., 1979,34, 1729 1733) for 1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone..sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.15 (d, J=6.10 Hz, 3 H),1.49 (m, 1 H), 1.79 (m, 2 H), 1.96 (m, 1 H), 2.27 (m, 1 H), 2.43(m, 2 H), 3.05 (m, 2 H), 3.15 (m, 1 H), 3.32 (m, 1 H), 6.15 (s, 2H), 7.62 (dd, J=8.48, 1.70 Hz, 1 H), 7.64 (s, 1 H), 7.78 (d, J=8.48Hz, 1 H), 7.97 (d, J=1.70 Hz, 1 H), 8.04 (d, J=8.48 Hz, 1 H), 8.15(d, J=8.48 Hz, 1 H), 8.37 (d, J=2.03 Hz, 1 H); MS (DCl/NH.sub.3)[M+H].sup.+ at 362.

Example 9

6-{2-[(2R)-2-Methyl-pyrrolidin-1-yl]-ethyl}-2-(6-methyl-thiazolo[3,2-b][1,-2,4]triazol-5-yl)-quinoline

The title compound was prepared using the procedure described inExample 1G substituting1-(6-methyl-thiazolo[3,2-b][1,2,4]triazol-5-yl)-ethanone (KeyOrganics Limited/Bionet Research, catalog number 7M-582S) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. .sup.1H NMR (300 MHz,CD.sub.3OD) .delta. 1.17 (d, J=6 Hz, 3 H), 1.48 (m, 1 H), 1.82 (m,2 H), 2.02 (m, 1 H), 2.33 (q, J=9 Hz, 1 H), 2.46 (m, 2 H), 2.96 (s,3 H), 3.05 (m, 2 H), 3.18 (m, 2 H), 7.70 (d, J=9 Hz, 1 H), 7.78 (s,1 H), 7.90 (d, J=9 Hz, 1 H), 7.99 (d, J=9 Hz, 1 H), 8.25 (s, 1 H),8.35 (d, J=9 Hz, 1 H); MS (DCl/NH.sub.3) m/z 378 (M+H).sup.+.

Example 10

2-(2,3-Dihydro-imidazo[2,1-b]thiazol-6-yl)-6-{2-[(2R)-2-methyl-pyrrolidin--1-yl]-ethyl}-quinoline

The title compound was prepared using the procedure described inExample 1G substituting1-(2,3-dihydro-imidazo[2,1-b]thiazol-6-yl)-ethanone (Kaugars, G.;et. al. Heterocycles 1994, 38, pages 2593 2604) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. .sup.1H NMR (300 MHz,CD.sub.3OD) .delta. 1.17 (d, J=6 Hz, 3 H), 1.47 (m, 1 H), 1.81 (m,2 H), 2.00 (m, 1 H), 2.34 (q, J=9 Hz, 1 H), 2.47 (m, 2 H), 3.03 (m,2 H), 3.17 (m, 1 H), 3.28 (m, 1 H), 3.97 (t, J=9 Hz, 2 H), 4.35 (t,J=9 Hz, 2 H), 7.63 (dd, J=9 Hz, J=3 Hz, 1 H), 7.72 (d, J=3 Hz, 1H), 7.93 (d, J=9 Hz, 2 H), 7.94 (s, 1 H), 8.23 (d, J=9 Hz, 1 H); MS(DCl/NH.sub.3) m/z 365 (M+H).sup.+.

Example 11

2-(2,7-Dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl)-6-{2-[(2R)-2-methyl-pyrroli-din-1-yl]-ethyl}-quinoline

Example 11A

1-(2,7-Dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl)-ethanone

A solution of 3-dimethylaminomethylene-pentane-2,4-dione (4 g, 25.8mmol) and 3-amino-5-methylpyrazole (2.45 g, 24.5 mmol) in ethanol(50 mL) was heated to reflux for 2 hrs, then cooled to ambienttemperature and stirred over night. The solid precipitate wascollected by filtration and washed with cold ethanol (50 mL). Thesolid was dried under vacuum to provided 3.8 g of the titlecompound. .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 2.52 (s, 3 H),2.68 (s, 3 H), 3.07 (s, 3 H), 6.55 (s, 1 H), 6.87 (s, 1 H); MS(DCl/NH.sub.3) m/z 190 (M+H).sup.+.

