AU2013216616B2

AU2013216616B2 - Cyclopropyl amine derivatives

Info

Publication number: AU2013216616B2
Application number: AU2013216616A
Authority: AU
Inventors: Youssef L. Bennani; Lawrence A. Black; Paul J. Brackemeyer; Marlon D. Cowart; Huaqing Liu; Zhenping Tian
Original assignee: AbbVie Bahamas Ltd
Current assignee: AbbVie Bahamas Ltd
Priority date: 2007-12-14
Filing date: 2013-08-14
Publication date: 2016-04-21
Anticipated expiration: 2028-12-05
Also published as: AU2013216616A1

Abstract

CYCLOPROPYL AMINE DERIVATIVES Compounds of formula (I) wherein R 1, R2, R3, R3a, R3b, R4, and R5 are defined in the description, are useful in treating conditions or disorders prevented by or ameliorated by histamine-3 receptor ligands. Also disclosed are pharmaceutical compositions comprising the histamine-3 receptor ligands, method for using such compounds and compositions, and a process for preparing compounds within the scope of formula (I).

Description

CYCLOPROPYL AMNE DERNATIVES BACKGROUND OF THE INVENTION Technical Field The invertion rates to cyclopropy amine compounds, compositions comprsmg such compounds, methods for making the compounds, and methods of treating conditions and disorders using son compounds and compositions Descriptinof Related Technoloqy Histamine is a weilknown ,modulator of neuronal activity At least four types of histamine receptors have been reported in the literature, typically referred to as histami.ne< histamine-2 histamine-3, and histamine-4 The class of histamine receptr known as histamine-3 receptors is believed to play a role in neurotrnamnission in the central nervous system. The histamine-3 (H-) receptor was first characterized pharmacoiogicafy on histaninergic nerve terminals (Nature. 302832-837 (1983) wher regulates the release of neurotransmitters in both the central o nervous system and peripheral organs particularly the lungs, cardiovascular system and gastraintestina tract H receptors are thought to be located presynapticaily on histaminergic nerve endings, and also on neurons possessing other activity, such as adrenerpgic, cholinergic. serotonmergic, and dopaminergic activity, The existence of H. receptors has been confirmed by the development of selective H , receptor agonists and antagonists ((Nature, 327:11>123 (1987); Leurs and Timmerman ed "The History of Hi Receptor: a Target for New Drugs) Elsevier (1998)), The activity at the H receptors can be modified or regulated by the administration of t receptor ligards. The ligands can demnstrate antgonist, inverse agonist, agonist or partial agonist actiMty. For example, H. receptors have been linked to conditions and disorders related to memory and cognition processes, neurologica processes, cardiovascular function. and regulation of blood sugar among other systemic activities Although various classes of compounds demonstrating Ha receptor-modulating activity exist. it would be benenciato Provide additional compounds demonstrating activity at the H,, receptors that can be incorporated into pharmaceutical compositions useful for therapeutic methods, BREVDESCRIPTON CTHRE DRMAANGS FGUIRE is a powder tray diffraotion pattern of 2(4[(1S2S>2-(S)-2Methyipyrroidin ) 1 ym ethyl)cyloropyL phenyl}-2H-pyridazine~one L-bitartrate monohydrate, FIGURE 2 is a thermogram of 2-{441IS.2S)2((Sy2 Methybpyrro1idr-1 y'methy) cyclopr opylgpheny)~2Hpyridazin&One L-bitartrate monohvdrate obtained by thermal gravmetrc analvsis (TGA), F RE 3 is a pcwder X-ray diffraction pattern of 24-[(1 25)24(S)2Methykpyrrolidi ylmirethvi)v cylpopyi]-phe~ny}-2H pyridazin- 3-one L-titartrate anhydrate. iURE 4 s a powder X-ray diffraction pattern of 2~{4-[(S2Se2-(S)2-Methykprroidin~ -ylmety) J~Cyclopropyl]-phenyi}-2H-pyridazmnone D-bitartrate dehydrate. FIGURE 5 is a thermoram of 24(i8,2$)-2.S2'Methyl-pyrroiidn .yimethyl) cyclopropyl-phenyl}--2H- pyridazn- 3-one Dhitartrate hydrate obtained by thermal gravimetric analysis (TGA). FGQ9RE. 6 is a powder Xray diffraction pattern of 2-{4-(1I 2S)2((S)2Methy-pyrreidn 1--yImethy)-cyclopropyphenyi}-2 H-pyridazin-3-one D-titartrateanhydrate. SUMMARY OF THE INVENTION The invention is directed to cyclopropy amines and, more particularly bicyclic-and tricyclic- substituted cyclopropyi marine dervatives, ANcordingiy, one aspect of the invention relates to compounds formula ( RR or a phamaceuti acceptable salt ester amide. or prodrug thereof, wherein: one of R, and R is a group of the formula LRwarR the other of t and R 2 is selected from hydrogen, alkyl, akoxy, halogen, cyano, and thioaikoxy; R _ R, and R, are each independently selected from the group consisting of hydrogen, alkyl, trifluoroalkyl, trifluorcalkoxy, akoxy, halogen, cyano. and thiocakoxy

R

4 and R! are each independently selected from alky. fluoroalky, hydroxyaikyl, alkoxyaWkyi, and cycloalkyl, or R 4 and R taken together with the nitrogen atom to which each is attached form a non-aromatic ring of the formula: "R Rj R, R, R13 R (a)o (b) R-, R, R and R-, at each occurrence are each independently selected from hydrogen, hydroxyakyL fluoroaikyl cycloalkyl and alky: R R. Ra. and RN are each independently selected from hydrogen, hydroxyaikyl alkyl, and fiuoroaikyh R, is selected from a 5- to remembered heteroaryl rng, cyanopheily. an 8- to 1 mernmbered bicyclic heteroaryl ring; and a 4- to 12-membered heterocycoc ring; R% is selected fror hydrogen, a to 6-membered heteroaryl ring; an ary! rin, an 8- to 1 2membered bircydic Peteroaryl ring., amd a 4 to 12rnembered heterocyclic ring; Q is selected from 0 and S; is selected from a bond, aikylere OW -C(=0) H -S-N 0N(R hO C(=O)N(R&, ~and -N(alkyl)~; s selected from a bond, alkylene, O - (=0 -)-, ~N(R}C(D) -C(=O)N(R)\ and -N(R)

R

1 is selected from hydrogen, alkyl acyl, aikoxycarbonyl, amido, and formlyl; RN and R,, at each occurrence are independentKy selected from hydrogen and aikyl, Rx and R at each occurrence are independently selected from hydrogen, hydroxy, alkyl, aikoxy, akylarino. fluoro; and diakylanino; k is 1,2 or 3; and m a an integer from Io . Another aspect of the invention relates to pharmaceutical composition comphsing compounds of the invention, Such compositions can be administered in accordance with a method of the invention, typically as part of a therape tic regimen for treatment or prevention of conditions and disorders related to H3 receptor activity. Yet another aspect of the invention relates to particular salts of somte compounds, processes for preparing such compounds and salts, and compositions comprising the -3- 4 same. Yet another aspect of the invention relates to a method of selectively modulating H 3 receptor activity. The method is useful for treating, or preventing conditions and disorders related to H 3 receptor modulation in mammals. More particularly, the method is useful for treating or preventing conditions and disorders related to memory and cognition processes, neurological processes, cardiovascular function, and body weight. Accordingly, the compounds and compositions of the invention are useful as a medicament for treating or preventing H 3 receptor modulated diseases. Processes for making compounds of the invention also are contemplated. Yet another aspect of the invention relates to use of an effective amount of a compound in the manufacture of a medicament for the treatment of a condition or disorder selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome, the compound having the structure of: 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl cyclopropyl)phenyl]pyridazin 3(2H)-one L-bitartrate monohydrate; 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl cyclopropyl)phenyl]pyridazin 3(2H)-one L-bitartrate anhydrate; 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl cyclopropyl)phenyl]pyridazin 3(2H)-one D-bitartrate dihydrate; or 4a 2-[4-((1 S,2S)-2-{[(2S)-2-methylpyrrolidin- 1-yl]methyl I cyclopropyl)phenyl]pyridazin 3(2H)-one D-bitartrate anhydrate. Yet another aspect of the invention relates to use of an effective amount of a compound in the manufacture of a medicament for the treatment of a condition or disorder selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type 11 diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome, the compound selected from: a crystalline salt of 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1 yl] methyl }cyclopropyl)phenyl]pyridazin-3(2H)-one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2-14-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl}-2H-pyridazin-3-one L-bitartrate monohydrate demonstrating at least one characteristic peak in the PXRD at values of two-theta of 7.157.+-.0.20, 10.064.+-.0.20, 14.356.+-.0.20, 16.727.+-.0.20, 19.198.+-.0.20, 20.119.+-.0.20, 21.222.+-.0.20, 22.146.+-.0.20, 24.048.+-.0.20, and 24.574.+-.0.20; a crystalline salt of 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1 yl] methyl Icyclopropyl)phenyl]pyridazin-3(2H)-one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2-14-[(lS,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl}-2H-pyridazin-3-one L-bitartrate anhydrate demonstrating at least one characteristic peak in the PXRD at values of two-theta of 4.589.+-.0.20, 9.206.+-.0.20, 13.85.+ .0.20, 14.335.+-.0.20, 15.824.+-.0.20, 16.272.+-.0.20, 16.825.+-.0.20, 18.083.+-.0.20, 18.514.+ .0.20, 19.588.+-.0.20, and 20.551.+-.0.20; 4b a crystalline salt of 2-[4-((lS,2S)-2-{[(2S)-2-methylpyrrolidin-1 yl] methyl Icyclopropyl)phenyl]pyridazin-3(2H)-one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2-14-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl}-2H-pyridazin-3-one D-bitartrate dihydrate demonstrating at least one characteristic peak in the PXRD at values of two-theta of 4.387.+-.0.20, 8.788.+-.0.20, 10.326.+ .0.20, 12.056.+-.0.20, 13.192.+-.0.20, 14.089.+-.0.20, 16.194.+-.0.20, 19.502.+-.0.20, 19.877.+ .0.20, 20.271.+-.0.20, 20.736.+-.0.20, 21.313.+-.0.20, 23.103.+-.0.20, and 23.937.+-.0.20; and a crystalline salt of 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1 yl] methyl Icyclopropyl)phenyl]pyridazin-3(2H)-one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2-14-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl}-2H-pyridazin-3-one D-bitartrate anhydrate demonstrating at least one characteristic peak in the PXRD at values of two theta of 5.004.+-.0.20, 10.590.+-.0.20, 13.548.+-.0.20, 14.219.+-.0.20, 15.279.+-.0.20, 15.723.+-.0.20, 16.990.+-.0.20, 18.723.+-.0.20, 19.052.+-.0.20, 20.827.+-.0.20, 21.293.+-.0.20, and 22.826.+-.0.20. Yet another aspect of the invention relates to a method for the treatment of a condition or disorder selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type 11 diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome, wherein said method comprises administering an effective amount of a compound having the structure of: 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyllcyclopropyl)phenyl]pyridazin 3(2H)-one L-bitartrate monohydrate; 2-[4-((lS,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl cyclopropyl)phenyl]pyridazin 3(2H)-one L-bitartrate anhydrate; 4c 2-[4-((1 S,2S)-2-{[(2S)-2-methylpyrrolidin- 1-yl]methyl I cyclopropyl)phenyl]pyridazin 3(2H)-one D-bitartrate dihydrate; or 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1-yl]methyl cyclopropyl)phenyl]pyridazin 3(2H)-one D-bitartrate anhydrate. Yet another aspect of the invention relates to a method for the treatment of a condition or disorder selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type 11 diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome, wherein said method comprises administering an effective amount of a compound selected from: a crystalline salt of 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1 yl] methyl }cyclopropyl)phenyl]pyridazin-3(2H)-one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2-14-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl}-2H-pyridazin-3-one L-bitartrate monohydrate demonstrating at least one characteristic peak in the PXRD at values of two-theta of 7.157.+-.0.20, 10.064.+-.0.20, 14.356.+-.0.20, 16.727.+-.0.20, 19.198.+-.0.20, 20.119.+-.0.20, 21.222.+-.0.20, 22.146.+-.0.20, 24.048.+-.0.20, and 24.574.+-.0.20; a crystalline salt of 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1 yl] methyl Icyclopropyl)phenyl]pyridazin-3(2H)-one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2-14-[(lS,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl}-2H-pyridazin-3-one L-bitartrate anhydrate demonstrating at least one characteristic peak in the PXRD at values of two-theta of 4.589.+-.0.20, 9.206.+-.0.20, 13.85.+ .0.20, 14.335.+-.0.20, 15.824.+-.0.20, 16.272.+-.0.20, 16.825.+-.0.20, 18.083.+-.0.20, 18.514.+ .0.20, 19.588.+-.0.20, and 20.551.+-.0.20; 4d a crystalline salt of 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1 yl] methyl Icyclopropyl)phenyl]pyridazin-3(2H)-one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2-14-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl}-2H-pyridazin-3-one D-bitartrate dihydrate demonstrating at least one characteristic peak in the PXRD at values of two-theta of 4.387.+-.0.20, 8.788.+-.0.20, 10.326.+ .0.20, 12.056.+-.0.20, 13.192.+-.0.20, 14.089.+-.0.20, 16.194.+-.0.20, 19.502.+-.0.20, 19.877.+ .0.20, 20.271.+-.0.20, 20.736.+-.0.20, 21.313.+-.0.20, 23.103.+-.0.20, and 23.937.+-.0.20; and a crystalline salt of 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidin-1 yl] methyl Icyclopropyl)phenyl]pyridazin-3(2H)-one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2-14-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl}-2H-pyridazin-3-one D-bitartrate anhydrate demonstrating at least one characteristic peak in the PXRD at values of two theta of 5.004.+-.0.20, 10.590.+-.0.20, 13.548.+-.0.20, 14.219.+-.0.20, 15.279.+-.0.20, 15.723.+-.0.20, 16.990.+-.0.20, 18.723.+-.0.20, 19.052.+-.0.20, 20.827.+-.0.20, 21.293.+-.0.20, and 22.826.+-.0.20. Yet another aspect of the invention relates to a compound selected from the group consisting of: (S)-3-hydroxy-1-(4-((1S,2S)-2-(((S)-2-methylpyrrolidin-1 yl)methyl)cyclopropyl)phenyl)pyrrolidin-2-one; and 2-14-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl)-cyclopropyl]-phenyl)-2H pyridazin-3-one (2S,3S)-2,3-dihydroxy-succinic acid; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. Yet another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of: (S)-3-hydroxy-1-(4-((1S,2S)-2-(((S)-2-methylpyrrolidin-1 yl)methyl)cyclopropyl)phenyl)pyrrolidin-2-one; and 4e 2-14- [(1S,2S)-2-((S)-2-methyl-pyrrolidin- 1 -ylmethyl)-cyclopropyl] -phenyl)-2H-pyridazin 3-one (2S,3S)-2,3-dihydroxy-succinic acid; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier. Yet another aspect of the invention relates to use of an effective amount of a compound selected from the group consisting of: (S)-3-hydroxy-1-(4-((1S,2S)-2-(((S)-2-methylpyrrolidin-1 yl)methyl)cyclopropyl)phenyl)pyrrolidin-2-one; and 2-14-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl)-cyclopropyl]-phenyl)-2H-pyridazin 3-one (2S,3S)-2,3-dihydroxy-succinic acid; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in the manufacture of a medicament for the treatment of a condition or disorder selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome. Yet another aspect of the invention relates to a method for the treatment of a condition or disorder selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, 4f neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome, wherein said method comprises administering an effective amount of a compound selected from the group consisting of: (S)-3-hydroxy-1-(4-((1S,2S)-2-(((S)-2-methylpyrrolidin-1 yl)methyl)cyclopropyl)phenyl)pyrrolidin-2-one; and 2-14-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl)-cyclopropyl]-phenyl)-2H-pyridazin 3-one (2S,3S)-2,3-dihydroxy-succinic acid; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. The compounds, compositions comprising the compounds, methods for making the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are further described herein. Detailed Description of the Invention Definition of Terms Certain terms as used in the specification are intended to refer to the following definitions, as detailed below. The term "acryl" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of acyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1 oxobutyl, and 1-oxopentyl. The term "acyloxy" as used herein means an acyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of acyloxy include, but are not limited to, acetyloxy, propionyloxy, and isobutyryloxy.

4g The term "alkenyl" as used herein means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, and preferably 2, 3, 4, 5, or 6 carbons, and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3 butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl. The term "alkoxy" as used herein means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term "alkoxyalkoxy" as used herein means an alkoxy group, as defined herein appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy incudebut are not mirted to, tert-butoxymeth;oxy, 2~ethoxyethoxy, 2-methoxyethoxv, and methoxymethoxy Tihe term "alkoxyafkyl" as used herein means an akoxy group, as defined herein appended to the parent molecular moiety through an alkl group, as defined herein Representative examples of aikoxyaikyl include, but are not limited totetbtoxyt 2ethoxyethyl 2-methoxvethy. and methoxymethyl The term "alkoxycarbonyl" as used herein means an alkoxy group, as defined herein. appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbony include, but are not limited to, methoxytarbonyi, ethoxycarbonyi, and tert-butoxycarbonyl The terry 'alkoxylrnino" as used herein means an alkoxy group, as defined herein, appended to the parent molecular moiety through an imino group, as defined herein. Representative erxampies of alkoxyimino include, but are not limited to, ethoxyimino)methyl and methoxymino)methyl The term "alkoxysulfonyl as used herein means an aikoxy group as defined herein, appended to the parent molecular moiety through a sulfonyl group; as defined herein. Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfony ethoxysulfonyi, and propoxysulfonyt The term alkyi as used herein means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, and preferably 1, 2 3. 4, 5, or 6 carbons, Representative examples of alkyl include, but are not limited to, methyl. ethyl, n-propyl, iso-propyl n-butyl, sec-butyl. iso-butyl tert-butyl n-penty isopentyl, neopenvi nhexyi 3-methylhexy, 2 2-dimethyl enty 2,3 dimethylpenty. n-hepty, n-octyi. n-nony. and n decyL The tern "alkylamino as used herein means an alkyl group, as defined herein. appended to the parent molecular moiety through a NH group, Representatve examples of alkylamino include, but are not limited to, methylamino, ethylamino, isopropylamino, and butylamino The term "alkyicarbony'as used herein means an alkyl group, as defined herein appended to the parent molecular moety through a carbonyl group, as defined herein. Representative examples of aikyicarbonyl include, but are not limited to, methyicarbonyl ethyloarbonyl isopropyicarbony, n-propylcarbonyi, and the like. The term "alkylene" means a divalent group derived from a straight or branched chain hydrocarbon of frorn I to 10 carbon atoms Representative examples of alkylene include, but are not limited to, CH -CH(CH), -C(CH3,) -CHCHr 'CHiOH 2 H