Example 11B

2-(2,7-Dimethyl-pyrazolo[1,5-a]pyrimidin-6-yl)-6-{2-[(2R)-2-methyl-pyrroli-din-1-yl]-ethyl}-quinoline

The title compound was prepared using the procedure described inExample 1G substituting the product from Example 11A for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. .sup.1H NMR (300 MHz,CD.sub.3OD) .delta. 1.17 (d, J=6 Hz, 3 H), 1.48 (m, 1 H), 1.82 (m,2 H), 2.03 (m, 1 H), 2.35 (q, J=9 Hz, 1 H), 2.47 (m, 2 H), 2.56 (s,3 H), 2.91 (s, 3 H), 3.06 (m, 2 H), 3.20 (m, 1 H), 3.28 (m, 1 H),6.59 (s, 1 H), 7.76 (dd, J=9 Hz, J=3 Hz, 1 H), 7.78 (d, J=9 Hz, 1H), 7.88 (d, J=3 Hz, 1 H), 8.05 (d, J=9 Hz, 1 H), 8.45 (d, J=9 Hz,1 H), 8.66 (s, 1 H); MS (DCl/NH.sub.3) m/z 386 (M+H).sup.+.

Example 12

2-Methyl-3-{6-[2-([2R]-2-methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-[1,-8]naphthyridine

The title compound was prepared using the procedure described inExample 1G substituting1-(2-methyl-[1,8]naphthyridin-3-yl)-ethanone (Reddy, K. V.; et. al.J. Indian Chem. Soc. 1986, 63, pages 443 445) for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. .sup.1H NMR (300 MHz,CD.sub.3OD) .delta. 1.16 (d, J=6 Hz, 3 H), 1.48 (m, 1 H), 1.76 (m,1 H), 1.84 (m, 1 H), 1.97 (m, 2 H), 2.28 (q, J=9 Hz, 1 H), 2.43 (m,2 H), 2.95 (s, 3 H), 3.08 (m, 2 H), 3.17 (m, 1 H), 6.59 (s, 1 H),7.47 (dd, J=6 Hz, J=3 Hz, 1 H), 7.62 (d, J=6 Hz, 1 H), 7.69 (dd,J=6 Hz, J=1.5 Hz, 1 H), 7.73 (s, 1 H), 8.11 (d, J=6 Hz, 1 H), 8.23(dd, J=6 Hz, J=1.5 Hz, 1 H), 8.25 (d, J=6 Hz, 1 H), 8.30 (s, 1 H);MS (DCl/NH.sub.3) m/z 383 (M+H).sup.+.

Example 13

6-{6-[2-([2R]-2-Methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-quinoxaline

Example 13A

1-Quinoxalin-6-yl-ethanone

A solution of 6-bromo-quinoxaline (261 mg, 1.25 mmol),1-ethoxyvinyltri-n-butyltin (0.47 mL, 1.4 mmol), palladium(II)acetate (16 mg) and tri-t-butylphosphonium tetrafluoroborate (41mg) in anhydrous DMF (4 mL) under a nitrogen atmosphere was heatedat 120.degree. C. for 1 hr. The reaction mixture was cooled toambient temperature and partitioned between ethyl acetate (25 mL)and H.sub.2O (10 mL). The organic extraction was washed with brine,dried (MgSO.sub.4), filtered, and concentrated. The concentrate waschromatographed on silica gel eluting with ethyl acetate:hexanes(1:1) to provide 110 mg of the title compound. .sup.1H NMR (300MHz, CDCl.sub.3) .delta. 2.79 (s, 3 H), 8.18 (d, J=9 Hz, 1 H), 8.36(dd, J=9 Hz, J=3 Hz, 1 H), 8.70 (d, J=3 Hz, 1 H), 8.95 (s, 2 H); MS(DCl/NH.sub.3) m/z 173 (M+H).sup.+.