~--

-CH2CHCH CH and -CH 2 CH(CHs)CHr' The erm "akysulfonyl" as used herein means an alkyi group. as defined herein. appended to the parent molecular moiety through a sulfonyl group, as defned herein ) Representative examples of alkyisulfonyl include, but are not limited to, methysulfonyl and ethylsuLfonyi. The term "alkyny as used herein means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms, and preferably 2, 3, 4, or' 5 carbons, and containing at least one carbon-oarbon tnple bond Representative examples of alkynyl include, but are not liirted to, acetylenyl, 1propynyti 2propyny! 3 butynyl. 2 pentynyl, and 1butyny[ The term amid" as used herein means an amino, akylamino, or dialkylamino group appended to the parent molecular moiety through a carbonyl group, as defined herein, Representative examples of anido include, but are not limited to, aminocarbony methylarnanocarbonyl, dim ethylaminocarbonyl. and ethylmethylaminocarbonyh The term amino" as used herein means a ~NH group The term 2ary" as used herein means a monocydic hydrocarbon aromatic ring system. Representative examples of ary4 include, but are not limited to, phenyt. The aryl groups of this invention are subst tuted with 0, 1 2. 3, 4, or . substituents independently selected from acyl, acyloxy, alkeny, alkoxy, alkoxyalkoxy. alkoxyakyi, alkoxycarbonvl alkoxyimino, aikoxysulfonyl, alkyl, alkyicarbonyl aikylsuifonyt aikynyl, amico, carboxy, cyano, cycloalkylcarbonyi, formal haloalkoxy haioalky halogen; hydroxy, hydroxyakyl, mercapto, nitro, thioaikoxy, NRR, and NRRjsulfonyt The term "arylakyl" as used herein means an aryl group, as defined hereirt appended to the parent molecular moilety through an alkyl group, as defined here Representative examples of arylalkyl include, but are not ied to; benyl,2-phenylethvi and 3-phenylpropyi The rm carbonyll as used herein means a C(=0) group. The term "carboxy as used herein means a -C0 2 H group, which may be protected as an ester group -COra lkyl The term 'cym as usfd hrein means a CN group The term "cyanopheny" as used herein means a -CN r oup appended to the parent molecular moiety a phenyl group, neluding but not lmited to, 4 cyanophenyl, 3-cyanopheny, and 2-cyanopheny. The term "cycloalkyl" as used herein means a saturated cyclic hydrocarbon group containing from 3 to 8 carbons. Examples of cycloalkyl include cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cyciohepty, and cyclooctyL '36- The cyclo-lkyl groups of the invention are subvstiu with 0, 2, 3, or 4 substtuents selected from acyl, acyloxy, alkenyl alkoxy, aikoxyalkoxy: akoxyakyi aikoxycafbonyl, akoxyimino, akyL alkynyl, amido. carboxy. cyano ethylenedioxy, formal, halcalkoxvy, haloalkyl, halogen, hydroxy, hydroxyaiky, methylenedioxy, oxo, thioalkoxy. and -NARR The term "cycloalkylcarbonyl" as used herein means a cyrdoalkyl group as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of cycloalkyloarbonyl include, but are not limited to, cyclopropykarbonyl cyolopentyicarbonyi cycotexylarbonyl and cycloheptyicarbonyt The term 'dialkylarruno" as used herein means two independent aikyl groups, as defined herein, appended to the Parent molecular moiety through a nitrogen atom. Representative examples of dialkylamino include but are not limited to, dimethylaminio, diethylamino, ethylmethylamino, and butyimethylamino. The term "fluro" as used herein means -F The term Tfluoroalkoxy" as used herein means at least one fluoroalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen group, as defned herein Representative examples of fluoroalkyl include, but are not limited to, trnfluoronethoxy (OCO), and difluoromethoxy (CHF20) The term tfuoroaikyP as used herein nieans at least one fluoro group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of fluoroalkyl include, but are not limited to; fluoromethyl, difluoromethyl, trifluoromethyi entafluoroethy and 22 ,2-trifluoroethyl. The term "formyl" as used herein means a -C(O) H group. The term "halo" or "haisgen" as used herein means Ci, Bri or. The term "haloalkoxy" as used herein means at least one halogen, as defined herein. appended to the parent rnoIecuiar moiety through an alkoxy group, as defined herein Representative examples of haloaikoxy include, but are not limited to. 25 fluoroethoxy; trifluorornethoxy, and pentafluoroethoxy The term "haloalkyl as used herein means at leastone halogenas defined herein, appendedto the parent molecular moiety through an. aikyi group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 24luoroethyl, trifluoromethyl, pentafluoroethy and 2<choro-uoropentyi. The term "heteroaryl, as used here, 'refers to an aromatic ring containing one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a tautomer thereof, Such rings can be monocyclic or bicyclic as further described herein. Heteroaryl -7, rngs are connected to the parent molecular moiy or to L or L- wherein and L are defined in forrnula ( through a carbon or nitrogen atom. The terms "mornocyclic heteroaryl or "5- or remembered heteroaryi ring', as used herein, refer to 5- or 6-membered aromatic rings containing 1, 2. 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a tautorner thereof. Examples of such rings include, but are not limited to, a ring wherein one carbon is replaced with an O or S atom: one, two, or three N atoms arranged in a suitable mariner to provide an aromatic ring; or a ring wherein two carbon atoms in the ring are replaced with one 0 or S atom and one N atom, Such rings can include. but are not limited to, a sx-amembered aromatic ring wherein one to four of the ring carbon atoms are replaced by nitrogen atorns fivemernbered rings containing a sulfur, oxygen, or nitrogen in the ring; five membered rings containing one to four nitrogen atoms and ive membered rings containing an oxygen or sulfur and one to three nitrogen atoms. Representative examples of 5- to 6-membered heteroaryl rings include, but are not limited to, furyl, irnidazoyi isoxazolyl, isothiazolyl, oxazolyl pyraziny, pyrazolyl, pyridaziny, pyridinyl, pyriniiny. plyrroiyi, tetrazolyl, " [2, 3]thiadiazolt 2,3oxadiazoly1, thiazol, thienyi [1 ,2 3triaznyl, [ 41 2 4riaziny1 [1 ,3:5]triaziny, [1,2,3]tnazolyl, and f[ ,2.4]triazol The term "bicyclic heteroarvi" or 38- to 12- merbered bicycle heteroary ring as ued herein. refers to an 8, 9-0 1- or 12-imenbered bicyciic aromatic rng containing at least 3 double bonds, and wherein the atoms of the ring include one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen. Representative examples of bicyclic heteroaryl rings iicude ndolyl, benzothienyl, benzofuranyi, indazolyl, benzimidazoiyl, benzothiazolyl, benzoxazolyi, benzoisothiazolyi benzoiisoxazo'y guinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl phthaiazinyl, pteridinyl, purinyl, naphthyridinyi, cinnoliny thieno(2 3-d]inidazole, thieno[3, 2-b~pyridiny, and pyrrolopyrimidinp. Heteroaryl groups of the invention, whether monocyic or bicyci, may be substituted with hydrogen, or optionally substituted with one or more substituents independently selected from acyl acyloxy, alkenyL alkoxy, alkoxyalkoxy, alkoxyaikyi, alkoxycarbonyl, alkoxyirmno. alkoxysulfony, alkyl, aikyicarbony, alkylsuloy! amido, carboxy. cyano, cycloalkyl, fluoroalkoxy, formyl, haoalkoxy halalkyl, halogen, hydroxy, hydroxyaiky. mercapto. nitro. alkylthio, -NRAR, and (NRA.R,)carbony Monocydic heteroary! or 5 or 6-nembered heteroary rings are substituted with 0, 1, 2: 3, 4 or 5 substituents. Sicylic heteroaryl or 8- to 12-membered bicyclic heteroaryl rings are substituted with 0, 1, 2. 3, 4, 5, 6, 7: 8, or 9 substituents. Heteroary groups of the Present invention may be present as tautomers. 843 The terms "heterocycic rng" and "heterocycle". as used herein, refer to a 4- to 12 mernbered monoc-yclic or bicyc ring containing one; two; three, four, or Fie heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur and also containing either at least one carbon atom attached to four other atoms or one carbon atom substituted with an oxo group and attached to two other atoms. Four and five-membered rings may have zero or one double bond, Six-nembered rings may have zero, one, or two double bonds. Seven, and eight-membered rings may have zero, one, two, or three double bonds, The non-aromatic heterocycle groups of the irwenton can be attached through a carbon atom or a nmtrogen atom. The non-aromatic heterocycle groups may be present in tautorneric form. Representative examples of nitrogen-containing heterocycles include, but are not limited to, azepanyl, azetidnyl, aziridinyl, azocan'y, dihydropyndazinyi, dihydropyridinyl, diydropyrimidinyl morphonyt piperazinyL. piperidinyt pyrrolidnyl pyrrolny dihydroihiazolyl, dihydropyridinyi and thomorholiny Representative examples of non-ntrogen containing non-aromatic heterocycle include, but are not limited to, dioxanyl, dithiany. tetrahydrofuryl, dihydropyranyl, tetrahydropyrany., and [1,3]dioxolanyl The heterocyces of the invention are substituted with hydrogen. or optionally substituted wth 0, 1 2, 3, 4, 5, 6, 7, 8, or g substtuents independently selected from acy. acyloxy, alkenyl. alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, akoxyimino alkoxysulfonyi aIkyl, alkyisulfonyi amido. arylalkyl, arylalkoxycarbonyl carnboxy yano formyl, haloalkoxy, haioaiky, halogen. hydroxy, hydroxyakyl, mercapto, nitro, Oxo, thioakoxy, -NRARi. and (NR ARs)sulfony'. Additional examples of heterocycles include, but are not limited to, azetidin-2-one, azepan-2-one, isondolin-1 3-dione, (Z)-IH-benzo[e][1 4]diazepin-5(4H)-one, pyridazin 3(2H)-one pyriin-2(1H)-one, pynimidir>2(1H)-one pyrinidir-2,4(1H,3H)-dione, pyrrolidin-2-one be.nzotdthiazoh2(3H)one, pyridin-4(1HV-one, midazolidirv2-one, -I ~ ~ pyn~udi-2(H I-one, iI--11-bern7oc)diimidazoi midazol-2(3H)-one. piperidir-2-one. tayrpriiiy(Hon Hbn1n~mdzi 2(3H)-one. [1,2,4]thiadiazolonyl 1 ,2,5thiadiazoionyl. [34]thiadiazinonyl [2,4]oxadiazoionyl [1 ,2 ,5]oxadiazolonyl, 3 4]oxadiazinony and 1 5-dihydro benzo~b][' ,4)diazepin--on-yt The term "hydroxy" as used herein means an ~OH group. The term "hydroxyalkyl" as used herein means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representaive examples of hydroxyalky include, but are not limited to, hydroxymethy, 2-hydroxyethyL 2 methyl2-hydrethythy 3-hydroxypropyl, 2,3 dihydroxypenty, and 2-ethy-4-hydroxyheptyi. -9- The term "hydroxy-protecting group" means a Which protects hydroxyl groups against undesirable reactions during synthetic procedures. Exampes of hydroxyt protecting groups indude. but are not limited to, methoxymethyL, benzyloxymethy, 2 ) mnethoxyethoxymnethyl, 2trimethylsi lyt~ethoxymethyl, benzyl, triphenylmethyt 22,2 tnchloroethyl. t-butyi, trirnethyisilyl, tbutyidirnethysi, t-butyldiphenylslyl, methylene acetal, acetonide benzyidene aceta, cvdic ortho esters, methoxymethylene, cyclic carbonates, and cyclic, bronates-'. Hrydroxy- protecting groups are appended onto hydroxy groups by reactions of the compound that contains the hydroxy group with a base, such as trethylamine, and a reagent selected from an alkyl halide, alkyl trifilate, trialkyisilyl halide. triaikylsilyl triflate, aryIdiaIkyisiytnifIate, or an alkylohioroforrmate, CH{. or a dnaloboronate ester for example with methyl iodide tratyisilylt.flate, acttyl chlorid, benzylchioride, or dimethylcarbonate. A protecting group also may be appended onto a hydroxy group by reaction of the compound that contains the hydroxy group with acid and an alkyl acetate The term imino" as defined herein means a <C(=NH)% group, The term meapto" as used herein means a -SH group. The term t NRA R" as used herein means two groups, RA and R, which are appended to the parent moleculair moiety through a nitrogen atom, R, and Rr, are ndependenty selected from hydrogen, alkyi acyl, and formyl Representative examples of 4NRRj incude, but am not mited to, amino, dimethylamio, metyliarnino, acetylamino ethylamino. The term "(NRR.)alkyl" as used herein means an -NR ARs group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representatve examples of (NRARyakyi include, but are not limited to 2 (methylamino)ethyl 2-(dimethyiamino)ethy 2(amiino)ethyl, 2(ethyimethylamino)ethy and the like. The term "(N RRs)carbony" as used herein means an ~N4RARr group, as defined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein, Representatve examples of (NRARs)Carbonyl include, but are not'imited to, arminocarbonyl, (rmethylamino~carbonyi, (dimethyiamino)carbonyi. (ethvlmethvaminokarbonyl and the like. The term "(NRRP)su'fonyr t as used herein means a 'NRARs group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein, Representative examples of (NRAR)suifony indude but are not limited to, aminosulfony(methyamino)sufonyl, {dimethylaminc)sulfonyi and (ethylmethylami no)sulfonyi. -10> The term 'nitro" as used herein mears a -NO, group, The term nitrogen protecting group" as used herein means those groups intended to protect a rirogen atr against undesirable reactions during synthetic procedures. Nitrogen oroteoting groups comprise carbamates, aides, Ntbenzyl derivatives, and imine derivatives. Preferred nitrogen protecting groups are acetyl, benzoyi benzyK benzyloxyoarbonyl (Cbz), formyi, phenylsulfonyij pivaoyl, tertbutoxycabol (Boc), tert butylacety triuoroacetyl, and triphenylmethyl (trityl) Nigen-protecting groups are appended onto priniary or secondary amino groups by reacting the compound that contains the amine group with base, such as triethylamine, and a reagent selected from an alkyl halide, an alkvi trifilate. a dialkyl anhydride, for example as represented by (alky 0}3C=z0. a diaryl anhydride, for example as represented by (aryi-)C=O an cyl halide, an alkylchloroformiate, or an alkylsuifonylhalide an arylsulfonylhaiide, or halo CON(aikylK for example acetylichloride, benzcylchloride, benzyibromide, benzyloxycarbonyloride, fornyifuoride; phenyisuifonyichioride pivaioyiohlonde, (teri butyvL-0C=0k, trifluoroacetic anhydride, and triphenylmethyihloride The term 'oxc as used herein means (.O). The term "suffony" as used herein means a -S(0)2 group. The term thicakoxy" as used herein means an alkyi group, as defined. herein, appended to the parent molecular moiety through a sulfur atomn Representative examples of thicalkoxy include, but are no lImited to: methyithio, ethyithio and propyithio. As used herein, the term "antagonist" encompasses and describes n that prevent receptor activation by an H 2 receptor agonist alone, such as histaminer, and also encompasses compounds known as "inverse agonists". inverse agonists are compounds that not only prevent receptor activation by an H3 receptor agonist, such as histamine, but also inhibit intrinsic t receptor activity. orgpongds oftinvention Compounds of the invention can have the formula () as described above, in compounds of formula (i), one of R, and R- 2 s a group of the formula -. RA t R, The other group of R, and R is selected frnm hydrogen, aIkyi akoxy, halogen, cyano, and thioakoxy, Preferably, R, is -L 2

-K.L

3 -KR and R, is selected from hy droge aikyl, alkoxy, halogen. cyano. and thioaikoxy, When one of R, or R 2 is ~L -Rgr then the other is preferably hydrogen. L, is selected from a bond, alkylene. -0, -C(=O)- -. S-, -NH- 0N(Rs)C-0 C(=O)N(R ),and -Ntalkyi)~ it is preferred that L is a bond. LU is selected from a bond, alkylene, -0(-, =&0)- -SN(R6)C(O) 411- C(=0)N(Rh and -N(R-, wherein Rg, is selected from hydrogen alkyi acyl alkoxycarbonyr amido, and formyl It is preferred that t 3 is a bond, R s i selected from a 5- to 6 membered heteroaryl ring, cyanophenyi. an 8- to 12 ) membered bicycic heteroary! ing and a 4- to 12-membered heterocyooi ring, The 5- to 6-membered heteroaryl ring 8~ to 12Umembered bicyclic heteroaryl ring and 4 to 12 rembered heterocyce rng for R, can be substituted or unsubstiuted, is selected from hydrogen, a 5- to 6&membered heteroaryl ring, an aryl ring, an 8- to 12-rembered bicyclic heteroary ring, and a 4-to 12-membered heterocyclic rng, The 5- to 6-menmbered heteroaryl ring, aryl rng, 8- to 12-membered bicyclic heteroaryl ing, and 4- to I 2-mnembered heterocyclic ng for R, can be substiauted or unsubstituited. Specific examples of 5- to 6-membered heteroaryl rings suitable forR, and RO include, but are not limited to, furyl imidazoly, isoxazolyl, isothiazoly, oxazoyl, pyrazinyl. pyrazoly, pyridatnylt pyrldinyl, pyrimiiny. pyrrolyi, tetrazoly [1,23:thiadiazoyl 2 3]oxadiazoMythiazoly, thienyl, [1.2 3]triny 1 2,4]triaziny, [1 3;]triazinyl [1,23]triazol, and (1,2,4]tnazoly. Preferred 5- to 6-membered heteroaryl rings are, for example, pyrimidnyl, pyridnyl. and pyrazolyl. Each of the 5 to 6-membered heteroaryl rings as independently unsubstituted or substituted with substituents as described herein, for example as in the Examples or the Definitions. Examples of 8-to 12-menbered bicyclie heteroaryl rings suitable for R, and R. include out are not limited to, indolyl, benzothienyl, benzofuranyl, indazolyl, benzinidazolyl, benzothiazoly, benzoxazolyl benzoisothiazoyl, benzoisoxazolyi, quinolinyl, isoquinoliny, quinazoliny quinoxalinyl, phthalazinyl, pteridinyl purinyl, naphthyridiny[ cinnoiinyl, thienoj2,3-dimidazre thieno[3,2-b]pyridinyi, and pyrrolopyrimidinyi Preferred 8- to 12-membered bicyclio heteroaryl rings are, for exanpie benzothiazolyi and thieno 3,2-bpyridiny Each of the8- to 12-membered bicycle heteroaryl rings is independently unsubstituted or substituted with substituents as descnbed herein, for example as in the Examples or the Definitions. Examples of 4- to I 2-membered heterocyclic rings suitable for R&, and Ri include, but are not limited to, azepany, azetidinyl, aziridinyl, azocany, di hydropyrdazinyl, dihyd rpyridiny dhhydropynmdinyl morpholnyl, piperazinyl, piperidinyl, pyrrolidinv, pyrrolinylt dihydrothiazoly, dihydropyridiny, thiomorpholinyl, dioxanyl, dithianyl tetrahydrofuryl, dihydropyranyl tetrahydropyranyl, [i,3}dioxolanyl, azetidin-2-ony, azepan-2-ony isoindolin-1,3 -donyit (Z) 1Hbenzoe1,4diazepir-54H) ony, pyridazin-3(2H)-:onyl, pyridin- 2(1 H)-ony, pyrimidin-2(1H)-onyl, pyrinidin--2A(1 H)3H) dionyl, pyrrelidin-2-onyl, benzo~dthiazoV2(3H)-onyl pyridir -4(1 H)-onyi imidazoidin-2 onyl, H-imnidazo-2(3H)-onyl, piperidin-2-ony tetrahydropyrimidin~2(1H)-onyl -12- [ .2,4]thiadazol onyl, [1 2,&)thiadiazoiony, (1 3$,4]thiadiazinonyi [1 2,4]oxadiazoionyt [1 2,5]oxadiazolrny [1 3,4]oxadiazinonyi, and Abenzo dimidazo2(3Hnyi. Preferred 4~ to 12-iembered heterocyclc rings are azetdin>2-ony, azepan2-onyt pyridazin-3(2H)-ony pyrrolidiw2onyl, and piperidin-bonyI Each of the heterocycli ngs is independently unsubstituted or substituted with substituents as described herein, for example as in the Exarnples or the Denitions. In one preferred embodimentthe group R, is L 3 .wK> wherein L is a bond, R is hydrogen: L is a bond, R is selected from a 5- or 6membered heteroaryi ring and R. Ks R, RR , R,, R- and L are as previously described hn another preferred embodiment, the group R is Er xLRo wherein Lrs a bond; Rz is hydrogen: L. is a bond; Rsis selected from a 8~ to 12-niembered bicyclic heteroary ring: and R 2 R, R, R&, R 4 Rs, and L ar- as previously described herein, in another preferred embodiment, the group R, is "U: R wherein L s a bond Rt is hydrogen; 3 is a bond: R e is selected from a 4- to 12-mernbered heterocyolic ring; and R 2 R R?,,, RPj R., R, and L are as previously described herein in another preferred embodiment, the group R, is -L Rm wherein L is a bond Rm is hydrogen: L-, is a bond, R is pyridazin(2H)-ny and R, R, Ra RR R. and L are as previously described herein Each of R; R 3 and RL, are each independently selected from the group consisting of hydrogen. alkyl, trifiuoroaky trifluoroaikoxy alkoxy, halogen cyano and thioalkoxy, Preferably, R 3 , R, and R are hydrogen, or, one of R, R:t., and R is halogen and the others are hydrogen. The preferred halogen is fluorine. R4 and P5 are each independently selected from the group consisting of alkyl, fluoroalky hydroxyaikyi, aikoxyalkyi, and cycloalky. Alternative'y, R4 and R, taken together with the nitrogen atom to which each is attached to form a non-aromatic rng of the formula: pR, Ra R R R 'IN RR bor) R, RftR and R , are each independently selected from hydrogen hydroxyaikyl, fiuoroalkyl, cycloalkyl, and aikyi R, and Ry at each occurrence are independently selected from the group consisting of hydrogen, hydroxy, hydroxyakyl, alky! aikoxy, alkylamino, fuoro, and ) dialkylamino. Preferably, at least one carbon in a group of formula (a) 's substitted, such that either one of R 7 ; R8, Rc, or Ri, or one of R, and R s other than hydrogen. The preferred substituents for R R R, or Rn, when substituted, are hydroxyaky fluoroaiky or akyL The preferred alkyl group is more parcuilariy, methyl. The preferred substituents for R, or R, when are alkyk fluoro, or hydroxy. Groups of formula (a) are referred for R4 and R. when taken together to form a ron-aronatic ring, The preferred group for F4 and R 5 when taken together with the mm-womaticmeoi eina1 The offered forniuo ' nitrogen atom to which each is attached to form a group of formula (a) is methylpyrrolidine or (2S)-methylpyrrolidine R, R R 1 and R1 are each independently selected from hydrogen, hydroxyaikyl, alky'. and fluoroalkyt Preferably, at least three substituents selected from Pi, R,, R, and R are hydrogen Q is selected from 0 and S. The preferred atom for Q is oxygen, The preferred group for R 4 and R when taken together wth the nitrogen atom to which each is attached to form a group of formula (b) is morpholinyl. The variable m is an integer from I to 5. L is N(R)(Rl)]wherein R, and R- at each occurrence are independently selected from hydrogen and alkyl and k is 1 2 or 3. Preferably k is 1 "r 2. One embodiment relates to coropoundis of formula 0i): RR2 N Re I) wherein L R _ R, R, R-., Rgand P are as previously described. In one preferred embodiment of compounds of the invention of formula (!), the group R is -L 2 -tin wherein L 2 is a bond: R is hydrogen L3 is a bond; R, is selected from a 5- or -membered heteroaryl ring, or a 4- to 1 2-membered heterocyclic ring; Rj and R, when taken together with the nitrogen atom to which each is attached, form a 4- to 8-nembered nornaromatic rng represented by formula (a) and R-t, R 2 R, -- l4- R- and L are as previously desorbed. Another embodment relies to compounds of formula (Il: 1 R R2 R L N ll R, wherein L RR, ,. R;.PS RKb R4, and 'Rar as previously descnbed. In one preferred embodiment of compounds of the invention of formula ( fl), the group R is LR 3 A wherein L is a bond; R( is hydrogen; L is a bond Rp is selected from a 5- or 6-membered heteroary ring, or a 4- to 12-membered heterocydic ring R, and R when taken together with the nitrogen atom to which each is attached to form a 4- to 8membered non-aromatic ring represented by formula (a) and R. R, R t, and L are as previously described, Specific examples of compounds contemplated as within the scope of the invention include, but are not Jimited to, the following: 4((1R 2S)-2-{[2R) -2 meth y pyjrroidin-1-ylmethy)cyclopropy 1 '-1biphenyi-4 carbonitrile; 4((1 2S)-2-{[(2R)-2-methylpyrrolidn-yi]methyi}cyclopropy)11 '-biphenyl-4 carbontr e; 4 ((1RB 2R)22-{[(2RP 2 methylpyrroiidin-1 yvlmethy!)ocdopropy -L 1 bphenyl4e carbonitr e: 49((1R2R)2-{(2S)-2 7 methylpyrroidir-i1-y methy(}oydcopropyl)- i -biphenyl-4 carbonriie 4 {{18 2S)-24(2-methylpyrrolidin-1 yl)mety!cyclopropyi}-1,1 -biphenyL carbonitri ec 5-[I(12S2i{{(2S)-2-methyvpyrrodin-i yI]methyl}cyclopropy Iphenyjpyrimidine 2-methoxyv [4((82S)g282)-2-methypyrrolidirn1~ ylnmethylcycoproyl~phenyl~pyrimidine; 2,6-dimethy 3-[4-((18,2S)-2-{[(2R)-2-methylpyrrolidin-1 y 'Im et hylkcyclo.prno pyp!henyJ] pyridine' 2~methoxy-54(4-((1 S 2S)-2-{(2R)-2-methylpyrroiidin-1 yi}methyi}oyclopropyl)phenyl'pyridine1 -15- 5 [((8,S)2R l2R-2methiy pyrreIndm In y mrty yclo p 5-"4-((1IR,2R)~2-{( ) nehlyrs I i ) y ]methy4}cycopropy )phlenylpyrimidne; S4(P ((1RR2((2R)2-meth ymethyi }cyc opropy)pheny pyrimidine; 24-dirnethoxy-5-[.4-(1R2R)-2-{[(2S)Y2Tmetypyrrohdin1 yl]methyl}cyclopropy phenlpyri midine 24-dimehoxy5-[4((1R,2R)2-{[(2R)2ethypyrroid y] ety }cylopropyA)penypyr inr 24440mtos 2,3 4-iethxyl 54 4 ,2(( 2 2~{[(2RS'2-met hyipyrroli:;di n-1I 2 4-dinethy~5,[-((8;8)2 [282 etypyroidn 244(1 R 2R)-2-{(2S) 2~methylpyrro idi n-1 ylmethytcyclopropyphenyiipyridazin 3(2H) one, 2-4&(1iS 2S)-2 [(S 2,ntyproii- ]mty~ylpoy~hniprdzr 3(2H)-one; 2-methy 5~[4~((1 S ,2S)-2-{[(2)2niethylpyrrol dmne 1y]methylyopropyfpheny>] 1 3Str methy 4 [4~S,)-n2{( 2 2-methylpyrro idi yflmethyl}cyciopropyl)phenyi]-1 H pyrazole; 2 6Sdimethy34( ) 52 -{[(2S)~2-methypyrro dvld 1~ y 2 imethyPhcclopropyihphenylpyridine N-44((1IS,28)>2[(2S)-2 methyypyrroliik iy~etynycorpy-hny yimdn 4j((iR2S)-24(2R)-methylpyrrodn1-yf]ethyl cyclopropyf)-1II biphenyk4 4 ((8,2R 2~2-[(R) 2metylpyro'ir-1 y'P]ethy~cyclopropyAfi,1 biphenyi-4 4'j(trans-2-yrroidin-1-y ethyilcyclopropyi}- ,1 >biphenyL-carbonine; N-{4-((18 2S)-2~{[ (2$) 2-methypyrrolidi 1ymethy}cyclopropylpher4i] 5 N44-((1, 2$)>2-{(23)--methypyrrolidin-i1 y1 methy!}cyclopropy)phenyIsonlictinamide; 2[4(}(18 2)2{(R2mthpyrdis -ylethy}cylopropy~phenyijpyridazin 3(H)-one 1-~(11 2S)-2-((2R)2-methylpyrrodin-1yl]rnethy)cycopropy)phenyflpiperidr. 2 -one one: 1-4 (1 S2S)2{(2R) 2-methylpyrroidin~1 -ymethy}cyloopy)pheny]pyrroidin 0 oe: 2 -one; 14{4-((1S[2S)-2-{[(2R)Y2-methylpyrrolidin- 1 yli imethy/}cyoopropylphenyflsazetidir 2-one: 1-4-((1 2S)~2~{(2S)-2-nethylpyrrolid4 n ylimethy}cycopopyt~peryjazetidin-2 one 144-((18 25)-2-{(2S)-2-methylpyrrolidin 1ylmethy}cy coprop phenyIHazepan-2 one: 1-18 S)-2([(28)'2-methyipyrrolidn-1 y~ehlcclpoypeyipprdn 2-one 14((1 S 2S)-24{[2S)-2-methylpyrroddnir iylmethyi}cyclopropy~phenyi]prrlidin 2c one; N-[14 ((S,2SY2-{[(28)-2-m;ethylpyrrogidin~1~ ymtyiyoprp)pnyaetmd and N4-(1 8.2-m {[(2s) 2 rnethylpyrroddirn1-ylnethy}cycdopropyl)pheny]11H-1 2.4 triazoles narboxamide, The following compounds can be made according to the methods and Schemes described err 5-(prro~ lidir- I1-ylcarbonvy!)h2{4 [trans)-2-(2-pyrrolidin-1 yiethyl)cyclopropyf)phenyA)pyridine 4~( {(1. 2R)-2-[2-(2-nethyipyrrolidih< y!)ethyiicyclopropy1)-1i 1 biphenyf-4 carbonitrile; 4t((1S;2R)%{2W(3R)4hrmoxyp yrrodn~1~y ethyi}cyclopropy )-1 'biphenyk4 carbonitriVe bipheny!~4-c3arbontle; 441 C 2R' t2-( azpn1yehlccorcf ,tihne abnt~tand More preferred embodiments are compounds sedected froin 2-methoxy 5 [4 ((1,2S)-2{[(2S)-2-methypyrroidrO y'limethyi}cycopropyi)phenylpyrimnidineQ -1 ' 214A((1S 2)2{2)2mehlyrldn-1 yMmethycydclopropyl)phenifpyridazwr (S)-3-hydroxy- 14{4-((1 S2S)-2(((S)-2-methyipyrroidin1 yi~met hy)cycdopropyiphenypyrrondin-2-one: 21{4-[(1 23)-2{(&)-2Methyi pvrrohdirv-ymethykoyclopropyi) phenyl>2H pyridaziri->one with (2S;3c)d3-dhydroxy-succind acid and 24((1S 23) 2-{[(2R)2-methylpyrroidin- 1 -y]methylcyclopropylephenyjpyrdazin 3(2H)-one, or salts thereof. Another more preferred embodiment relates to the compound 2-[4(1, 23)-2 {(23P2-methyipyrrolidin-1-y imethyi}cyclopropy) phenyljpyridain-3(2H)-one or a sait thereof. Another more preferred embodiment related to the compound 2-(44(18 2)-2 ([(23)2methypyrroidin-1 -ymethyi}cycopropyi)phenypyridazin-3(2H)On and its L bitartrate ronohydrate, L-bitartrate anhydrate, D-bitartrate dihydrate, and D-bitartrate Compounds of the invention were named by ACD/ChemSketch version 5.01 (developed by Advanced Chemistry Deveiopment. inc, Toronto, ON, Canada) or were given names consistent with ACD nomenclaturtmatively, compounds were assigned names using Chemflraw (Cambridgesoftl The practice o sinn ae oceia .., pacn of assigning names,, to chemical compounds from structures, and of assigning chemical structures from given. chemical names is weH known to those of ordinary skil in the ar.. Compounds of the invention may exist as stereoisomers herein, asymmetric or chiral centers are present. These stereoisomers are "R" or "S& depending on the onf ation of substituents around the chiral carbon atom. The terms " and "S used herein are confiurations as defined in IUPAC 1974 Recommendations for Secton E Fundamental Stereochenistry, in Pure Apph Chem 1976, 45: 13-30. The invention contemplates varous stereoisomers and mixt.ures thereof and these are specifically included within the scope of this invention Stereoisomers include enant homers and diastereomers, and mixtures of enantiomers or diastereomers. individual stereoisomers of compounds of the invention may be- prepared synthetically from commercially available starting materais which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution weli known to tnose of ordinary skIi in the art. These methods of resolution are exemphfied by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optical pure product from the auxHiary as described in Furniss, Hannaford, Smith, and Tatchell, "Vogel s Textbook of Practical '-18~ Organi Chemistry 5th edition (1989), Longman Scientfc & Technica, Essex CM20 2JE, England or (2 direct separaton of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystal.ization niethods, Compounds of the invention may exist as cis or trans isomers 'wherein subsiuenson a ring ma attached in such a manner that they are on The same side of the ring (ois) relative Wo each other, or on opposite sides of the ring relative to each other (trans) For example, cyclobutanes and cyclohexanes may be present in the cis or trans configuration, and may be present as a single isomer or a mixture of the cis and trans isomers. individual cis or trans isomers of compounds of the invention may be prepared synthetically from commercially available starting materials using selective organic transformations, or prepared in single isomeric form by purification of mixtures of the cis and trans isomers, Such methods are well known to those of ordinary skill in the art. and may include separation of isomers by recrystallization or chromatography lt should be understood that the compounds of the nvention may possess tautoneric forms, as well as geometric isomers, and that these also constitute an aspect of the invention. It is also understood that the compounds of the invention may cxist as zsotopomners, wherein atoms may have different weights; for example. hydrogen, deutenum and tritiurn or C C and -C,, or "F and 8F Salt propertes Particular salts of compounds of the invention also have been identified and are described herein, More particularly, such salts are 2{-(1 S).2(S)2Methy[ pyrrolidin1-yimethyl)-cyc lopropyi] phenyi2 H-pyridazin-done Lbitartrate nonohydrate., L-bitartrate anhydrate. D-bitartrate dihydrate. and D-bitartrate anhyriate. 244(182S)27(S)/-Mehypyrrlidn--ylmt-hyi);cilopropyl)-phenyl]} 2H.