Example 13B

6-{6-[2-([2R]-2-Methyl-pyrrolidin-1-yl)-ethyl]-quinolin-2-yl}-quinoxaline

The title compound was prepared using the procedure described inExample 1G substituting the product of Example 13A for1-(4H-thieno[3,2-b]pyrrol-5-yl)-ethanone. .sup.1H NMR (300 MHz,CD.sub.3OD) .delta. 1.18 (d, J=6 Hz, 3 H), 1.47 (m, 1 H), 1.83 (m,2 H), 2.04 (m, 1 H), 2.37 (q, J=9 Hz, 1 H), 2.51 (m, 2 H), 3.07 (m,2 H), 3.21 (m, 2 H), 7.74 (dd, J=9 Hz, J=3 Hz, 1 H), 7.83 (d, J=3Hz, 1 H), 8.13 (d, J=9 Hz, 1 H), 8.22 (d, J=9 Hz, 1 H), 8.25 (d,J=9 Hz, 1 H), 8.44 (d, J=9 Hz, 1 H), 8.75 (dd, J=9 Hz, J=3 Hz, 1H), 8.84 (d, J=3 Hz, 1 H), 8.94 (dd, J=9 Hz, J=3 Hz, 2 H); MS(DCl/NH.sub.3) m/z 369 (M+H).sup.+.

Example 14

6-(2-Methyl-benzothiazol-5-yl)-2-[2-(2R-methyl-pyrrolidin-1-yl)-ethyl]-qui-noline

Example 14A

6-Bromo-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}quinoline

(2R)-2-Methylpyrrolidine L-tartrate (7.00 g, 0.0298 mole, milled),potassium carbonate (9.04 g, 0.0655 mole, milled), and acetonitrile(190 mL) were combined and heated at 60.degree. C. with agitationfor 48 hours. The mixture was allowed to cool to 30.degree. C., andtreated with the product from Example 42C (8.00 g, 0.0197 mole).The reaction mixture was heated at .about.60.degree. C. for 36hours and then distilled down to .about.1/4 volume, and isopropylacetate (200 mL) was added. The mixture was washed with 5%NaHCO.sub.3 aq. solution (200 mL.times.2), and 25% brine (200 mL).The upper organic was dried over anhydrous sodium sulphate,filtered, and the filtrate was concentrated to dryness. The crudeproduct was purified with a short-path silica gel column elutedwith heptane:ethyl acetate:TEA (60:40:1) to give 5.8 g (92% yield)of product as an oil, which solidified on standing; mp 4950.degree. C. (uncorrected); MS (ESI): 319, 311 (M+H).sup.+;.sup.1H-NMR (CDCl.sub.3) .delta. 7.95 (1 H, d, J=8.5 Hz), 7.91 (1H,d, J=2.2 Hz), 7.89 (1H, d, J=8.9 Hz), 7.72 (1H, dd, J=8.9, 2.2 Hz),7.35 (1H, d, J=8.5 Hz), 3.23 (2H, m), 3.18 (2H, m), 2.55 (1H, m),2.38 (1H, m), 2.25 (1H, q, J=8.9 Hz), 1.93 (1H, m), 1.80 (1H, m),1.71 (1H, m), 1.42 (1H, m), 1.11 (3H, d, J=6.0 Hz); .sup.13C-NMR(CDCl.sub.3) .delta. 161.3, 146.1, 134.7, 132.3, 130.3, 129.2,127.6, 122.2, 119.2, 59.9, 54.0, 53.6, 38.6, 33.0, 22.0, 19.4.