pyridazin-one L-bitartrate monohydrate can be identified by characteristic peaks in its powder Xray diffraction pattern (Figure 1 ;, One with skil in the art of analytical chemistry wouid be able to roadity identify 2-{4[(18,2S)>2(S2-Methyyrrolidin-1-ylmethyl) cyclopropyl)-phenyl}2H-pyidazin.3~one Lbitartrate monohydrate solid by as few as one characterstic peak in its powder Xray diffraction pattern. Twotheta angle positions of characteristic peaks in a powder X-ray diffraction pattern ffor 2-4[(18 2)-2(- 2(8 Meth ylpyrroiidi n.iylmethylgcyclopropyl]phenyi}-2Hpyridazn.one L-bitartrate monohydrate are 7,157± 020. 10 064± 0.20. 14.356± 0.20, 16727± 0.20, 198198 0.20, 20,119±0:20, 21.222± 020, 22146i 020, 24.048± 0-20, and 24.574± 0,20, The solid was also analyzed by thermal gravimetric analysis. The TGA (Figure 2) shows the ~19~ dehydration of 24[( 2hyp 2H-pyridazin-3-one L-bitert nonohydrate 2-{4-f( 16,28)2{(S)-2Methy-pyrrolidin- -yImethy!)-cyclopropyl pheny,} 2H-pyridazin-3-one bitartrate anhydrate can be identified by characteristic peaks n its powder X-ray diffraction pattern (Figure 3), One with skll in the art of analytical chemistry would be able to readily identify 2-{4(iS,28)-2-(($)2-MethyV pyrrol id in-I -ylmethy1)cyclopropyi]-phenyl}.-2 H-pyridazin-3 -one L-bitartrate nonohydrate solid by as few as one characteristic peak in its powder X-ray diffraction pattern. Twitheta angle positions in a powder Xray diffraction pattern for 2-{4-({S,23)-2-((S)-2-Methyl-pyrroldin- 1 -ylmethyl)-cyclopropyl-]phenyl)-2H pvridazin-3-one L-bitartrate anhydrate are 4.589±0 20, 9.206+0.20, 13.85±0,20, 14335t0,20, 15,824±0.20, 16272±0.20, 16.825±0.20, 18.083±0.20, 18.514±0,20, 19.588±0,20, and 20.551±0.20. 2-4-((1 8 28)-2-((S)2-Methyl-pyrrolidhtr-ylmethyi)--cyclopropykphenyl)-2H pyndazir-3-one D-bitartrate dihydrate can be identified by characteristic peaks in its powder X-ray diffraction pattern (Fgure 4 One with skill in the art of analytical chemistry would be able to readily identify 244{( I S.2 ((S)-2-Methylpyrroiidin-ylmethyl) cyclopropy'lyphenyl}2pyidazn-one DN-btartrate dhydrate solid by as few as one characteristic peak in Its powder X-ray diffraction pattern. Two-theta angle peak positions in a powder X-ray diffraction pattern for 2-44(18,2S).2(()-2-Methy-pyrroidin4 ylmethyl)-cycopropyl]~ph~enylb2H-pyridazin3-one D-bitartrate dihydrate are 4 387±0.20, 8j88±0.20, 10.326±020, 12.056±0.20., 13.192±0,20, 14.089 0 ,20, 16,194i020, 19,502-0 20. 19.877±0.20 20.271±020, 20.733±0.20. 21.313±0.20 23.103±.20, and 23:937±0.20, The solid was also analyzed by thermal gravimetrc analsis. The TGA (Figure 5) shows the dehydration of 2.-{4,[((18 S28)-2((S)-2-Methytpyrrlidir-1-yinmethyi) cyclopropyl-pheny!}2Hpyridazin4one D-bitartrate dihydrate, 24[(1 S;2SP2-.((S)-2-Methyl.-pyrroiidin-1 yethyl)-cyclopropyl-phenyl-2l pyridazin-3-one Dbitartrate anhydrate can be identified by characteristic peaks in ts powder X-ray dfracton pattern (Figure 6). One with skill in the art of analybcal chemistry would be able to readily identify 2-{4-[(I1,28)-2-((&)-2-Methyipyrreldir-1-yimethyl) cyclopropypheny)-2Hpyridazin3--one D-bitartrate anhydrate solid by as few as one characteristic peak in its powder X-ray diffraction pattern, Two-theta angle peak positions in a powder X-ray diffraction pattern for 2-(4-[(1S,2)-2-((S)-2-MetyKpyrroliin4 yimethyi-cyoopropyi]-phenyl}s2H-pyridazinone D-bitartrate anhydrate are 5.004±0,20, -20- 10590±0.20. 13 548±0.20 14,219±0:20, 15,279.20 0,1723±0.20. 16990±0.20, 18723±0.20, 19.052±0-20 20.827±0.20, 21 293t0.20, and 22,826±0,20, Compounds of foriula (I) and salts thereof with any level of purity (including pure and substantialy cure) are within the scope of Applicants' inventon. The term substantial pure" in reference to a compound/saltfisomer means that the preparationconmposition containing the compoundsaitsomer contains more than about 85% by weight of the compouncisaliisomer, preferably more than about 90% by weight of the compound/sptisomer, preferably more than about 95% by weight of the compound/saltisorner. preferably more than about 97% by weight of the ompound/saiisoner and preferably more than about 99% by weight of the co mpound/sait/isomer The term "substantially phase pure" in reference to a particular crystallne form of a compound, means that the preparation/composition containing the crystalne form contains more than about 85% by weight of the crystalline form, preferably more than about 90% by weight of the crystaliine forr, preferably more than about 5% by weight of the crystalne form preferably more than about 97% by weight of the rcrystaline orm, and preferably more than about 99% by weight of the crystaine form. The term 'purity". uness otherwise quail fed, means the chemical purity of a compound according to conventional HPLC assay. The term "phase purty" means the solid-state purity of a compound with regard to a particular crystalline or amorphous form of the compound as determined by X-ray powder diffraction analytical methods. The term "phase pure" refers to purity with respect to other solid-state fomis of the compound, and does not nicessariy imply a high degree of chemical purity with respect to other compounds. The term "crystaline" or "crystaliine form" as applied to a compound refers to a solid-state in which the compound molecules are arranged to form a distinguishable crystal lattice (i) comprising distinguishable unit cells, and (ii) yieidng diffraction pattern peaks when subjected to X-ray radation. Methods for Preparing Compounds of the Invention The compounds of the invention can be better understood in connecton with the following synthetic schemes and methods which illustrate a means by which the compounds can be prepared, Abbreviations whih have been used in the descriptions of the schemes and the examples that follow are: Ac for acetyi: atm for atmosphere(s: AIBN for 2'-azobis(2 -21methylpropBonitr Ie)BINAP for 2,2bis(diphenylphosphino1)- 1 1binaphthyL Boc for butBu for butyl dba foriberyidineacton DBU for 1 8 diazabicyco[5. 4 .Oundeo-ene; 0CM for dichioromethane DiBAL- for dsobutyiaumin urn hydride: OMAP for 4DNN-dimethylaminopyrdine; DME for 1 2 diimethoxyethane; DMF for N, N-dimethyformarnide; DMSO for dimethyisupfoxide; dppf for 1 -1bis(dipheny phosphno)ferrocene EDTA for ethyenediaminetetraacet acid: Et for ethyl EtOH for ethanol EtOAc for ethy acetate: HPLC for high pressure liquid hromatography iPA for isopropyl alcohol IPAC or IPAc for isopropyl acetate: LDA for ithium diisopropylamide NEBS for N-bromosuccininde; NIS for N-iodosuccinmide- Me for methyl MeOH for methanol; Ms for methanesulfonyl: MTBE for tert-butyi rnethyl ether Pd for palladium; Ph for phenyI tBu for tert-butyt TE buffer for a combination Tris and EDTA buffer TEA for triethylamine: TFA for tiforoacetic acid; THF for tetrahydrofuran, Tris for 2-amino-2-hydroxymethyI 3-propanedioi and Ts for para-toiuenesulfoyA; rt for "room temperature" or ambient temperature suftably ranging 15-40 'C. As identifiers of compounds available from descriptions reported in the iterature or available commercially, CAS numbers may be usedG AS numbers are identifier numbers assigned to compounds by Chemical Abstracts Service of the American Chemical Society and are wail known to those of ordinary skill in he art The compounds of this invention can be prepared by a variety of synthetic procedures, Representative procedures are shown ir, but are not limited to, Schemes 1 7. -22xx 00 RR R 0, R RR H R, R 3 3R ' R~~~N 'RoN\ ~ ' R RF4H X X 1 Ro Rn R 2,dso ,uk 11and(4, her.nR3R, j R Rae ~ N0 i(O' N K -" F ~R R - F R B kORK"' delirn in f u~ d j is -1P-Li-t.and :Rt, i hydrogen, akyl &kory, h'Y'srsen Vcyao, or thiakoxy, wvherein L,, s abond . (H) , 4N(&kl), - or -S-. and F ., L, and ii.ae as do-fired mn formula (I) ca b prepared as desced n Scheme 1. EEsters of tormu'aI (3) wncrem~i R Is a lower alkyl, and X is 0, Br, I, or trifiate, purchased or prepared using methodologies known to those Of' oruJMar.y s,,kil in the art, can be reduced with a ,reducing agent such as, but not iirrtted to, DUBAL to provide allylic alch-ois of formula (2tt Mlykc Achols of formula ,(2) can be converted to cyclopropyl aK'c-ics of fomnua (5) anid (6)1 following the mehooogy of A, Charette, ~n hi.1% Tec Cpoy alcoholsmof fomuas (5) and ( 1) can be oxidZecd v a a reaction known as Swar oxdation by an agent, such as, but not limited to DM A and oxavid chloride to profe aldehydles -23- Of formula (7) and () Referes. describe this methodoogy n may 'be found n the following: Tdwell, Thomas T Organic Reacdons (New York) (1990), 39 27-572 and the references cited in the article. Aldehydes of formulas (7) and (8) can be treated with ) reducing agents sucn as, but not limited to, sodium cyanoborohydride or sdiurn triacetoxyborohydride, in the presence of an amine of formula (9) via a reaction known as reductive amination, to provide amines of formula (10) and (11) respectively. References that describe this methodology may be found in the following M. D. Bomann et al, J. r Chei., 60:595960(1995); A, E Mooirmann et al Synth Commun 23:789 795(1993 and A, Pelter et aL J. Chem Soc PT , 4.717720(1984) A F. Abdel Magid et al, rg. Chem. 199 61, 33493862 The Suzuki reaction can be used to convert anines of formula (10) and (11) respectively to compounds of formula (13) and (14). wherein R R P\ R, 4 and R are as defined in formula (I), R2 is hydrogen, alkyl, aikoxy, halogen, cyano. or thioalkoxy, and R, is R r wherein L, is a bond and R and t and R are as defined in formula (). in such a Suzuki reaction armies of formula (13) and (14), wherein X is triflate, 1: Br; or Cl can be reacted with boronic acids or boronic esters of formula (12) wherein R. is hydrogen or alkyl, a metal catalyst such as, but not limited to, pahadium diacetate or Pd(PPM)X optionally with a Pd ligand added such as 2 (dicyclohexyiphosphino)hipheny or is(2furylphosphine and a base such as but not limited to, aqueous 0;2 M K 3 P0, or sodium carbonate. Aiternatively, pinacol borane reagents such as, but not limited to those represented by formula (1 2a) can be used in Place of boronic acids or esters of formula (12) in the Suzuk reaction. References that describe the preparation and use of such reagents useful the Suzuki reaction methodogy may be fund in the following N Miyaura et al,, Chem. Rev. 952457(1995) and references cited n the arucie There are many aryl, heteroaryl, and heterocycl boronic acids and boronic acId esters that are avaabe mommiercall y or that can De prepared as dn the scientific literature cf synthetic organic chemistry Exampnles of boronic acid and boronic acid ester reagents for the synthesis of compounds of formula (I) are provided, but not ignited to reagents shov in Table 1 below, and the following description. Table 1 Examples of Boronic Acid and Boronic Acid Ester Reagnt Boronitc Acid or Soronic Acid Ester.commrercial Source, Chemical Abstracts Number (CAS #): or Literature Reference _24- 2-pymd none 5 baroniC acid GAS #'373384-19-1 t oxrmidine 5boronic Frontier Scientific, Inc., Logan, UT. USA pdSpecs, Ferninglaan the Netherlands acd CAS #705323-227 Schinazi Raymond F Prusoff, Wiliarmn H. Synthesis of 5 (dih ydroxybory>2- deoxyuridine and related br~onmcontaining vpyrmidines, Journal of Organic Chemistry (1985) 50(6), 841 pyid ne 3 -baronic acid CAS #1692-25-7. Frontier Scient fic Inc., Logan, UT USA 4 dimethoxyprmidine5-barni CAS #89641-18-9, Frontier Scientific inc acid Logan, UT, USA 2-methoxy$-pyridine boronc acid Digita Specialty Chermicais, Dublin: NH: CAS #16105-89-3, New sheif-stabie halo- and alkoxy-substituted pyrdylboronic acids and their Suzuki cross-coupiing reactions to yield heteroaryipyridines, Parry, Paul R; Bryce Martn R.; Tarbit Brian, Department of Chemistry Synthess (2003) (7) 1031038: Functionalized Pyridylboronic Acids and Their Suzuki CrossCoupling Reactions To Yield Novei Heteroaryipyrdines, Parry Paul R Wang, Chansheng Batsanov. Andre: S, Bryce, Martin R,; Tarbit Bihan Journa of Organic Chemistry (2002), 67(21). 75417543. pymidinebtoronic ac:d CAS #1092998-7. S. Gronowitz, et aL, On the synthesis of various thieny and elnieiyipyrimidines' Chem Scir. 26(2' 305 309 l"986). pyrimidine-5-boronic acid, pinacol Umemnoto, et al Angew Cher. nt Ed ester 40(14):2620-2622 (2001). 2~-methylpyridne-boronic acid SYNCHEM OHG hydrate Heinrich~Plett-Strassse 40, Kassel, D34132; Germany CAS #659742-21-9 25- 2H-Pyran3,6-dihydrc-44 4.5- GAS # 287944-165; Murata, Miki Oyama tetranethyl 132-dioxaboroia-2- Takashi; Watanabe, Shinil Masuda Yuzur y Synthesis of alkenyboronates via padladiu cataly.zed boryiation of aikenyl trifiates (or odides) with pinacodborane Svnthe sis(2000) 2HyPyridinecartoxy3 acid, 3,b GAS # 286961-14-6 A versatifle synthesis of hynvdr-444455tetramethy 4-aryitetrahydropyridines via palladvun 12doxbran2yr- mediated Suzki ctrosscouplin wiith cyclic dimethyethyl ester vinyi bormnates, Eastwood, Paul R, Discovery Chemistry, Aventis Pharma Essex, UK, Ir ahedron Letters (2000), 41(109) 3705 5.cyanc3-.pyr dirnyl-boronic ado CAS # 497147-930 nstitut du PIN University Bordeaux 351 cours de la liberation Talence Oediex, 33,450 Boronic acids or boronic acid esters of formula (12), and (12a) can be prepared from corresponding halides or triflates via either (1) metal exchange with an organo ithium agent followed with addition of aikyi borate or pinacoiborate or (2) cross coupling with a reagent such as, but not limited to bis(pinacoiato)diboron (GAS #73183-34-3). References that desonbe the first methodology may be found in the following B T. OYNeilil et aL Organic Letters: 2-4201 (2000). M. D, Sindkhedkar at al. Tetrahedron. 57 2991 (2001); W. lack, ei. al, J. Med Chem 421274 (1999 R, L. Letsinger et al' J AmeTr. Chem Scc., 81 498-501 (1959); and F. . Carrol et ai. Med (Them 44 2229-2237 (2001). References that describe the second methodology many be found in the fhaowig:T ishiyama et ai. Tetrahedron. 57:9813-9816 12001) T ishiyama et a t Og. Chem, 60:7508 -510(1995); and Takagi et a. Tetrahedron Letters. 43 5349-5651 (2002), Another method for preparaon of boronic acids and boronic acid enters is the reaction described in 0. Baudoin, et alJ., J Org. Chem., 65:9268-9271 (2000), in which aryl and heteroaryi halides or inflates a reacted with a dialkyloxyborane such as -6 pinacoborane in the presence of triethytamine and paladium (l) acetate in dioxane. Alternativey, utilzng other coupniio methods such as Stile coupling, Compounds of formulas (13) and (14) wherein R. i R. R4, and R are as defined in formula (I), R, ) is hydrogen, aikyl. aikoxy, halogen, cyano or thioalkoxy, and RIs ytw~are wherein L is a bond and Re, L and R are as defined in formula (i, Can be prepared from amines of formulas (10) and (11) respectively, by treatment with organostannanes of formula (R,) SnR wvherein R 1 2 is alkyl or aryl. in the presence of a palladium source such as tris(dibenzylidneacetonejdipaladium (CAS # 52409-22-0) or palladium diacetate, arid a ligand such as triury!)phosphine (CAS # 5518-52-5) or triphenylarsine The reaction is generally performed in a solvent such as OAF at a temperature from about 25 "C to about 150 TC Such methods are described, for instance in J, K, Stille Angew. Chem Int. Ed. 25t0(1986) and' N. Mitchell, Synthesis, 803(192) While many stannanes are commercially available or described in the literature tnat support the Sbtille coupling reaction where compounds of formulas (10) and (11) can be transformed to compounds of formulas (13) and (14); respectively, it is also possible to prepare new stannarnes fror arylhalides, aryltrifiates, heteroarylhalides. and heteroaryltrifiates by reaction with hexa-aiky distannanes of formula ((R Snjwherein Rj 1 0 is akyl or aryl, in the presence of a palladium source like Pd(PhP), E example of hexa-aiky distannanes include, but not limited to, hexamethyidistannane (CAS # 661~69, 8), Such rnethods are described, for instance in Krische, et. al, Helvetica Chimica Acta 81(11);1909-1920 (1998) and in Benagia et a> Tetrahedron Letters 384737-4740 (1997) These reagents can reacted with (10) and (11) to afford compounds of formulas (13) and (14) respectively as described under Stille conditions, or for example under the conditions reported by A. F Litke et a., I, of Amer. Chen. Soc. 124:6343 6348 (2002), Compounds of formulas (13) and (14) wherein R- R- R-,, R4 end R are as defined in formula (1), R,! is hydrogen, alkyl, akoxy, halogen, cyano or thioalkoxy, and R, is LyReg wherein L- and Rt are as defined in formula () L is a bond, and Rs a nitrogenicontaining heteroarvl or heterocycic ring linked to the parent moiety through the nitrogen, can be prepared by heating compounds of formulas (10) and (11) respectively, with heteroaryl or heterocyclic rings of formula H-RLR,> wherein H is a hydrogen on the nitrogen atom, in the presence of a base such as, but not limited to, sodium t-butoxide or cesium carbonate, a metal catalyst such as, but not limited to copper metal or Gul, palladium diacetate, and optonaliy with a ligand such as, but not limited to, SINAP or tri-tertbutylphosphine. The reaction can be conducted in a solvent such as- but not limited to, dioxane. toluene or pyrdine. References that descnbe these methods may -27.be found in the following: J Hartvig et al Angew. Chem lnt. Ed. 37:20462067 (1998 J. Wolfe et a Acc. Chem. Res. 1-;805-818 (1998): M. Sugahara et al, Chen. Pharn Bul. 45--721 (1997): J P Wolfe et aL. J Org. Chem, 651158-1174(2000), ) F. Y, Kwong et a[i Org. Lett, 4:581-584(2002): A. Kapars et al, J. Amer. Chem. Sc. 123'772T7-729 (2001):B H. Yang et a J Organomet. Chem, 5761325 146 (1999): and A Kiyomori et aI, Tet. Lett, 40 2657-2640 (1999) Compounds of formulas (13) and (14) wherein R-, 3 , R-,, - R 4 and R-, are as defined in formula (I)y R is hydrogen. alkyl alkoxy, halogen, cyano, or thioalkoxy, and R, is LRwLR, wherein L is -NH- or -N(alkyl>. and Rae R, and L, are as defined for a compound of formula (1) can be prepared by heating compounds of formula (10) and ( ) respectively with a compound of formula H 2 N RRLZRror HN(akyl Re with a base such as, but not limited to sodium buoxide or cesium carbonate in the presence of a metal catalyst such as, but not limited to, copper metal or Cui, palIadum diacetate, and also optionally with a hgand such as, but not limited to, BNAP, or tri-tat butylphosphine, The reaction can be performed in a solvent such as dioxane, toluene, or pyridine. References that describe these methodologies may be found in the following J, Hartwig, et a. Angew. Chen. Int. Ed., 3712046-2067 (1998); J. P Wolfe et at Ace Them. Res., 13:805-818 (1998), J P, Wolfe et al, J Org. Chern., 65 1158-1174 (2000 F. Y. Kwong et aS, Org. Lett, 4581-58 4 (2002); and B. HYang et al., J. Organomet. Chaem, 576.125-446 (1999). Compounds of formulas (13) and (14) wherein R R, R 4 and R, are as defined in formula (): R is hydrogen, alky! aikoxy, halogen, cyanoor ticalkoxy, and R 5s LwRerL-R' wherein L is oxygen and R , and L7 and Rb are as defined in formula () can be prepared by heating compounds of formula (10) and (11) respectively with a compound of formula HO~e~YRe using a base such as. but not limited to, sodium hydride in a solvent such as toluene or NNdimethyiformamie n the presence of a metal containing catalyst such as Cui or palladium diacetate. References that describe these methodologies may be found in the following: 3. Hartwig et a,: Angew, Chem. nt, Ed., 372046~2067 (1998) K. E. Torraca et al J. Amer Chem. Soc.,12310770-10771 (2001): G. Kuwabe et ata, J. Amer Chem. Soc, 12:3:12202-1220t (2001), K. E. Toracca et al., J. Am. Chem. Soc, 122:12907-12908 (2000); R. Olivera et al-, Tet. Lett., 41:4353- 435A (2000): J, Marcoux et al J. Am. Chem. Soc. 119:10539-10540 (1997): A. Aranyos et al. J Amer. Chem. Soc. 121:4369-4378 (1999); T, Satoh et al, Bull. Chen. soo Jpn. 71 2239-2246 (1998); J F. Hartwig, Tetrahedron Let, 38.2239,2246 (1997): M. Palucki at al,, J. Amer. Cher. Soc 1193395-3396 (1997); N. Haga et al: J. Org, Chem, 61:735-745 (1996); R. Bates et al, J, Org. Chei,. 47:4374~4376 (1982): T. -28- Yamamoto et aL Can. J. Chern 61 86-91 (198); A. Aranyos et al. J, Amer. Chem. Soc. 121 4369-4378 (1999); and E. Baston et aL, Synth. Commur 28:2?25-730 (199g) Compounds of formikis (13) and (14) wherein R,, R 3

R-

4 and R 5 are as defined in formula (),- is hydrogen, alkyl, akoxy, halogen, cyano, or thioaikoxy, and R, is L 2 -RlyR, wherein L2s ufur and R: and L and R are as defined for a compound of formula (F) can be prepared by heating compounds of formula (10) and (11) respectively with a compound of formula HSR-LzN in the presence of a base, and with or without a metal catalyst such as Gul or palladium diacetate, in a solvent such as dimethylformanilde or toluene References that describe these methodologies may be found in the following: G Y. Liet al.. J. Org, Chem,, 6686-77-868i (2001): Y Wang et aci, oorg Med. Cheat Lett., 11:891-894 (2001); G. Liu et aL, J Med. Chern 44:1202 1210 (200); (. Y. Li et a. Angew Cherm. hInt Ed, 40:1513-1516 (2001) U. Schopfer et al. Tetrahedron 57:3069K3074 (2001). and C Paloo et aL, Tet. Let. 41.12831286 (2000); A. Pelter et a, Tet. Lett, 42:8391-8394 {2001),V Lee et al J. Org. (hem 68:474-480 (2001): and A.' Toshimitsu et al., Het, Chem., 12:392-397 (2001) N N RR R Ra R R N G"O O' Ra RR , HO N N R R wpud X f Ro Xls 4 a.-,d 1' R R ,ad R2 r wh ri 5iab n ,.N H ,. "lyl .- or -- S- and? '5j, .

1 a dR s s -323 I RR 20 RtYV 226 Siirly compounds of fonrulas (24) and (25l) vwerei R~0 R R R nd R are as defined in formula (,R, s hydrogen, aikyl. alkoxy, halogen, cyan or thiakoxy, and R*2 is$-"LrReb whereinl is a bond, -N(H). N(alkyl)4Y O r -St ano R 6 a, LU and Rb are as defined in formula (1) can be prepared as desenoed in Scheme 2, from compondos 0of formula (15) wherein R is a lower alkyi. X is Ci, Br, I iiate using the reaction con'ditions that are outlined in Scheme 1. except for substituting boronic acid or esters of formula (23) for (12) arnd pinacot borane reagents of form'ula (23a) for (12a) for the SuLzuki reactions, and except for substituting organostannes of formula (R1 3 SnR 2 for (RfjlQnh, for stie coupling References that describe the Suzuk reaction methodology may be found n the foibwing N. Miyaura et al Chen. Rev, 95:2457(1 995) and references cited in the article X X s P . a R R 2 ----- ------ +X RO" R3 R 3 R R RR4 f.2 R3 R) R, RrN R Ra0R N' ' s 1 R5R NTorF N'N RI X x s iuas3 )a )where, R R RL .dR A R PF; 3 3 defined in formula (1), Ri and R2 is hydroger alky alkoxy, 'halogen, cyano, or thicalkoxy, wherein L,- is a bond. 4N(H), 4N(alkyi), -Onr or -S-, and R.,_ L-, and R,6 are as defined in formula ( ),can be prepared as described in Solheme 3. Aldehydes, of formulas of (214) and (25) prepare,, d accordin,-g to the recinconditions in Scheme-1 from esters of formula (1) wherein R isalwralkyl -an be treated with 31methvtriphenylphosphonium iodide in the presence of a base such as, but not irnited to, potassium tbutoxide, to provide lkenes of formulas (26) and (27.) respectively Reference for this method may be found in Johnson 7le CThemistry, Academic Press New York, 1966, and Hopps, H, B, Bie J. H. Aidricihimica Acta (1969) 2(2) 3 6 Alkenes of formuas (2$) and (27) can be converted to alcohols of formulas (28) and (29) via a reaction sequence known as Alohs of formulas (28) and (29) can be treated with an agent such as. but not mited to, triflate anhydride, tosy chloride, or mesyl chloride in the presence of a base such as. but not imited to, potassium carbonate, to provide the corresponding relate, tosylate. or mesylate respectively The resulting triflate, tosylate, or mesyiate can be treated with an amine of formula (9), optionally in the presence of a base such as, but not limited to. potassium carbonate orsodum carbonate. to provide amines of form uas of (30) and (31) respectvely, Compounds of formulas of (30) and (31) can be converted to amines of formulas (32) and (33) repectiveIy using the reaction conditions described in Scheme 1, -32- R -------- R - - B- - - -- R -A KOxuH0 Ra R R Ra aR R. FZ2 RR. XX R, RR R S c g R23 40' P RrR imry fopud of.- foiia (2an(4)whri ,R-,;, ,,anR 3. 3 3~ N 3P HD N R 3 are as defined in fomIan ;R=sM LR anidR, Is hydrogen akyl alkoxy, halogen, cyano,) or thoaikoy, whereiri LQ is a bond, -N(H), -N(alkyi.),-O Acr -Sand R,, L3 and RI- are as defied in formnuis (I can be prepared as descenbed in Scheme 4. Esters of formula (1 5) wheken R is a lower alky , X is Br cli or, 1, can oe converted to amnin~es of formulas (42) and (43) using the r*eactlion,, conditions as described in Scheme 3, except for su ,bstituting baronic acid or esters of formula (12) for (23) and pin aco barane reagents of form-ula (1 2a) for {23a) for the Suzuki reactio.ns, and except for substituting organostannes of formula (R.,s~o R)2SR o tillie couplirg, -33- X R R2A SS P R2 R R R Ra~ R2) RO' R RsR R " R 3 R 0' H4 ara deie nfom a1),cn'bepeaA ~ e, cie nScheme ,Etesa RK N R R2 R Re Compouinds of formulas (46) and (47) wheren R1 , Ra Re and R, are as defined in formula (1) RPs hydvrogen. aikyK alkoxy, halogen. cyano, or thioalkoxv: and R~ s -4Lr<PL%. wherein Ls a bond, -N(HV N(alkyD) O(t or -S> and R.a K, and R% are as defined in formula (). can be prepared as described in Scheme 5. Enters of formula (1) wherein R is a lower alkyl, X is 8r, C ori can be converted to alcohols of formulas (28) and (29) according Scheme 3. Alcohols of formulas (28) and (29) can be -. 4 xdNzed via a reaction known as Swern oxidaion, by an agent, such as but not limited to. DMSO and oxaiyl choride in the presence of a base such as tnethylamine to provide adehydes of formuas (44) and (45), Adehydes of formulas (44) and (45) can be ) converted to amines of formulas (46) and (47) respecey using thne reaction conditions described in Scheme 3 transforming compounds of formulas (24) nd (25) to compounds of forruias (32) and (33) Rj',7 XX ocnV.