Example 14B

6-(2-Methyl-benzothiazol-5-yl)-2-[2-(2R-methyl-pyrrolidin-1-yl)-ethyl]-qui-noline

Tetrakis(triphenylphosphine) palladium (0) (28.8 mg, 0.025 mmol),2-(dicyclohexylphosphino)biphenyl (17.5 mg, 0.05 mmol),2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazole(0.375 mmol), and sodium carbonate (40.0 mg, 0.375 mmol) werecombined in 1,2-dimethoxyethane (4 mL) and water (1.5 mL). Themixture was then treated with the product from Example 14A (80 mg,0.25 mmol) and heated at 80.degree. C. for 24 hours. The reactionmixture was allowed to cool to room temperature and diluted withethyl acetate (20 mL). The organic layer was separated, washed with5% NaHCO.sub.3 (25 mL.times.3), 25% brine (25 mL), dried overNa.sub.2SO.sub.4, filtered, and the filtrate was concentrated todryness. The residue was purified by column chromatography(heptane:acetone:CH.sub.2Cl.sub.2:TEA (60:40:5:1) to provide thetitle compound. The title compound was treated with HCl inIPA:ethyl acetate to give the trihydrochloride salt. Mp=182183.degree. C.; MS (ESI) 388 (M+H).sup.+; .sup.1H NMR(trihydrochloride, DMSO-d.sub.6, 400 MHz) d 8.92 (1H, d), 8.63 (1H,d), 8.44 (2H, m), 8.40 (1H, d), 8.21 (1H, d), 8.00 (1H, d), 7.90(1H, dd), 3.94 (1H, br, m), 3.75 (2H, br, m), 3.52 (3H, br, m),3.26 (1H, br, m), 2.93 (3H, s), 2.21 (1H, m), 2.00 (2H, br, m),1.70 (1H, br, m), 1.43 (3H, br, d).

Example 15

7-(2-Methyl-benzothiazol-5-yl)-3-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-isoq-uinoline

Example 15A

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.sub.2SO.sub.4 (10 mL) dropwise, keepingthe temperature at 20 40.degree. C. The mixture was stirred at roomtemperature for 88 hours and then heated at 50.degree. C. for 4hours. The mixture was cooled to 10.degree. C., treated with 40 gof ice water, and extracted with 50 mL of CH.sub.2Cl.sub.2. Theorganic phase was washed in succession with 2.times.50 mL 5%NaHCO.sub.3, 50 mL 10% Na.sub.2S.sub.2O.sub.3, 50 mL water, andconcentrated to colorless oil. The residue was purified by columnchromatography (silica gel, 10:90 EtOAc:hexane) to provide thetitle compound. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.92 (d,J=4 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.27 (dd, J=8, 4 Hz, 1H), 3.92(s, 3H); MS (DCl/NH.sub.3) [M+NH.sub.4].sup.+ at 358,[M+NH.sub.3NH.sub.4].sup.+ at 375.

Example 15B

(5-Bromo-2-iodophenyl)methanol

To a stirred mixture of NaBH.sub.4 (11.18 g, 0.296 mol) in EtOH(200 mL) at 5.degree. C. was added the product from Example 15A(50.4 g, 0.148 mol) in THF (100 mL). The mixture was alowed to warmto room temperature and stirred for 18 hours. The mixture wastreated with additional NaBH.sub.4 (8.4 g, 0.222 mol) and wasstirred for 22 hours. The mixture was cooled to 0.degree. C.,treated with 100 mL of 15% aqueous citric acid slowly, andextracted with 600 mL of CH.sub.2Cl.sub.2. The organic phase waswashed with 200 mL of 15% NaCl and concentrated to provide thetitle compound. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.64 (d,J=8 Hz, 1H), 7.61 (d, J=4 Hz, 1H), 7.12 (dd, J=4, 8 Hz, 1H), 4.63(d, J=8 Hz, 2H), 1.98 (t, J=8 Hz, 1H). MS (DCl/NH.sub.3)[M+NH.sub.4].sup.+ at 330, [M+NH.sub.4-H.sub.2O].sup.+ at 312.

Example 15C

5-Bromo-2-iodobenzaldehyde

A solution of oxalyl chloride (1.53 g, 0.012 mol) inCH.sub.2Cl.sub.2 (15 mL) was cooled to -70.degree. C., and DMSO(1.41 g, 0.018 mol) in CH.sub.2Cl.sub.2 (15 mL) was added at -65 to-70.degree. C. The mixture was stirred under nitrogen for 10minutes at -70.degree. C. and then treated with the product fromExample 15B (2.35 g, 7.5 mmol) in 60 mL CH.sub.2Cl.sub.2. Theslurry was stirred at -65.degree. C. for 15 minutes and treatedwith triethylamine (3.8 g, 0.037 mol). The mixture was allowed towarm to -10.degree. C. over 1 hour. The mixture was treated with 20mL of water and allowed to warm to room temperature. The organiclayer was separated and concentrated to provide the title compound..sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.97(s, 1H), 7.97 (d, J=4Hz, 1H), 7.79 (d, J=8 Hz, 1H), 7.40 (dd, J=4, 8 Hz, 1H). MS(DCl/NH.sub.3) [M+NH.sub.4].sup.+ at 328.

Example 15D

N-[(1E)-(5-Bromo-2-iodophenyl)methylene]-N-(tert-butyl)amine

The product from Example 15C (2.28 g, 7.3 mmol) in THF (10 mL) wastreated with t-butylamine (1.61 g, 22.0 mmol) and stirred undernitrogen at room temperature for 40 hours. The mixture wasconcentrated under reduced pressure and the residue was dissolvedin 30 mL of methylene chloride. The methylene chloride was washedwith 10 mL water and concentrated to provide the title compoundwhich was used in the next step without further purification..sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.29 (s, 1H), 8.05 (d,J=4 Hz, 1H), 7.66 (d, J=8 Hz, 1H), 7.19 (dd, J=4, 8 Hz, 1H), 1.34(s, 9H). MS (DCl/NH.sub.3) 366 [M+H].sup.+.

Example 15E

2-(7-Bromo-3-isoquinolinyl)ethanol

The product from Example 15D (1.3 g, 3.6 mmol), 3-butyn-1-ol (0.3g, 4.3 mmol), CuI (0.04 g, 0.2 mmol), andPdCl.sub.2(PPh.sub.3).sub.2 (0.08 g, 0.1 mmol) were combined intoluene (15 mL). The mixture was treated with diisopropylamine(0.54 g, 5.3 mmol) and stirred at room temperature for 4 hours. Themixture was then treated with additional CuI (0.07 g, 0.4 mmol) andheated at 100.degree. C. for 4 hours. The mixture was allowed tocool to room temperature, diluted with 30 mL CH.sub.2Cl.sub.2, andfiltered. The filtrate was washed with 2.times.10 mL 15% NaCl andconcentrated under reduced pressure. The residue was purified bycolumn chromatography (silica gel, 10:90 MeOH:CHCl.sub.3) toprovide the title compound. .sup.1H NMR (CDCl.sub.3, 400 MHz).delta. 9.08 (s, 1H), 8.09 (d, J=4 Hz, 1H), 7.73 (dd, J=8, 4 Hz,1H), 7.63 (d, J=8 Hz, 1H), 7.48 (s, 1H), 4.08 (t, J=4 Hz, 2H), 3.92(s, 1H), 3.15 (t, J=4 Hz, 2H). .sup.13C NMR (CDCl.sub.3, 100 MHz).delta. 153.8, 150.3, 134.5, 133.8, 129.4, 127.6, 120.0, 118.6,62.3, 39.4. MS (DCl/NH.sub.3) 252, 254 [M+H].sup.+.