RR

3 RR X H S0 h o n 4 R - ------- - - - -O 'FU R R Xj R RV ~Scheme 4R (R c1) 33- &Smilarly cornpounds of formulas (50) and (51), wherein R, R, Rc R, ad Rs are as defined in formula (I' R is hydrogen alkyl ,ikoxy, halogen, cyano, or thiamoxy: and R 2 is LwRer wherein L' is a bond: -N(H), -N(alkyl), -0-: or -S-, and R. L and R are as defined in formula (I) can ne prepared as described in Scheme 6. Esters of formula (11) wherein R is a lover alkyl X s Br, C or I can be converted to alcohols of foImuas (38) and 39) as described in 4, Alcohols of formulas (38) and (39) can be oAdized via a reaction known as Swern oxidation by an agent, such as but no! limited to, DMSO and oxalyi chloride to provide aldehydes of formulas (48) and (49) respectively Aidehydes of formulas (48) and (49) can be converted to amines of formulas (50) and (51), respectively, using the reacton conditions described in Scheme 4 transforming compounds of formulas 38) and (39) to compounds of formulas (42) and Scheme 7 36 X RRR R3 RO 0 52 rX XRaa R, 3tR Ph P' -<< R R3 OHO; heat RR K'O- -lb RRO R-" R R 3 3R R CHO hent (15)' Esters of formu a (1) w-erein X is Br or &r hydroxy; R is a kower aky R R 'n5 are as defined in formula (I) and R- is hydrogen alkyi, akoxy, halogen cyano, or thicalkoxy; can be purchased or prepared as described in Scheme 7. Haildes of formula (52), wherein Y is 1. Br, or trflate (prepared by the treatment of phenols with triflate anhydride) can be treated with ethyl acrylate in the presence of a palladium source such as dihlorobis(triphenylphosphinepaladiumQ!) (CAS# 13965-03-2) or 3-7 tris(dibenzylidineacetone)dipaladium (CAS # 52409-22-0) or paladiumn diacetate, and a ligand such as tr24urybphosphine (CAS 4 5518-52-5) or triphenyl phosphine, in a solvent such as DMF at 251500 to provide the esters of formula (y Aternatively, esters of formula (1) can be prepared through substtuted benzaldehydes of formula (53) via the VVttg reaction, which is wel-known to those skilled in the art of organic synthesis. References that describe these methods may be found in the fo lowing S. Li et aL, Chemische enIhte, 123:14414442(1990); T. Kauffmann et a, Tetahedr Let 22:50310 9) Similarly, esters of formula (15) wherein X is , Br or Cl or hydroxy R is a lower akylt, Ra arid R are as defined in formula ( and P 1 is hydrogen, alkyi akoxy, halogen, cyano, or thiocakoxy, can be purchased or prepared as described in Scheme 7. The compounds and ntermediates of the invention may be isolated and purified by methods we knon t those skBled in the art of organic synthesis Examples of conventional methods for isolating and purifying compounds can include, but are notimited to, chromatography on solid supports such as silica gel alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatogrphy, distillation at various pressures. sublimation under vacuum, and trituration. as described for instance in *Vogers Textbook of Practical Organic Chemistry" 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchei, pub. Longman Scientific & Techncal, Essex CM20 2JE, England The compounds of the invention have at least one basic nitrogen whereby a desired salt of the compound can be formed by treatment of the compound with an acid Examples of acids suitable for the reaction include, but are not limited to tartaric acid, lactic acd, succinic acid. as weli as mandeic, atrlactic m aufonic, ethanesulfonic, toluenesulfonic, naphthalenesufonic benzensulfonio, carbonic, fumaric, maleic, giuconic, acetic, propoonic. salicylic, hydrochloric, hydrobrornic, phosphoric, sulfuric, citric or hydroxybutyric acid, canphorsulfonic., malic, phenylaceti c, aspartic glutamic, and the like 90fih00N~g Inveyntion The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula () in combination with a pharmaceuticaly acceptable carrier. The compositions comprise compounds of the invention formulated together with one or more non-toxic pharmaceutical acceptable carriers. The pharmaceutical compositions can be formulated for ora administration in solid or liquid form, for parenteral injection or for rectal administration, 3-no The term 'pharma ceutically acceptable carrier" as used herein, means a non toxic, inert sold sernsclid or liquid filler; dluent, encapsulating material or formulation auxilary of any type, Some examples of materials which can serve as pharmaceutically ) acceptable carriers are sugars such as lactose, glucose and sucrose: starches such as corn starch and potato starch, cellulose and its derivatives such as sodiurn carboxymethyl cellulose. ethyl cellulose and cellulose acetate; powdered tragaQnth malt, gelatin; talc; cocoa butter and suppository waxes: ols such as peanut oft cottonseed oil, safflower oil sesame il, olive oi, corn oil and soybean oil; glycols: such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar- buffering agents such as magnesium hydroxide -and aluminum hydroxide alginic acid, pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible ubricants such as sodium laury sulfate and magnesiun stearate. as we as coloring agents, releasing agents coating agents. sweetening flavoring and perfuming agents, preservatives and anticxidants can also be present in tne composition: according to the judgment of one skilled in the art of formulations. The pharmaceutical compositions of this invention can be adrmnistered to humans and other mammals orally, rectally, parenterally, intracistemaily intravaginally intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term parenteraly", as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion. Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions dispersions, suspensions or emulsions and stenle powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, dliuents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol glycerol and the like, and suitable mixtures thereof), vegetable oils (such as Oive o)il and injectable organic esters such as ethyl oleate., or suitable mixtures thereof. Suitable fluidity of the composition may be maintained, for example, by the use of a coating such as leithin, by the maintenance of the required particle size in the case of dispersiOris, and by the use of surfactants, These compositions may also contain adiuvants such as preservative agents, wetting agents, emulsifying agents, and dispersing agents Prevention of the action of microorganisms may be ensured by various antibacterial and antifungal agents. for example, parabens, chlorobutanol, phenol sorbic acid, and the like it may also be desirable to include isotonic agents. for example, sugars, sodium chloride and the like,

-%

Prolonged absorption of the injectable pharmaceutical form may be brought about by the use of agents delaying absorption, for example, aluminum mronstearate and gelatin In sore cases, in order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or itramuscuiar injection. Tis may be accomplished by the use of a liquid suspension of crystalline or amorhous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Aiternativeiy, delayed absorption of a parenteraly administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyetylerne sorbitol and sorbitan esters, microorystaiine cellulose, aluminum mnetahydroxid bentonite agar agar, tragacanth: and mixtures thereof if desired, and for more effective distribution, the compounds of the invention can be incornporated into slow-release or targeted-delivery systems such as polymer matries, liposomes, and nicrospheres. They may be sterlized, for example, by filration through a bacteriavtairing filter or by incorporation of steriiizing agents in the form of sterile solid compositions, which may be dissolved in sterile water or some other sterile injectable medium immediately before use Injectable depot forms are made by forming microencapsulated matrices of the drug i biodegradable polymers such as polylactide-poiyglycolide Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controled. Examples of other biodegradable polymers include poy(orthoesters) and poly(anhydrdes) Depot injectable formulations also are prepared by entrapping the drug in liposomes or micr'emulsiors which are compatible with body tissues, The inectable forruiuons can be sterilized, for example, by filtration through a bactearetaining filter or by incorporating steriizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use. Iniectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, The sterle injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nomoxic parenterally acceptable diluent or solvent such as a solution in 13-butanediol Among the acceptable vehicles and solvents that may be employed are water, Ringears solution, US.P, and isotonic -40sodium chiorde solution. In addition, steri, eixed oils are conventionaiy employed as a solvent or suspending medium. For this purpose any bland fixed o1 can be employed Including synthetic monc- or diglycerides, In addition, fatty acids such as oleic acid are used in the preparation of injectabies, Solid dosage forms for oral administration include capsules, tablets, puis, powders, and granules. in such solid dosage forms, one or more compounds of the nvention is mrxed with at least one nert pharmaceuticaly acceptable carrier such as sodium citrate or dicalcium phosphate and/or a) fiers or extenders such as starches lactose, sucrose, glucose manntl, and salicylic acid; b) binders such as carboxymethylcelulose alginates, gelatin. polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glyceroK d) disintegrating agents such as agar-agar calcium carbonate, potato or tapioca starch alginic acid. certain silicates, ard sodium carbonate e) solution retarding agents such as paraffin f) absorption accelerators such as quaternary ammonium compounds: g) wetting agents such as cetyi alcohol and glycerol monostearate h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc! calcium stearate, magnesiun stearate solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forn may also cornprise buffering 4 agents olid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar as we as high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, plis, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients) only or preferentially, in a certain part of the intestinal tract in a delayed manner Examples of materials which can be useful for delaying release of the active agent can include polymeric substances and waxes, Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this inventmn with suitable non irritatirg carriers such as cocoa better po lhylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert dluents commonly used in -4 1 The art such as, for example water or other solvents, solublizing agents and emusifiers such as ethyl acoho[ isopropyl alcohol ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate. propylene glycol, . 3-butylene glyco, dimethylformamide, oils (in P articular. cottonseed, groundnut, corn germ. oive, castor. and sesame cia) glycerol, tetrahydrofurfuryl alcohol, polyethylne glycois and fatty acid esters of sorbitari, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents Dosage forms for topcal or transdermal administration of a compound of this invention include ointments, ptes, creams, lotions, gels, powders. solutions, sprays, inhaiants or patches A desired compound of the invention is admixed under sterile conditions with a pharmaceutical acceptable carrier and any needed preservatives or buffers as may be requred. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. The ointments, pastes, creams and gels may contain. m addition to an active compound of this invention, animal and veqeta bie fats, oflS, waxes, paraffs, starch, tragacanth, cellulose derivatives. polyethylene glycols. silicones, bentonites, -icic aeid, talc and zinc oxide, or mixtures thereof Powders and sprays can contain, in addition to the compounds of this invention lactose, talc. silicic acid, aluminum hydrokide, calcium silicates and polyamide powder, or mixtures of these substances Sprays can additional contain customary propellants such as chlorofluorohydrocarbons Comoounds of the invention may also be administered i the form of liposomes As is known in the art, liposomes are generally derived from phosphohipids or other lipid substances. Liposomes are formed by mnon~ or muiti~lamellar hydrated liquid crystals that are dispersed in an aquecus medium. Any non-toxic physiologically acceptable and metabolizabie lipid capable of forming liposomes may be used. The present compositions in ioosome for may contain, in addition to the compounds of the invention, stabilizers, preservatives. and the like. The preferred lipids are the natura! and synthetic phospholipids and phosphatidylcholines (lecithins) used separately or together. Methods to form liposones are known in the at 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 this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile -42conditions w a oharmaceuticall acceptable carrier and any needed preservatives, buffers or propeiants, which can be required, Opthalnc formulations, eye ointments, powders and solutions are contemplated as being within the scope of this invention. Aqueous liquid compositions comprising compounds cf the Invention also are contemplated, iThe compounds of the invention can be used in the form of pharmaceutcally acceptable salts, esters, or amides derived from inorganic or organic acids. The tern pharmaceuticaiIy acceptable salts, enters and amides. as used heren, refer to carboxylate salts, amino acid addition saits, zwitterions esters and amides of compounds of formula (I) which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower anirmnals without undue toxicity irritation allergic response, and the like, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use The term "pharmaceuically acceptable salt" refers to those salts which are, within the scope of sound medical udgmirent, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation allergic response; and the like, and are commensurate with a reasonable benefit/risk ratio, Pharmaceutically acceptable salts are weiknown in the at The salts can be prepared in situ during the final isolation and purification of the compounds of the inventron or separately by reacting a free base function with a suitable organic acid Representative acid addition salts include, but are not limited to acetate, adipate, alginate. citrate, aspartate, benzoate, benzenesulonate, bisulfate. bitartrate, butyrate, camphorate, camphorsulfonate digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate. fumarate, hydrochloride, hyorobromide, hydroiodide, 2-hdroxvethansulfonate (isethionate) lactate, maleate, methanesulfonate ricotinate, 2-naphthaIenesulfonate, oxalate. pamoate, pectinate, persulfate, 3phenyipropionate piorate, pivalate proponate, sucoinate, tartrate, thiocyanatel phosphate, glutamate, bicarbonate, pf-toluenesufocnate and undecanoate. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such Inorganic acids as hydrochloric acid hydrobromic acid, suphuric acid and phosphoric acid and suoh organic acids as oxalic acid, maleic acid, succinic acd, and citric acid, Basic addition salts can be prepared in situ during the final isolation and purification or of this invention by react:ig a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary. -43secondary or tertiary arvne, Pharmaceuticaly aoceptabie salts include, but are not limited to, cautions based on aikali metals or alkaline earth metas suc h as Uithrum, sodium, potassim, calcium, magnesium and aluminum salts, and the like, and nontoxic ) quaternary ammonia and amine nations including arnmonium tetramethyammonium, tetraethylammoniurnmethyiamne drrethylamine, trimethylamine, triethylamine, diethylamine, ethylarnine and the such as. Other representative organs arnnes useful for the formation of base addition salts include ethylenediamine, ethenoiamine, diethanoiamine, piperidine, and pperartine Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyi halides such as methyl, ethyl, propy and butyl chborides, bromides and iodides. dialkyi sulfates such as dimethyl, diethyl, dibutyi and diamyl sulfates; long chain halides such as decyl, lauryl myristyl and stearyl chlorides bromides and odides aryal kyi halides such as benzy and phenethyl bromides and others. Water or oiiscluble or dispersible products are thereby obtained. The term pharmaceuticay acceptable ester', as used herein, refers to esters of compounds of the invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Examples of pharmaceutically acceptable, non-zoxc esters of the invention include CAoC< alky esters and Co<Ccycloalkyl esters, although Crio-C4 aikyl esters are preferred. Esters of the compounds of formula (I) may be prepared according to conventional method, For example, such esters may be appended onto hydroxy groups by reaction of the compound that conta ins the hydroxy group with acid and an alkyicarboxylic acid such as acetic acid, or with acid and an aryicarboxylio acid such as benzoic acid. In the case of compounds containing carboxylic acid groups the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide. alkyl trifilate, for example with methyliodide, benzyl iodide, cyclopentyl kodide They also may be prepared by reaction of the compound containing the carboxylic acid group with an acid such as hydrochioric acid and an alcohol such as methanol or ethanol. The term 'pharmaceuticaily acceptable amide', as used hereirefers to non-,oxic amides of the invention derived from amrnonia, primary &Io-C alkyl amines and secondary C<tO-Cr dialkyi mines, In the case of secondary amines the amine may also be in the form of a 5- or 6@membered heterocycle containing one nitrogen atom. Aides derived from ammonia, Cto~C< alkyl primary amides and C-to<C diaikyl secondary aides are preferred. Amides of the compounds of formulai may be prepared according to conventional methods, Pharmaceuticaliy acceptable aides are prepared -44trom compounds contaning primary or secondary amine groups by reaction of the compound th at contains the amino group with an aikyl anhydride aryl anhydride, acyA halide, or aryl halide. In the case of compounds containing carboxyhi acid groups, the ) pharmaceutically acceptable esters are Prepared from compounds containing the carboxylic acid groups by reaction of the conpound with base such as triethylamine, a dehydraing agent such as dicyclohexyl carbodiimide or carbony dii midazole and an aikyi amine diaikylamine, for example with methylarmine, diethylamine: piperidine. They also may be prepared by reaction of the compound with an acid such as suifuri acid and an aikylcarboxviic acid such as acetic acid; or with acid and an arylcarboxyilic acid such as benzoic acid under dehydrating conditions as with molecular sieves added. The composition can contain a compound of the invention in the form of a pharmaceuticals acceptable prodrug. The term pharmaceutically acceptable prodrug' or "prodrugr, as used herein, represents hose prodrugs of the compounds of the invention which are. within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans and lower animals without undue toxcity, rritatin. alergic response. and the like. commensurate vith a reasonable brenefitirisk ratio. and effective for their intended use Prodrugs of the invention may be rapidly transformed in vivo to a parent compound of formula (!), for example, by hydrolysis n blood, A thorough discussion is provided in T Higuchi and V, Steia, Pro-drugs as Novel Delivery Systems, V, '14 of the AC S. Symposium Series, and' in Edward BS. Roche, ed, Bioreversibie Carriers in Drug Design, American Pharmaceutical Association and Pergarnon Press (1987), hereby incorporated by reference. Tne invention contemplates pharmaceutically active compounds either chemically synthesized or formed by in vivo biotransformation to compounds of formula (I). Methodscx of tne invention The compounds and compositions of the invention are useful for treating and preventing certain diseases and disorders in humans and animals As an important consequence of the ability of the compounds of the invention to modulate the effects of hisanmine-3 receptors in celis, the compounds described in the invention can affect physiological processes in humans and animals In this way, the compounds and compositions described in the invention are useful for treating and preventing diseases and disorders modulated by histamine-3 receptors. Typically, treatment or prevention of such diseases and disorders can be effected by seiectiveiy modulating the histamine-3 receptors in a mammal, by administering a compound or composition of the invention, -45either alone or in combination with another active agent as part of a therapeutic regimen. The compounds of the invention. including but not limited to those specified in the examples, possess an affinity for the histamirie-3 receptors and therefore, the compounds of the invention may be useful for the treatment and prevention of diseases or conditions such as attention-deficit hyperactivity diorder (ADHD), deficits in attention, dementia, and diseases with deficits of mernory. learning, schizophrenia, cogniive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mid cognitive impairment, epiepsy, seizures, afiergic rhintis, and asthma. motion sickness. dizziness, Meniere's disease, vestibular disorders, vertigo, obesity. diabetes, type i diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome pain, including neuropathic pai, neiuropathy, sieep disorders narcolepsy, pathological sleepiness, jet lag: drug abuse o alteration, bipolar disorder; depression:, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, and medulary thyroid carcinoma, nnelanoma, and polycystic ovary syndrome. The ability of histamine- 3 receptor modulators, and consequenty the compounds of the invention, to prevent or treat such disorders is demonstrated by examples found in the following refererCes. The abiity of the compounds of the invention, including, but not limited to, those specified in the exanpies, to treat attention-deficit hyperactivity disorder (ADHD), and deficits in attention, may be demonstrated by Cowart, et al. J. Med. Chem 2005t 48, 38 55 Eox, G. B. et al. "Pharnacogical Properties of ABT~239 .t Neurophysiological Characterization and Broad Preclinic& Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H. Receptor Antagonist Journa of Pharmacoiogy and Experimental Therapeutics (2005) 313, 17610; "Effects of histamine H 3 receptor ligands GT~2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup Fox, B,, et al, Behavioura Brain Research (2C,02) -131(2), 11 161, Yates, et al JPET (1999) 2.$9, 1151 1159 ldenaicatn ad Pharmacological Characteization f a Series of New 1H4ubstutedimidazoyl Histamine H Receptor Ligands";Ligneau et al. Journal of Pharmacology and Experimental Therapeutics (1998), 287, 6358-666; Tozer, Expeirt Opinion Therapeutic Patents (2000) 10, 1045 M, T, Haipern, GT-2331" Current Opinion in Central and Peripheral Nervous System Investigational Drugs (1999) 55-24-527; Shaywitz et a, Psychopharmacology, 82:73-77 (1984); Dumery and Blozovski. Exp, Brain Res., 67:61 69 (1987) Tedford et aJ. Pharmaco, Exp. Ther.. 275:598-604 (1995): Tedford et al, Soc. Neurosci. Abstr., 22:22 (1996);' and Fox. et al., Behav. Brain Res,, 131:151161 (2002): Glase, 8 A.. et aL "Attention deficit hyperactivity disorder: pathophysiology and 46design of new treatments " Annual Reports in Medi&na Cheistry (2002), 37 11 -20 Schweitzer, J. B- and Hoicomb, H. H. "Drugs under investigation for attention-deficit hyperactivity disorder" Current Opinion in investigative Drugs (2002) 3 207 The ability of the compounds of the inveton, including, but not ited to those specified in the examples, to treat dementia, and diseases with deficits of memory and learning, may be demonstrated by "Two novel and selective nornidazoc H receptor antagonists A-304121 and A-3179:20. H. In vivo behavioral and neurophysiologcal characterization ,Fox; G. B atL Journal of pharmacology and experimental therapeutics (.2003 Jun), 305(3), 897-908 Identifiation of nove H 3 receptor (H 3 R) antagonist with cogntion enhancing properties in rats. " Fox, G, B.; inflammation Research (2003). 52(Supp. 1) S31-S32; Bernaerts, P., et ai "Histarnine H, antagonist thioperamdle dosesdependently enhances memory consodaton and reverses amnesia induced by dizoripine or scopolamine in a one-trial inhibitory avoidance task in nice" Behavioural Brain Research 154 (2004) 211 -219 Onodera, et a. NauynSchmiedebergs Arch, Pharmacoi, (1998), 357, 508-513; Prast, et al Brain Research (1996) 734, 316-318 Chen, et a, Brain Research (1999) 8391 1861i89 " Effects of histamine on MK-801 induced memory deficits in radial maze performance in rats; Passani. et i. ' Central histantergic system and cognition" Neuroscience and Biobehavioral Reviews (2000) 24 107 113 The abiity of the compounds of the invention, including, but not limited to. those specified in the examples, to treat schizophrenia, cognitive deficits of schizophrenia. and cognitive deficits, may be demonstrated by Fox, G. B. P at iPharmacological Properties of ABT-239: li Neurophysiological Characterization and Broad Predinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H 3 Receptor Antagonist, Journal of Pharmacology and Experimental Therapeutics (2005) 313 176 190 and by" Enhancement of prepulse inhibition of startlein mice by The H 3 receptor arntagonststioperamde and ciproxifan," Browman, Kathin E., et al Behavioural Brain Research (2004), 153(1 69-7; H, receptor blockade by ticoperamide enhances cognition in rats without inducing locomotor sensitization."; Komater, V A., et al r (Berin Germany) (20v03)17( V 63-372; AA Rodrigues. FP Jansen. R Leurs, H Timmerman and CD Prel Interaction of clozapine with the histamine