Example 15F

7-Bromo-3-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}isoquinoline

The product from Example 15E (0.5 g, 2.0 mmol) and triethylamine(0.5 g, 4.9 mmol) were combined in THF (15 mL) at -15.degree. C.The mixture was treated with methanesulfonyl chloride (0.24 g, 2.1mmol) and stirred at 0 10.degree. C. for 2 hours. The mixture wastreated with additional methanesulfonyl chloride (0.2 mmol) andstirred at room temperature for 16 hours. The mixture was treatedwith (2R)-2-methylpyrrolidine hydrochloride (0.72 g, 6.0 mmol) andK.sub.2CO.sub.3 (0.27 g, 2.0 mmol) in acetonitrile (25 mL) and thenthe mixture was heated at 60.degree. C. for 20 hours. The mixturewas allowed to cool to room temperature and was concentrated underreduced pressure. The residue was dissolved in 20 mLCH.sub.2Cl.sub.2, washed with 5 mL of water and concentrated underreduced pressure. The residue was purified by column chromatography(silica gel, 10:90 MeOH:CHCl.sub.3) to provide the title compound..sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.10 (s, 1H), 8.09 (d,J=4 Hz, 1H), 7.72 (dd, J=12, 4 Hz, 1H), 7.64 (d, J=12 Hz, 1H), 7.58(s, 1H), 3.46 3.40 (m, 2H), 3.34 3.29 (m, 2H), 2.91 1.85 (m, 1H),2.81 2.68 (m, 1H), 2.59 2.49 (m, 1H), 2.11 2.02 (m, 1H), 2.00 1.91(m, 1H), 1.88 1.79 (m, 1H), 1.71 1.61 (m, 1H), 1.32 (d, J=8 Hz,3H). .sup.13C NMR (CDCl.sub.3, 100 MHz) .delta. 152.5, 150.6,134.5, 133.6, 129.2, 127.8, 127.7, 120.0, 118.7, 61.7, 53.7, 53.4,36.0, 32.4, 21.9, 17.9. MS (DCl/NH.sub.3) 319, 321 [M+H].sup.+.

Example 15G

7-(2-Methyl-benzothiazol-5-yl)-3-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-isoq-uinoline

The product from Example 15F (0.30 g, 0.9 mmol),2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzothiazole(0.39 g, 1.4 mmol), 2-(dicyclohexylphosphino)biphenyl (66 mg, 0.2mmol), and PdCl.sub.2(PPh.sub.3).sub.2 (66 mg, 0.1 mmol) werecombined in isopropanol (15 mL). The mixture was treated with asolution of Na.sub.2CO.sub.3 (0.15 g, 1.4 mmol, in 5 mL water) andheated at 65.degree. C. for 7 hours. After cooling to roomtemperature, the mixture was diluted with 20 mL of CH.sub.2Cl.sub.2and filtered. The filtrate was concentrated under reduced pressure,the residue was re-dissolved in 20 mL of CH.sub.2Cl.sub.2 andwashed with 5 ml of water. The methylene chloride layer wasextracted with 10 ml of 2N HCl. The aqueous HCl layer was treatedwith 20 mL of CH.sub.2Cl.sub.2 and basified with 4N NaOH. Themethylene chloride layer was concentrated to oily residue which waspurified by column chromatography (silica gel, 10:90:1MeOH:CHCl.sub.3:Et.sub.3N) to provide the title compound. .sup.1HNMR (CDCl.sub.3, 400 MHz) .delta. 9.24 (s, 1H), 8.24 (dd, 1H), 8.15(dd, 1H), 7.97 (dd, J=3, 12 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.85 (d,J=8 Hz, 1H), 7.67 (dd, J=3, 12 Hz, 1H), 7.61 (s, 1H), 3.46 3.39 (m,1H), 3.35 3.28 (m, 1H), 2.86 (s, 3H), 2.88 2.81 (m, 1H), 2.73 2.68(m, 1H), 2.53 2.47 (m, 1H), 2.08 1.58 (4H), 1.30 (d, J=8 Hz, 3H)..sup.13C NMR (CDCl.sub.3, 400 MHz) .delta. 167.4, 153.7, 152.3,151.9, 138.7, 138.0, 135.2, 134.8, 129.8, 127.2, 126.6, 125.0,123.8, 121.5, 120.5, 118.4, 61.3, 53.7, 53.7, 36.3, 32.4, 21.8,20.5, 18.1. MS (DCl/NH.sub.3) [M+H].sup.+ at 388.