H

3 receptor in rat brain" British Journal of Pharmacology (1995), 114(8), pp 1523-1524' Passani et al "Central histaminergic system and cognition" Neuroscience and Bobehaviora Reviews (2000) 24. 107-113 Morriset S , et al. "Atypical Neuroleptics Enhance Histan-,ne Turnover in Brain Via 5-HydroxytryptanIne. Receptor Blockade" Journal of Pharmacology and Experimental Therapeutics (1999) 288. 590-596 -47- The ability of the compounds of the invention, including, but not limited to, those specfied in the examples, to treat dysfundion in psychiatric disorders. Alzheimer's disease, and mild cognitive impairment may be demonstrated by Meguro, et al, ) Pharmacology, Biochemistry and Behavior (1995) 50(3). 321-325; Esbenshade T,, et al, "Pharmacologica and behavioral properties of A-349821 a selective and potent human histamine H3 receptor antgonist" Biochemical Phaoiaccogy 68 (2004) 933945 Huang, Y.W et aI"Effect of the histarnne H3-antagonist ciobenpropit on spatial memory deficits induced by MK-801 as evaluated by radia& maze in Sprague-Dawley rats" Behavioural Brain Research 151 (2004) 287-293; Mazurkiewicz-Kwflecki and Nsonwah, Can J PhysioL Pharmacol (1989) 67, 75-78 P, Panula et ai, Neuroscience (1997) 82, 993 -997; Haas et a Behav. Brain Pes. (1995) 66 4t44 ; De AImeida and lzquierdo, Arch. nt. Pharmacodyn. (1966)! 283, 193-198 Kamei et ali, Psychopharniacoloy, (1990) 102, p. 312-31; Kamei and Sakat, Jpn. J PharmacoL (1991), 57, 437482; wartz et alPsychopharmacology, The Fourth Generation of Progress Boom and Kupfer (eds). Raven Press, New York, (19%5) 397; and Wada. et a!. Trends in Neurosci. (1991) 14 p 415. The ability of the compounds of the invention, including but not limited to, those specified in the examples, to treat epilepsy and seizures, may be demonstrated by Harada, C e al (. Inhibitory effect of iodophenpropit. a selective histamine H3 antagonist on amygdaloid kindled seizures" Brain Research Bulletin (2004) 63 143-146; as well as by Yokoyama, et al Eur, J. Pharmaco!. (1993) 234.129-133 Yokoyama, eat u. uropean Journal of Pharmacology (1994) 260: 23: Yokoyama and inuma, ONS Drugs (1996) 5: 321; Vohora, Life Sciences (200) 66: 297-301; Onodera et a, Prog. Neurobiol (1994) 42 685; Chen, Z. et al "Pharmacological effects of carcinine on histainsergic neurons in the brain" British Joumal of Pharmacology (2004) 143; 573-580 R Leurs, R,C. Voilinga and H. Tirmmerman 'The medicinal chemistry and therapeutic potential of ligands of the histamine H, receptor" Progress in Drug Research (1995) 45-17065; Leurs and Timinerman, Prog. Drug R (e. (1992) 39127; H. Yokoyama and K. linuma, "Histamine and Seizures implications for the treatment of epilepsy", CNS Drugs, 5(5); 321-330 (1995) and K Hurukami, H. Yokoyama, K Onodera, K linurna and T Watanabe, "AQ-0145, A newly developed histamine HI antagonist decreased seizure susceptibility of electricaiy induced convulsions in mice", Meth. Find, Exp. lin. Pharrnacol., 17(C70-73 (1995) Yawvata; et a!, "Role of histaminergic neurons i development of' epileptic seizures ir EL mice" Molecular Brain Research 132 (2004) 13 The abiity of the compounds of the invention, including, but not limited to, those -48specified in the examples, to treat allergic rhnits, and asthma, may be demonstrated by McLeod, RL. Mingo, G G, Herczku, C., DeGennaro-Cuiver, F., Kreutner. V Egan, R.W., Hey, J.A "Combined histamine HI and H3 receptor blockade produces nasal ) decongestion in an experimental model of nasal congestion" Am J. Rhinol (1999a) 13: 391 .. 399: McLeod. Robbie L' Egan, Robert W Cuss, Francis M.; Bolser; Donald C-; Hey, John A. (Allergy, Schering-Plough Research Institute, Kenlworth, NJ, USA. Progress in Respiratory Research (2001), 31 (in New Drugsfor Asthoa, Atlergyand CQPD) 133-136; A. Delaunois A., et al, "Modulation of acetyicholine: capsaiin and substance P effects by histamine H 3 receptors in isolated perfused rabbit lungs,* European Journal of Pharmacology (1995) 277 243-260 Dimitriadou. et at "Functional relationship between mast cells and C-sensitive nerve fibres evidenced by histamine He receptor modulation :n rat lung and spleen " Clinical Science (1994). 87 151-163 The abity of the compounds of the invention, including, but not lmited to, those specified in the examples, to treat motion sikness. dizziness, Meniere's disease, vestibular disordersand vertigo, may be demonstrated by Pan, et al. Methods and Findings in Clinical Pharmacology (1998), 20(9), 7714-7; O'Nell, et al Methods and Findings in Clinical Pharmacology (1999) 21(4), 285~289; ard by R Leurs, RC, Vollinga and H. Timmerman. "The medcnal chemistry and therapeutic potential of ligands of the histamine H- receptor:" Progress in Drug Research (1995), 45. 170-165, Lozada, et at "Plasticity of histamine H receptor expression and binding in the vestibular nuclei after labyrinthectomy in rat BocMedCentral Neuroscience 2004, 5:32. The ability of the compounds of the invention, including, but not limited tothose specified in th- examples, to treat obesity, diabetes, type iI diabetes Syndrome X, insulin resistance syndrome and metabolic syndrome, may be demonstrated by Hancock, A. A. " Antiobesrty effects of A-331440, a novel nan-imidazole histamine H3 receptor antagonist " European Journal of Pharmacology (2004) 487, 183- 197; Hancock. A. A,, et al. Histamine H antagonists in models of obesity" inflamm. res. (2004) 53, Sapplement 1 S47-848', as well as by E Itoh, M. Fujintay, and A, inul "Thioperamide, A histamine H receptor antagonist powerfully suppresses peptide YY-induced food intake in rats," Biol. Psych. (1999) 45(4). 475481; $. Yates. et aT "Effects of a novel histamine H receptor antagonist, GT-2394; on food intake and w eight gain in Sprague--Dawley rats," Abstracts, Society for Neuroscence, 102.10:219 (November 2000) and C. Bjenning, at al "Peripherally administered ciproxifan elevates hypothalamic histamine levels and potently reduces food intake in the Sprague Dawiey rat," Abstracts, international Sendai Histamine Symposium Sendai, Japan, #P39 (November, 2000): Sakata T; et al. "Hypothalamic neuronal histamine modulates ad ibitum feeding by rats." Brain research -49- (1990 De c24), 537(1 2), 303 The abiitv of the compounds of the inventor, including but not tilted to those specified in the examples, to treat pain, including neuropathic pain and neuropathy, may ) be demonstrated by Malmberg-Aieiio, Petra; Larrberti, Claudia; Ghelardini. Carla; Glotti Alberto: Bartolni, Alessandro. British Journal of Pharmacology (1994), 111(4), 1269 1279; HriscuAnisoara, Gherase, Florenta; Pavelesu, M,' Hriscu; E, "Experimental evauaton of the analgesic efficacy fsome nihistanines as proof of the histamineric receptor involvement in pair. Famacia, (2001), 49(2). 23-30 7 The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat sleep disordersncluding narcolepsy and pathological sleepiness, and jet lag, roay be demonstrated by Barbier, A. J., at a. Acute wake promoting actions of JNJ-5207852. a nova diamine-based H antagonst" British Journal of Pharmacoiogy (2004) 1-13; Monti et a. Neuropsychopharmacology (199) 15 31-35; Lin et af Brain Pes (1990) 52: 325-330; Monti. et al Neuropsychopharmacology (19M) 15: 3135; Ugneau et ai, Journal of Pharmacology and Experimental Therapeutics (1998) 28, 658-666; Sakai, et at. Life Sci. (1991) 48 2397-2404; Mazurkiewicz-Kwiiecki and Nsonwah, Can. J, Physiol Phanmaol (1989) 67: 75-78 P. Panula et ail Neurosciernce (1998) 44 465-481 Wada, et at. Trends in Neuroscience (1991) 14 415 and Monti, at al Eun J. Pharrnacoi (1991) 205 283 Dvorak, C, et at "4 Phenoxypiperidines: Potent, Conformationaily Restricted, Nondmidazole Histamine H Antagonists" Journal of Medicinal Chemistry (2005) 48, 2229-2238. The ability of the compounds of the invention, including, but not limited to, those specified in the examples, to treat diru abuse. Amphetamine is an abused stimulant in humans. it, and sirmanr abused drugs stimulate locomotor activity in animals, and it has been found that the H 3 antagonist hoperamide suppresses the locomotor stimulation induced by amphetamine therefore H antagonists are likely to be useful for treating drug abuse as may be demonstrated by Clapham J.; Kilpatrick G, J, "Thioperamide, the selective histamine H% receptor antagonist, atten.uates stimulantinduced locomotor activity in the mouse', European journal of pharmacology (19941, 259(2), 107-14, The ability of the compounds of the inVention, including, but not irnited to, those specified in the examples, to treat mood alteration, bipolar disorder, depression, obsessive compulsive disorder, and Tourette's syndrome, may be demonstrated by Lamberti, et al. British Journal of Pharmacology (1998) 123: 1331-1336; Perez -Garcia, et. al., Psychopharrnacoogy (Berin) (1999) 142(2): 215-20. The ability of the compounds of the invention, including but not limited to, those specified in the examples, to treat Parkinson's disease (a disease wherein patients have -50deficits n ability to initiate movements, and patients brain have low dopamine levels) may be demonstrated by SEnchezLemus , et at. Histamine H. receptor activation inhibits dopamine D, receptcrnduced cAMP accumulation in rat striatal skes" Neuroscience Letters (2004) 364, p. 179-184 Sakai. et al Life Sci 991) 48 239e-2404; Fox G B, et a. Pharnacalogical Properties of ABT239' t Neurophysiological Characterization and Broad Prechnica Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine iK4 Receptor Antagonist" Journa of Pharmacology and Experimenal Therapeutos, 313:176-190, 2005 Chen, Z, et al, Pharmacological effects of carcinine on histaminergic neurons in the brain" British Journal of Pharmacology (2004) 143, 573 50 The ability of the compounds of the invention, including, but not limited to, those specified in the examples, to treat medulary thyroid carcinoma, melanoma, polycystic ovary syndrome, may be demonstrated by Polish Med Sci, Mon. 1998) 4(5) 747; Adam Szelag, "Role of histamine K-receptors in the prolferation of neoplastic cells in vitro, Med. Sc. Monitor (1998) 4(5)747- :755 annd C H. Fitzsimons, et aL, "IHistamine receptors signalling n epidermal tumor cel lines with H-ras gene alterations." inflammation Res. (1998) 47 (Suppl 1);S50 S51. Compounds of the invention are particularly useful for treating and preventing a condition or disorder affecting attention-deficit hyperactivity, Aizheimers disease or dementia. Compounds of the invention are particularly useful for treating and preventing a condition or disorder affecting schizophrenia or cognitive deficits of schizophrenia. Compounds of the invention are particularly useful for treating and preventing a condition or disorder affecting narcolepsy, sleep disorders, allergic rhinitis, asthma, or obesity. Actual dosage levels of active ingredients i the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration The selected dosage level will depend upon the activity of the particular compound the route of administration, the severity of the condition being treated and the condition and prior medical history of the patients being treated. However, it is wthin th skil of the art to start doses of the compound at levels lower than requ red to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable sat, ester, aide or prodrug form Alternatively, tihe compound can be administered as a pharmaceutical composition -51 containing the compound of interest in combination with one or rnore pharmaceutical acceptable carriers The phrase 1therapeuticaily effective amount" of the compound of the invention means a sufficent amount of the compound to treat disorders, at a ) reasonable benefitlrisk rato applicable to any medical treatment, It wji be undersood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medicS judgment, The specific therapeuticaliy effective dose level for any partiular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder activity of the specific compound employed; the specific compositon employed; the age, body weight general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed: the duration of the treatment drugs used in combination or concidental with the specific compound employed; and like factors wedl known in the medica arts, For example, it is well within the ski of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. For treatment or prevention of disease, the total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0,001 to about 30 mg/kg of body weigt For purposes of oral administration, more preferable doses can be in the range of from about 0.001 to about I mg/kg body weight. If desired the effective daily dose can be divided into multiple doses for purposes of admlrmstration consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. The compounds an.d processes of the invention wii! be better understood by reference to the following examples whih are intended as an illustration of and not a limitation upon the scope of the invention. EXAMPLEfS Example 1 41(1S,2S924(26Y2-Methviprroiidir< yx~methyglopropy\ 11 aiphenyIegrcayonitrie axmolei1A trns34-BromophienyIuor2~en 1-ol To a solution of ethyl trans4-bromocinnamate (8 m.L 42.6 mmol) in anhydrous dichioromethane (150 mL) under N, was added disobutyialunum hydride in -52diloromethane (128 m ' M. 128 mmol) at -78 *C dropwise, After the additor the mixture was allowed to warm frorn -78 OC to -30'C over two hours. The mixture was then cooled back to -78 'C and aqueous I N HCi was added i acidic (pH=2) The ) organic layer was separated and the aqueous layer was extracted with dichoromethane; The combined organic layers were died with MgSO 4 , filtered and concentrated under reduced pressure to provide the tide compound. 1 H NMR (300 MHz, CDO. 3 1 44 (t J 6 Hz, 1 H), 4,32t J45Hz2 637(dt J=16.5Hz J m6 Hz, IH,657(t J15 Hz J =3 Hz, IH 7.25 (d, J 9 Hz 2H), 7,45 (d, J= 9 Hz, 2H). MS (DCINH) m/z 214 (M+H)+. (18S :r dmoph. n dcyloropyllrnethanoi The title compound was prepared by the method of A , Charette and H Label (Organic Synthesis, 1998, 76. 86-96) substituting tans34(4-brmopheny) prop-2-en-1-ol (the product of Example 1A)for 3-phenykprop2'eHnoi H NMIR (300 MHz, CDC): 3 0.2- Cm, 2H, 1,45-1 .4 (m 2H), 1 76-1.5 (m I H), 361 (d J =7.5 Hz, 2H) 6.95 (d J = 9 Hz, 2H). 737 (d, J = 9 Hz, 2H) MS (DCNH 3 ) mz 228 (M+H) t . E xamp)e 10 DMSO (0.8 ml, 3 equivalents) was added dropwise to a solution of oxadyl chlonde (.48 mL) in anhydrous dicrlornimetane (50 mL) under N 2 at -78 *C, A solution of (1 2)- 4ypyl]rethanol (the product from Exampie 18, 823 mg) in dichloromethane (20 rLU) was then added dropwise at -78 C, Stirring at this temperature was continued for 30 minutes, then Triethylamine (2 roL 4 equivalents) was added, and the dry ice bath was removed After stirring for I hour, the mixture was treated with saturated aqueous NH 4 CI. The mixture was extracted with diethyl ether twice. The combined organic extracts were dried (MgSO) and filtered. The fitrate was concentrated under reduced pressure The residue was purified by elution through a pad of silica gel with hexane to provide the title compound. 'H NMR (300 MHz, CDCY): 5 1 48 (rm 1H 1,65 (dt, J3 9 Hz, J = 6 Hz, 1KH 215 (m, 1H) 2,57 (m, 1 H), 69 (d, J = 9 Hz,. 2H). 7.45 (d, J = 9 Hz, 2H), 9-46 (d J = 4 5 Hz, )I MS (DClNH,) mtz 226 (M+.H)+. 12 (romohnylcy copYimethyj2C)_met~ggraiine5 -53- A solution of (1 2()-2-(4-romophenyijcyclopropsnecarbaidehyde(the product of Example IC, 820 rg. 3,64 mmo!) and (S)2methypyrrodin tartaric acid salt (112 g, 473 mno) in ethanol (30 mL) was treated wi sodium cyanoborohydride (345 mg 5.46 1mmo6) The mixture was stirred at room temperature for two hours. The mixture was basified to pH = 10-12 with NaOH (10%) and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2x), The combined organic layers were dried (MgS0) and fitered. The fijtrate was concentrated under reduced pressure and the residue was purified on siica gel eluting with I % to 2% methanol (containing 10 % concentrated NI-40) in dichloromethane to provide the title compound, 'H NMR (300 MHz CDCIl): § 0 87-0,92(m I H), 0.97-02 Oi, IW).,1.16 (d, J=6 Hz, 2H): 1,22 (m, I1H), 1.39 , 49(m, iH):, 7381( 3H), 2 0 (m, 2H), 236 (q J 6 Hz, 1 H), 2,45 (n, H) 3.13 (dd, J=12 Hz, J=6 Hz, 1H 3.25 (m, 1H 7,00 (d, J=6 Hz, 2H), 737 (d J=6 Hz 2H) MS (DC -NH 3 ) m z 294 (M+ H) (S)-2-methylpyrrolidine and its salts are available commercial from a number of sources including; (S)2-methypyrrolidine (Chemical abstracts registry number 59335-84 1) frormo Sigma-Aldrich Chemical Company, F. 0. [Box 14508 St Louis, MO 63178 USA, and (Simethylpyrroidine hydrochloride (Chemical abstracts registry number 174500 74-4) from Astalech, Inc. Keystone Business Park 2525 Pearl Buck Road Bristol PA, 19007 USA. Methods of obtaining (S)-2-methyipyrrolidine by enantioselective re-rystalliation with tataric acid have been descrbed for example in Sakurai, et al, Crystal Growth & Design (2006) vol. 6(7) pages 1606-1610. (S)-2-Methylpyrrolidine i tartaric acid salt (313 grams) was recrystallized from a mixture of 4.8 L-iters of ethanol and 1 .2 liters of methanol heated at 60 WC and aowed to cool 1. deposit (S)2 rmethyipyrrolidine Ltariaric acid salt ExamplgE 41E3 2dtvyrldnegahic loovP .1 .biphenvw4 carbon triie To a solution of 1-(1 S 25) 2(4-bromo- phenyi)cyciopropyinethyi>2(S)methyP pyrroiioine (the product of Example ID, 50 mg, 0 7 imol) in isopropyl alcoho (4 mrL) under an atmosphere of nitrogen was added 4-cyanophenyioronic acid (30 mg, 0.2 mmol) dichlor obis(triphenyiphosphine)palladium(li) (6 mg, 8.5 pmol) and potassium carbonate (59 img, 0.43 mmol) The mixture was heated to 90 *C for 5 hours, cooled to ambient temperature and partitioned between ethyl acetate (25 iL) and HO (10 rnL). The separated organic layer was washed with brine, dried (MgSO 4 ), filtered, concentrated under reduced pressure and chromatographed on silia ge eiuting with 3% methanol -54- (contairng 10 % concentrated NH 4 OH) n dichoromethane to provide the tle compound 'H NMR (300 MHz D 01 (mn ), 1.13 (n, 1H). 1 25 (d, J6 Hz, 3H 136( H) 1,54 (m, H, .89 (m. 3H) 211 (m, 1 H). 2 m. 1H) 2.65 (m , 1Hx 2,79 (m, 1H), 3.27 (-d J=12 Hzc J=6 Hz, 1 H), 3.40 (n I H) 7.22 (d, J=9 Hz, 2H) 7.59 (d, J=6 Hz 2H 7.78 (s, 4H). MS (DCi4) m/z 317 (M tHY Examre2 41 2 22Mtvrrii-vmho ipheny4-carbonitr e 1 2,- 44-Bro Dmog-ohnl1 2g loroo etyll'2RI-- 2eehlrodine The title compound was prepared using the procedure described in Example 1D substituting (R)2-methylpyrrolidie for (S)2methyipyrroidine. H NMR (300 MHz, CDOD): , 0.92(r I H), 0 9 Km. 1H), 1 13 (d, P=6 Hz, 3H), 124 (i, H), 1.43(m, 1H), 1,77(m, 3H), 1.98 (to, 2H), 213 (dd. J12 Hz, J=6 Hz. IH), 2,30 (q, J=9 Hz, 1H 2.41 (m,. IH), 2.94 (dd, J=12 Hz, J=6 H z, 1 H), 325 (in, I H), 700 (d J=9 Hz, 2H), 7.36 (d, J=9 Hz,2H). MS (DCl-NH..) m/z 294 MHi. (R$-2-methylpyrrolidine and its salts are available commerciaLly from a number of sources, including; (R)&rnethylpyrroidine (Chemical abstracts registry number 41720 98-3) from Sigma-Aldrich Chemical Company, P, 0 Box 1450, St. Louis, MO, 63178 USA and R)-2-methylpyrrolidine hydrochloride (Chemical abstracts registry number 135324-85 5) from AstaTech Inc: Keystone Business Park 2525 Pearl Buck Road Bristo, PA, 19007 USA. Methods of obtaining (R).m2- iiethypyrroidine by enantoseective recrystaWlzaion with tartaic acid have been descrbed for example in Sakurai, et aL Crystal Growth & Desgn (2006) voi 6(7) pages 1606- 1610 and in Pu, et at Orgaric Process Research & Development 2005, 9, 45-50, ( - S2S)-2? 2R) 2M t lyroir1vlm hvcyclopoy -1 0ih ry4 a n e The title compound was prepared using the procedure described in Example 1E substituting I -2-(4-bromo-phenyi)~(S1 2Sycycilooropylimethy)](2R)2-methy-pyrrolidine (the product from Example 2A) for 1-1S 25)(2S(4-bromo-pheny)cyclopropyimethyi] 2(S)-methytpyrrolidine (the product from ID). H NMR (300 MHz, ODOD): 0.92(m. 1H), 0 99 (min 1H) 1.13 (d, J=6 Hz, 2H), 1,24 (m. IH), 1.43(m. f, 1 77(m3, 1.98 (i, -55- 2Hx 2.13 (dd, -12 Hz J=6 Hz, 1H), 2.30 (q J9 Hz, IH), 241 (m I H), 2,94 (dd, J=12 Hz. J6 Hz, 1H) 3.25 (m, IH), 7,00 (d, J=9 Hz, 2H) 7.36 (d; J=9 Hz, 2H MS (DC NH) m/z 294 (M+H) )q Exame Example 3A (1R 2R)42-f 2 -4 Brohey oroovom!ethanoi The title compound was prepared by the method of AB Charette and H. Lebel (Organic Synthesis, 1998, 76 8696) substtutin ians44-Bromophenyl) prop-l-en i-o (the product from Example IA) for 3-Pheny prop-2-en1-ol. H NMR (00 MAz D001 6 k S21 2- (m 2H), 1.45-148 (n, 2H) 1.76485 1m, 1H) 361 (ci, J 7-5 Hz, 2H); 695 (d J =Hz,2H), 7.37 (d, J = 9 Hz, 2H). MS (D-*NH-) m/ 228 (M+H) RlB 2RY2*(4%BromophenyjQcyloprooanecarbaldenyde DMSO (0,8 mL, 3 equivalents) was added dropwise to a solution of oxaiyi chloride (0.48 mL) in anhydrous diohloromethane (50 ml) under N2 at -78 GC A solution of (1R 2R)42-(4-bromnophenylyclopropylmethanol (the product of Example 3A, 823 mg) in dichioromethane (20 mL) was then added dropwse at -78 t, Stirring at this temperature was c continued for 30 minutes, then trithyiamine (2 mL, 4 equivalents) was added and the dry ice bath was rem dAfter stirring for 1 hou, the mixture was treated with saturated aoueous NH 4 CL The mixture was extracted with diethyl ether The combined organic extracts were dried (MgSO) and filtered The filtrate was concentrated under reduced pressure The essidue was puifled by elution through a pad of silica gel with nexane to provide the title compound. ' iR (300 MHz, 0Dh) 6 1 48 (m, I H), 1 65 (t, J 9 Hz, J = 6 Hz 1H), 2.15 (m 1H), 2.57 (MI., 1 H. 98(, J= 9 Hz, 2H), 7.45 (7.d J =9 Hz, 2H) 9.46 (i, J= 4.5 Hz, 1H. MS (DClNH) m/z 226 (M+H)+. Example 30 1124-Bromo-phenvi) (1RB,2R)-cyc'opropnylmethyil&(2R-2-methyl-pyrrolidine A solution of (1RB 2R2(Abromcpheny)cyclopropanecarbldehyde (the product -56of Example 36, 600 mg 2-67 mmol) and (R)methylpyrofidine tartaric acid salt (0.82 g, 3.47 mmol) in ethanol (30 mL) was treated wit sodium cyanoborohydride (252 mg 4 nmol) The mixture was stirred at room temperature for two hours. The mixture was ) quenched with HCI (IN) and then adjusted wth base to pH = 10-12 with NaOH (10%) and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, The combined organic Iayers were dried (MgSO 4 ) and Otered. The filtrate was concentrated under reduced pressure and the residue was purfied on silica gel with 1% to 2% methanol (containing 10 % concentrated NH40H) in dichioromethane to provide the title compound, 1 H NIR (300 MHz, GD 'OD): 089(m 1H), 998 (rn fH) 1,14 (d J=6 Hz, 2H 1, 19' (m, 1 H),1 .43 (rn, 1 7'1.5 (m 3H), 1.95 (in. 2H), 2 30 (. J=9 Hz, 1 H) 2.37 (m 1H) 3 14 (ddI J=2 Hz, J=6 Hz, 1H). 3 22 (m. I H) 7.00 (d, J9 Hz, 2H). 7.36 (d, J9 Hz, 2H) MS (DCi-NH?) m/z 294 (M+H)t eL 3D 2A R Mehyvrr d nvtme 1ithyliycor yi biihenvy4 To a solution of 142-(4-bromo-phenyl) (1R 2R-cyclopropylrmethy>(2R)2-methyl pyrrolidine (product of Example 3C50 mig, 0.17 mmol) in sopropy alcohol (4 mL.) under an atmosphere of nitrogen was added 4-cyanophenyiboronic acid (30 mg, 0.2 mmol), dichiorobis(triphenylphosphine)paladiunil) (6 mg, 85 pmo) and potassium carbonate (59 mg, 0.43 mmol) The mixture was heated to 90 C for 5 hours cooled to ambient temperature and partitioned between ethyl acetate (25 mL) and H 0 (10 nL). The organic extraction was washed with brine,; dred (MgSO4, filtered, concentrated under reduced press uee and chromatographed on silica gel eiuting with methanol containingg 10% concentrated NH 4 OH) in dichloromethane to provide the title compound. H NMR (300 MHz; C0D) 6 1. 08 (n 1H, 1 19 (m, 1H) 1,32 (d, J6 Hz, 3H). 1.42 (m 1H) 163 i'm, 1H 1.99 (m. 3H), 2.20 (m, 1 H), 2.65 (m 1H) 2.94 (m. 1H)W 3.07 (m, 1H). 3.34 (dd, J=9 Hz, J=6 Hz, 1K). 3.51 ('m, 1H). 7.24 id, J=9 Hz. 2H), 7.60 (d, J=6 Hz, 2). 7. ( ) MS (DCNHi) mz 317 (M+H Examole 4 4 1R2R 2Methyiv - methyl rbipheny4 car 7trile -57- Examp le4A 1A2 4irm-enUl. dn The title compound was prepared using the procedure described in Exampe 30 substituitng (S)+2ehylpyrroliine taaric acid sat for (R)2rnethylpyrroidire tartaric acid sat 1 H NMR (300 MHz, CDOD): 6 ,93 (m, 1H, 0.99 (m, iH) 1.13 (d J=6 Hz, 3H) 1-24 (m 1H) 1 44 (m, 1H). 1,76 (n, 3H), 1.98 (m, 1H) 2.14 (dd. J=12 Hz, J=6 Hz, 1H), 2.32 (q J=9 Hz, 1H), 2.43 (r, 1H 2.94 (dd, J=12 Hz J=6 Hz, 1H): 326 (n, 1H)i 7 00 (d, J=9 Hz 2H), 736 (d, J9 Hz, 2H) MS (DC NH ) m/z 294 (M+) t ysni .4 B 4L32R 2~{2 g2S 2-Methvridin -Lmeth --- yc---- o--oY...phenK. carbonitrle The title compound was prepared using the procedure described in Example 3D substituting 1 [214-bromno-phenyi(1R, 2 R)cydopropymethylk-(2 S2-methyl-pyrroldine (the product from Example 4A) for 1I2(4-bromo-pheryl)iR 2R);copropyrnethyY (2R) 2-methyApyrroisdine (the product from Example 30) 'H NMR (300 MHz, CDOD) 5 1,22 ( 2H) 1,42 (d J6 Hz, 3H, 13 ( 1 H) 1 H) 2:08 (m, 3H) 2.31 (ni 1H), 3.09 (dd J=12 Hz, J=6 Hz, 1H), 223 (m 1H), 2.39 (dd, J12 Hz, J6 Hz: 1H), 3 50 (rr. 1H) 3~ 67 (r 1H), 727(J9 H2H) 761 (d, J=6 Hz2H), 77 (78 4H), MS (DCL NH4) miz 317 (M+HY. 4 3.S2622-Mvethyloroldin 1ylethyVicyclorOD b1 bi 'phenvi4-carbonitrde 1f24443rag-ph !&~nhiS acytNjpopvimeth2~eh vrldi The tite compound vas prepared using the procedure described in Exanmle 1D substituting racemic 2-methyipyrroidine for (S2-rnethylpyrroiidine. H NR (300 MHz, CDC:) 1 60. 87-0, 92(rr 1H) 0 97 1.2 m1H 16 (d, J=,3 Hz 2 H), 1.22 (2r0 s' .1 , 9 1,49(m 1H), 1,73-1 81( 3), . (m 2H), 2,36 (q. J=6 Hz, 1H) 2.45 (.m,1 3 13 (dd, J=12 HZ, J6 Hz. 1H), 3 25 (m, 1H), 7.00 (d, J=6 Hz, 2H) ? 37 (d J Hz, 2H). MS (DCI iNHA mi 294 (M+H) Example 53 -508 4tf18 8-4(24Methvkp'rn dm4% n r'4y~eh~ylpoylh.1JbigherlyV4arbote The tile compound was prepared using the procedure described in Examp!e I E substituting 1 9(2.<4-bromo..phenwyt(1S,2 28)cycopropylmethyij2 methyapyrrolidine (the product from Example 5A) for 1[( 'S, 2 (4-bromo-pheny)cycopropyimethyf2(S) methykpyrrot!dine (the product from E xarnple 10). IH NMR (300 MHz, CDOD) 0. 98 (m, 1 H) 11 Im I H), 1 20 (d, J6 Hz, 2H 1 34 (m 1K) 1 H 49(m 1H), 1 84 (m3H). 2. 06 (n 2H) 2.51 (m 1H) 201 (i, 1H): 306 (dd, J,12 HzHz O.SH) 3 22 (dd, J=12 Hz, J=6 Hz, 0.H5): 3,34 (nn, 1H) 7,22 (dd, J=12 Hz, J=6 Hz, 2H), 7.59 (d: j=9 Hz, 2H) 77 (s 4K). MS (DCI0NH0) mi/z 317 (M+Ht 541 S,2)2f2S2-Methvipyrroidn1vmt yoroovDphenyv urnmdine The title compound was prepared using the procedure described in Example 1 E substituting 5-pyrimidineboronic acid foir 4-cyanophenyiboronic acid. 'H NMR (300 MHz, C0fOD) 5 0.96 (n 1H), 1.09 (n, 1H), 1.16 (d, J=6 Hz, 3H). 1.31 (i, 1H), 1,.4 (In, H), 1.76(m, 2H), 1. 86(t, 1H), 1.9 (m 2H). 235 (n, 1H), 2,41 m, 1H) 3,29 (dd J12 Hz, J=6 Hz,1H) 3.5 (in, 1H) 726 (dd, J=12 Hz, J=6 Hz, 2H) 6.60 (d, J9 Hz, 2H), 7 77 (s, 4H) MS (DO N 11) m/z 317 (M+H)t 2 -Methoxy~54((18$,2SY24{28) 2 mnethylpyrroidinV vilnmethy4}cyclogwpphnypyr mlchne The title compound was prepared using the procedure described in Examplme 1E substituting 2a-ethoxy pyrimidineboronic acid for 4 cyanophenyboronic ad 1 H NMR (300 MHz, C0D)36 0,94 (I H) i (0m 5 iH 115 (d, J=6 Hz. 3H): 126 (m, 1H), 1.43 (mn, 1H) 1 177(rn 3H .94(m 2H) 2.32 (m 2H) 3.21 (m, 2H 4,04 (s, 1H), 7 21 (d, J=9 Hz, 2H) 7.52 (d, J=9 Hz 2K) 878 (s, 2H). MS (DClNH 1 ) rz 324 (M+H) t L xanlme S 2,6-D-imthy3 44(1 2$-22F-2 mehviyrroidina yine pr& unil reidne The titie cornpaunc was prepared using the procedure described in Examplie 2B g. .subsUtittng 2&6dimethyl-3(4,4 5, 5..tetramethyik[1, 2Jdioxaborola&2Yyri dine (prepared according to the procedure described in J Orq Chem. 67:75417543(2002)) tor4-cyanophenyboror.oti acid. "H NMR (300 MHz, C5>OD) 6095 (n, 1H), 1.06 (m IH). 1 1 (d: J=6 Hz, 3H) 1 33 (m, IH 1. 47 (m, 1 H) 1 80(m, 3H). 20O(m, 1HI 2.20 (dd J=12 Hz, d=6 Hz, 1H), 2-37(, 2H 2. 41 (s3 H 2.48 (m 1H) 2 2 (s. 3 0 (dd, J=12 Hz. J=6 Hz, 1H). 7. 19 (rn, 5H), 751 (d J=9 Hz. IH) MS (DCLNH) mi/z 321 (M +H) Eixampcie 9 2Mhxv54 2 22R2 xmthyapyrr im1 The litie compound was prepared usng the procedure described in Exannple 2B substituting 2g methoxy-5-pyrdinebonic acid for 4-cyanophenylboronic acid H NMR (300 MHz, CC)D) 8 1.21 (m, 2H), 1.45 (d. J=6 Hz 3H), 1.50 (m, 1H) 176 (m, 1H), 2.00(m, 3H), 2.34(m., 1H) 3.14 (dd J=12 HIz, J=6 Hz, I1H) 3 27(m; 1H). 3,44 (dd J12 Hz J1=6 Hz, 1H), 3.54 (m 1 H). 3.73(m, 1H) 3.95 (s 3H) 6,88 (d, J=9 Hz, 1 H) 72 (d =9 Hz 2KH, 7.51 (d, J=9 Hz 2H), 7.93 (dd, J12 Hz, J=6 Hz, 1 H) .33 (d. d3 Hz, 1H) MS (DCWNH3) mi/z 323 (M+H). Example 10 5i-1 2 F2-Methylv n 2r o The title compound was prepared using the procedure described in Example 26 substtutng 5-pyrimidineboronic acid for 4-cyanophenylboronic acd 'H NMR (300 MHz, CD3D) 1,26 (m2H) 1A5 (d =6 Hz 3H) 1.56, (mI 1H, 1 76 (mi 1 ) c0( 31H) 2.35 (I, 1H, 3.12 (dd, J=12 Hz, J=6 Hz, 1H), 3,26 (im1 3AC 46 (dd, J=12 Hz J=6 Hz, 1H). 3.5 (m , 1 H). 3.73 (m, 1H 7.32 (d, J=9 Hz, 2 7.656 (d J=9 Hz. 2H). 9,04 (s; 2H) 9, 12 (s, IH. MS (D"HNH.) m/z C317 (M+Hj') Example 11 5-44{1R;2R>2 3 (2SE2Methyyrroidi~nitvimethyvh hiopropylipheny{lpyrimidine The title compound was prepared using the procedure described in Example 4B substituting 5-pyrmidineboroni acd for 4cyanophenylboronic acd, H NMR (300 MHz; 0D 3 OD) S1.09 (mi H) 1 1;7 (rm. 11H) 1 29 (d. J=6 Hz, 3H 1.45 (m, 1H), 161 (m 1H)N 1.95(m, 3H),2,16 (m, IH). 2.66 (dd J=12 Hz, J=6 1H 2.79 (q, = 9 Hz, 1H) 2,99 (im, 1H 3.20 (dd, J=12 Hz, J=6 Hz, IH) 3.49 (m 1H 7.29 (d, J9 Hz. 2H), 7.63 (d, J=9 Hz. H 9' 03 (s 2H). 9. 10 s, 1 H), MS (DCiN m 3 17 (M+H+ The -itie compound was prepared using the procedure desebed in Example 3D substitutin 5cprimidineboroig acid for 4<vanophenylboronic acid. H NMR (300 MHz, OCDOD) 1 00 (m, I H), 1.11 (n, 1 H), 1.21 (d, J=6 Hz, 3H); 11 34 (in. I H) 1.51 (n. 1H), 1, 82rn 2H) I90(m, 1H 2.08 (n, 1H) 2.18(i, 1H), 2,53 (q, J= 9 Hz, IH), 2.62 (m. 1H), 323(dd,J=12 Hz, J=6 Hz, 1H) 3.34 (m. 1H), 7 27(d J=9 Hz, 2H) 7.62 (d, J= Hz, 2HL 9.03 (s 2H, 910 (s, 1H) MS (DCINH 3 ) in/z 317 (M+H) vi'me cExmpe 13 2,4IDimnethoxv.'54.((1R.2.222 )2eviprrolid n 1" viimethyllcvciorqpy~peviiyrmdine The title compound was prepared usang the procedure described in Example 48 substituting 2 .6-dimethoxy5-pyrimidineboronic acid for 4-acanophenyoor acid. 'H NMR (300 MHz. CDOD6) 1.03 (m 1 H> 1.11 (.i H), 1 27 (d J=6 Hz, 3H) 1.39 (m, 1H), 1,59 (m 1,93(i OH, 2.15 (in 1H, 258 (id, J=12 Hz, J=6 Hz, 1H, 273 (q7 J= 9 Hz, 1H) 2.91 (rn 1H) 3 15 (dd; J=12 Hz, J=6 Hz, 1 ,53'45 (m1H) 4 03 (s 6H), 7.16 (d. J=9 Hz. 2H), 7 40 (d, J*9 Hz, 2H) 8.22 (s 1H), MS (DC1INHj) m/z 354 (M+H). Example 14 2.4.-imethoxv-54441R 2R) 2R/.h2"methvipyrrOli' vilmetvycvco'-rovi)phenv]]ij NNiflidine The title compound was prepared using the procedure described in Example 3D substitutirg 2 6dimethcxy-5-pyrimidineboronic acid for 4-cyanophenylboronic acid. H NMR (300 MHz, CDOD) 6 1,04 (i, 1H), 1,15 (m, 1H, 1.31 (d, j=6 Hz, 3H), 1,38 (m, H) -1I 1.62 (im, IH), I .97(m. 3H), 2.18 ( 1H), 2.57 (dd, J12 Hz J6 Hz, 1H), 2 87 (qJ= 9 Hz, 1H) 3.02 (im 1H). 3.34 (dd, J=12 Hz. J=6 Hz, Iii) 3.50 (m, 1H) 4.03 (, 6H), 7.16 (d: J=9 Hz. 2H), 7.41 (d. J=9 Hz; 2 8.22 (s, 1H). MS (DCi-NH 3 ) rz 354 (M+H) 2,4lDrmethoxy44418 S22 .2RY25methvpvrodm yj!]et~yjqfl'129yoed)2 yrnming~ The tie compound was prepared using the procedure described in Example 28 susdtuting 2,6-dimethoxy~5 pyrmdineoonic acid for 4-cyanophenyboronic add H NMR (300 MHz, CD,0D) 1 .04 (, 1K), 112 (n 1H), 1.28 (d, J=6 Hz, 3H) 1 39 (m, 1H), 1.60 (mi 1H), 1.94(m; 3H) 2.15 (m 1H),. 2,65 (dd, ::12 Hz J= Hz 1H)., 2.78 (r =9 Hz, 1H) 2,98 (rn, 1H), ".17 (dd, J=12 Hz; J=6 Hz, IH), 3.47 (, 1H), 4.03 (s, 6H), 7.17 (d J=9 Hz 2H), 7:41 (d, =9 Hz, 2K 8,22 (s, 1H). MS (DU N H-) miz 354 (M+Ht. The titie comPound was prepared using the procedure described in Examp0e E substitutng 26-dimethoxy~5pyrimidineboronc acId for 4-cyanophenyiboronic acid, 'H NMR (300 MHz. CDQOD) b 1,04 (m, 1H), 1. 12 (m1:H) 1.28 d,j=6 Hz, 3H). 1.39 (ni 1H> 1 60 (m,; 1H) 1 94(m 3H) 2.15 (n: 1H) 2.65 (dd, J=l2 Hz, J=6 Hz, IH), 2,78 (4J 9 Hz, 1H) 2.98 (m, 1H) 3.17 (dd, J12 Hz, ;=6 Hz, 1K), 3.47 (m, 1H) 4,03 (s, 6H), 7,17 (d 1=9 Hz, 2H1)7.41, 7 d J=9 Hz. 2H), 8 22 (s, 1 H), MS 'DN m MY 1 354 (M+H)+ Exampe 17 241R,2RN2 {22)2Methyipyrrol din~~1 vi methvtcyclopropvuphen~jylrdazinK3(2HY A solon of the Product from Exanple 4A (47 g 0.16 mmoi14244 bromo pheny),(iR, 2R)-cyclopropyimethyH2S) 2"nethyl-pyrroidine) 3(2H)-pyridazinone (CAS ft 504-303, 20 rng, 0.2 mmol), copper odide (1, mg, 0,008 rnmo), N.Nran&.dimethL cyclohexan&1 ,2~diamine (2 3 mg. 0.01 mml) and potassium phosphate (75 mg, 0.35 6205 mrnol) n a mixture of touene and isoproparnol (4 ) was heated to 110 "C in a screw capped vial for 16 hours The mixture was cooled to ambient temperature, treated with H2O and extracted with ethyl acetate (2 x 25 mL) The organs layer was separated, )washed with brine and dried with magnesium sulfate. After filtration, the organic layer was concentrated under reduced pressure and the resulting of was purified on sica gel with 1% to 3% methanol (containing 10 % concentrated NH 4 0H) in dichloromethane to provide the title compound. H NMR (300 MHz CDsOD) 3 1 07 (n, I H), 1, 14 m, 1 H), 1 26 (d J= Hz 3 40 (m 1i) .1 58 m, I H) 1 .90(m, 3H), 213 (m, 1H)2.58 (m H) 2,70 (q J=9 Hz 1H) 2.89 (m, 1H), 3. 14(,dd, J=12 Hz, J=6 Hz, IH), 3.44 (m, i H) 7.07 (d J9 Hz 1H), 7 24 (dJ =9 Hz, 2H, 744 (d, J=9 Hz, 2H, 7.47 (n, IH). 8.03 (in, 1H) MS (DCl~NH mz 310 (M+H). The title compound was prepared using the procedure described in Example 17 substituting the product from Example iD 1[(18 28)"2,4-romo-pheny) cycpropymethy2Snethylpyrroine as starting material in place of the 142-(4 Bromo.phenyl)-(1R, 2R)cyclopropyimethl}-(28)>2 methyi-pyrrohdine. H NMR (300 MHz, r'nD) 0.97 (m, 1H), 113 (m, 1H) 1.23 (d, J=6 Hz, 3H) 1,34 (m, lH), 1 A51(m, 1 H);, 1.85m, 3H), 1.93 (m. 1 H) 2,01m, 1 H), 2.68 (J=9 Hz; 1H), 2 85 (r,' 1H, 3,08 (, 1Hl), 2.23 (m 1H) 7,07 (d, J9 Hz, 1H) 7.22 (d J=9 Hz, 2H), .44 (d, J9 Hz, 2H). 7,47 (m, IH). 8. 03 (m H) MS (DC -H 3 ) m/z 310 (M4H) E_~JJ I BA 2M18.SN24(2S)2-MethvivridnvLethv,1,cycloxroyphn 1rdzn32H one L-bitartrate0onoate Example 18 freebase (9.9 g 4i 270 mL 2-propanol) was combined with L-tartanc acid (4.8 g in 30 mL water) in a round-bottoni flask. This suspension was heated to about 70, A solution was obtained wNile heating, The solion was there slowly cooled to 1QC Crystallization was observed upon cooling. Crystals were collected and anayzed by powder X-ray diffraction (PXR-D), which indicated that the solid was of rcrysta'lne 2-[4 ((1 S,2S)2{(2S)2~Methylpyrroiidin1 -. yl]methyl}cy ciopropyDphenyljpyridazin-3(2H)-one L-bitartrate morohydrate (Figure 1).