Example 16

Determination of Biological Activity

To determine the effectiveness of representative compounds of thisinvention as histamine-3 receptor ligands (H.sub.3 receptorligands), the following tests were conducted according to methodspreviously described (European Journal of Pharmacology, 188:219 227(1990); Journal of Pharmacology and Experimental Therapeutics,275:598 604 (1995); Journal of Pharmacology and ExperimentalTherapeutics, 276:1009 1015 (1996); and Biochemical Pharmacology,22:3099 3108 (1973)).

Briefly, male Sprague-Dawley rat brain cortices were homogenized (1g tissue/10 mL buffer) in 50 mM Tris-HCl/5 mM EDTA containingprotease inhibitor cocktail (Calbiochem) using a polytron set at20,500 rpm. Homogenates were centrifuged for 20 minutes at40,000.times.g. The supernatant was decanted, and pellets wereweighed. The pellet was resuspended by polytron homogenization in40 mL 50 mM Tris-HCl/5 mM EDTA with protease inhibitors andcentrifuged for 20 minutes at 40,000.times.g. The membrane pelletwas resuspended in 6.25 volumes (per gram wet weight of pellet) of50 mM Tris-HCl/5 mM EDTA with protease inhibitors and aliquotsflash frozen in liquid N.sub.2 and stored at -70.degree. C. untilused in assays. Rat cortical membranes (12 mg wet weight/tube) wereincubated with (.sup.3H)-N-.alpha.-methylhistamine (.about.0.6 nM)with or without H.sub.3 receptor antagonists in a total incubationvolume of 0.5 mL of 50 mM Tris-HCl/5 mM EDTA (pH 7.7). Testcompounds were dissolved in DMSO to provide a 20 mM solution,serially diluted and then added to the incubation mixtures prior toinitiating the incubation assay by addition of the membranes.Thioperamide (3 .mu.M) was used to determine nonspecific binding.Binding incubations were conducted for 30 minutes at 25.degree. C.and terminated by addition of 2 mL of ice cold 50 mM Tris-HCl (pH7.7) and filtration through 0.3% polyethylenimine-soaked Unifilterplates (Packard). These filters were washed 4 additional times with2 mL of ice-cold 50 mM Tris-HCl and dried for 1 hour. Radioactivitywas determined using liquid scintillation counting techniques.Results were analyzed by Hill transformation and K.sub.i valueswere determined using the Cheng-Prusoff equation.

Generally, representative compounds of the invention demonstratedbinding affinities in the above assay from about 810 nM to about0.02 nM. Preferred compounds of the invention bound to histamine-3receptors with binding affinities from about 100 nM to about 0.02nM. More preferred compounds of the invention bound to histamine-3receptors with binding affinities from about 20 nM to about 0.02nM.

Compounds of the invention are histamine-3 receptor ligands thatmodulate function of the histamine-3 receptor by altering theactivity of the receptor. These compounds may be inverse agoniststhat inhibit the basal activity of the receptor or they may beantagonists that completely block the action of receptor-activatingagonists. These compounds may also be partial agonists thatpartially block or partially activate the histamine-3 receptor orthey may be agonists that activate the receptor.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to betaken as limitations upon the scope of the invention, which isdefined solely by the appended claims and their equivalents.Various changes and modifications to the disclosed embodiments willbe apparent to those skilled in the art. Such changes andmodifications, including without limitation those relating to thechemical structures, substituents, derivatives, intermediates,syntheses, formulations and/or methods of use of the invention, maybe made without departing from the spirit and scope thereof.

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