oeLpbitaltrate mponohvdrate Example 18 freebase (250 g) and L-tartanc acid 1 34 g) solids were added to a solvent mixture consisting of 2-propanol and water at 9/1 volume ratio (50 ml) This suspension was heated to about 65 0 C. A clear solution was obtained while heating. The solution was then siowiy cooled to 20tC over a time not longer than 16 hours, Crystallzation was observed upon cooling, Crysta s were harvested by tilration Th nitrate was washed three tines with 10 mL of solvent mixture (90:1 0 2-propanowater vi). Drying was achieved at 5 C n a vacuum oven overnight The crystals were analyzed by PXRD, which indicated that the solid was of crystalline 2 4(18 2S)2 {vlpyrro idin-y ]methyIcylopropyiphenyljpyridazin32Hn one Litarrate monohydrate (Figure 1), The solid was also analyzed by thermal gravimetric analysis and was found to have a weight loss (Figure 2) 18C one L-bitartrate anhydrate Example 18 freebase (O99 g n 10 rmL 200 proof ethanolt was oontined with L tartaric acid (0.48 g in 20mL 2-propanol) in a 50 mL roundbottom fast The suspension was stirred and heated to 70CC to obtain a clear solution. The solution was then slowly cooled to room temperature. Crystallization was observed upon cooling The crystals were collected and dried at 50C in a vacuum oven. The solid was analyzed by PXRD, which indicated the solid was of crvstalhlne 2~[4((1 2S)~2[(2S)2Methylpyriidn1 vljnmethyi}cyciopropyl)phenylpyridazin-3(2H)cne L-bitartrate anhydrate (Figure 3) 244((1S?:2f2(i2S:2Mthviprrohdirn1yimethyl> coropyvuphenvlpyridazin-32H% one L-bitartrate anhydrate Example 18 freebase (148 mg) was dissolved in 0 2 mL 200 proof ethanol at 504C with stirring. L-tartaric acid (35mg) was dissolved in 0$S ml 200 proof ethanol at 50*C with stirring. The L-tartanc acd solution was then added drop-ise to the freebase solution at 50"C with starring. After the addition of L-tartartic acid solution, the combined smOuion was allowed to slowly cool to ambient temperatures, Crystallization was observed upon cooling. The soiid was collected and dried at 50%C in a vacuum oven. -34- The solid was analyzed by PXRD. whh ond6ated the sold was or crystalline 244 ((1S 2$>2 (2S>2-Mtethylpyrrolidi~1ylmethy!}cy clopropyl)phenyl~pyridazrn 3(2H)-one Ltbitartraie anhydrate (Figure 3). 2I4Q1S 2S)~24(2S'2Methviyrrolidin- 1 ylimethvlcyclooro iDhenyp ridazing 2 Exarrmle 18 freebase (250 mg) was dissolved in 1 0 mL 2-propanot D-tartaric acid (124 mg) was dissolved in 2.0 mL. 2-propanol. The acd and base sAutions were mixed together while stirring, Precipitation was observed upon mixing the two solutions, Water (0, 1 5 mL) was then added to the suspension. The suspension was heated to about 501C, and was then slowly cooled to ambient temperatures. The solid was collected and analyzed by PXRD., which indicated the solid was of crystaline .2-[4 ((1S,.2S>2-{<2S) -2 ethylpyrrolidin-1I-ym~rethylcycopropy)pheryl]yridaar.(2H5--one D-bitartrate dihydrate (Figure 4). The solid was also analyzed by thermal gravimetric analysis and was found to have a weight loss (Figure 5) 4( SlMethylpyrrolidijr1-yflmethiopropv)ohenyipyridazin(2H) one 0-btatrt dhvdrate example 18 freebase (250 mg) was dissolved in 0.5 mL 2-propanol. D-tartaric acid (129 mg) was suspended in 1,0 mL :2-propanol. The base solution was added to the acid suspension at 50VC with stirring. Water (02 mL) was added to the suspension as well The suspension was then cooled to -1SN for about one hour. The solid was collected and analyzed by PXRD, which indicated the solid was of crystalline 2-[4 ((1S, 23)-2-{ (2 S)-Methylpyrrolidnir-yi~methyi}cyclopropylphenylpyridazin-3(2Hivone D-bitartrate dihydrate (Figure 4) Ex st !sti180 ? n M i lulyttdg~aely}ytgoype~|prdazinfi2k> one D-bitartrale dihydrate E xarnple 18 freebase (2 5 g) wvas dissolved in 10.0 mL 2-propanot. DX tartaric acid (1.34g) was dissolved in 5.0 mL water. The acid and base solutions were combined and heated to 5C resulting in a clear solution. 2--propanol (35.0 mL) was added to the solution. Solution was then cooled to 38*C over about ~65~ three hours. Additional 2-propanol (3.0 mL) was added during the cooling, Seeds of 24-((1 2S>2{(2S2-Mthypyrridiro ylimethy }oyclopropy)phenyjpyridazn(2H-one DObitartrate dihydrate were added and the temperature was held at 38C for three hours, during which crystal growth was observed, The suspension was then cooled to 1540 over about ten hours The crystals were collected by filtration and the filtrate was washed three times with 15 mL 2-propano'. The solid was analyzed by PXRD, which indicated the solid was of crystaline 2-4(1S,2S)~2([2S)2Mthyprrcfdi1 vmethyl}cyC.opopyi)phenyipyridazin3(2H.one D-biartrate dihydrate (Fig ure 4) Exampe 18H 26 .- _ S S-d(S2-Methvyr! dn1y 'tyavlorplpeylvrdzn32) one Oitrtrai annvdrate Crystalline 2[4-((1 S,2S) 2-{[(2S2Mthypyrrold I -yi]methyIcylopropyl phenyllpyridaz-3(2H)-one D-bitartrate anhydrate was prepared by dehydrating the title compound D-bitartrate dihydrate, for instance at 55"C in a vacuum oven, The solid was analyzed by PXRD, which indicated the solid was of crystalline 244 ((1St2)2-{(23)-24viethylpyrroid>In 1-yflmethyi}zyclopropyl) phenyf)pyridazin-3(2H)-one D-bitartrate anhydrate figuree 6) triazoieKaryarmngi The title compound was prepareA usng the prcedure desorbed in Example 34G substituting 1H-1 H24-triazoie-3-carboxamide for pyridazin-3(2H)-one H NMR (300 MH:: 0 D) 6 1 11~1 18 m I ) 1 22-1 28 (m, 1 138 (d J 6 Hz, 3H), 1.41.3 (m1 1H), 1.67 -1,74 (m, 1H), 2 01-2.15 (m 3H) 2.24-2 .35 (m 1H)H 2 91 -2.99 (m 1H), 313 3 23 ( m: I H 3 33 3 43 (n, 21- 3 0 -3. 8 (i, WI 7 34 (d, J 9 Hz, 2H). 7. 79 d, Je9 Hz 2H), 9 ,5 (s 1H) MS (DCN 3 ) m/z 326 (M+HI Example 20 2-Methyl-544 (18.2S>241(2_S_2m ethy vcIpyrr opropyp phenvlii 3 b0ezcQihaz oe -66- 2..h.45 .. etraenthyid1 3 2..doxaborolan-2~vI)-benzothiazole A solution o 5romo~2methy(benzothiaze. (2 g, 8,8 rnrno, 4 4 45 5'5 5 octamthy22b(3 2-dioxaborolane) (2.7 g, 1;16 mmo!; CAS 73183-34 3) potassium acetate (3. g, 31,7 mmo) and Pd(dppfh lC di.hmronethane complex (1 1)O360 mg, 0,51 mmol) in anhydrous tetrahydrofuran (70) under a nitrogen atmosphere was heated to reflZx overnight. After coomig to ambient temperature, the mixture was filtered through diatomaceous earth and washed wi t h ethyl aceta t e The nitrate was washed with water and brine. dhed (MgSO), fitered and concentrated under reduced pressure. The residue was chromatographed on siflo gel eluting with 10% ethyl acetate in hexanes to Provide the title compound 1 H NMR (300 MHz, CDC) 51.37 (s 12 H), 284 (sa 3 H), 7,75 (d j=9 Hz, 1 H) 7,82 (dJd=9 Hz 1 H), 8.38 (s, 1 H); (DCi/NH 3 ) m/z 276 (M+H) t 2-ethl:5I4dSx 2802/ "'"2S) 2-ntypyrldn-- ehloropyn'hnyfi-.3~. benzothazcle The title compound was prepared using the procedure described in Example 1 E substituting the product from Example 20A for 4-aaph enylboron ' u H NMR (300' MHz, CDiOD) 6 1.01 (i iH) 1.14 (m, 1H), 1.26 (d o=6 Hz; 3H) 1 35 (m 1H) 1.55 (n, 1H) 1.91(tm, 3H), 2.12(m, 1H), 2,34 (m, 1H), (m , IH). 2,75 (m 1H) 2.85 (s, 3H) 3,26 (m 2) 3,41 (i iH) 7,21 (d, J=9 Hz 2H) 7.60 (d, J=9 Hz, 2H) 6 (dd J=9 Hz, J3 Hz, 1H), 7. 96 (dJ=6 Hz I H), 8.06 (d: J=3 Hz IH). MS (DC-NH) m/z 362 (M+H)+. iH.pyrzole The title compound was prepared using the procedure described in ExaIle 1E substituting 1I ,.3trimnethyi4(4,435 tetramety'(1 3,2iioxaboroian~-2 y!H-pyrazcle (CA$ # 844891-4-9) for 4-cyanophenylboronc acid 'H NMR (300 MHz CDOD) 6 0,99 (I I) 1, 07 (m 1H) 1.22 (d, J=6 Hz: 3H) 1 .29 (m, IH). 1.51 (m, 1H) 1,86 (m, 3H). 2,08 (m H IN 2,15 (a, 3H), 2.18 (m, 1H), 2.21 (s 3H), 2.66 (m, 1 H). 2,65 (n, 1H), 324 (I H) 3 38 (m. I H), 7.14 (s, 4H). MS (DC~NH) mz 324 (M+H)t ~67- 2&D~Qmegy4K4'e[1S2,).{[(2Strethylatrrou>1 The the compound was prepared usinh procedure descft)d in Exarnpe E. substiting~ 2 6-dimethypyidine 3-orniacid ftor 4~cyanphenyiborcnc acid, 'H NMR (300 MHz, CDOD) 3 0.97(m, 1H) 1.09 (n 1H), 1,22 (d 6 Hzl 3H), 1 32 'mi H), 1,51 H1 86 (m 3H). 207 (m, 1H), 2.18 (r1H); 241 (, 3H); 252 (s 3H), 2,55 (m, 1H), 2.62 (,n I H) 3 25 (m, 1H) 3.37 (m, 1 H> 7.19 (m, 5H , 749 (d J=9 Hz, 1H). MS (DC-NH,,) m/z 321 (M+H) E xamoe 23 5.4'41S,2S) 2S)~ Methy 'pyrroiidin- 1-v mehiccorpnhnprmdn The title cormpound was prepared using the procedure described in Exanple "HE substituting pyrimidine--boronic acid for 4-cyanophenyiboronic acd H NMR (300 MHz, CDOD) 6 096(m 1H) 1i m, 1H) 1 16 (d, = Hz, 3H 1.31 (min 1H, 1.45 (m, 1H), 1,77 (i, 2H) 1 86 (m 1H) 2,0 (m 2H) 2.4 mn 2H 338 (m, IH). 327 (m, 1), 7.26 (d, J=9 Hz 2H) 762 (d. J= 9Hz. 903 (s 2H) 9.09 (s, 1). MS (DCIVN:) m/z 294 Example 24 4~ggh $2 (Y 2Mehy{[(2Si ggyginethyjmt%2 cygcpgrygeai gmg A soution of the product from E xampIe 1D (640 mg, 2.18 mmoI 1 S(1S 2 2(4 brcmcophenyi) -cydiopropyimethyi}-2 (Sminethyl-pyrrolidine), ithium bis(trimnethylsity.)aide (56k0, mg) Pd2), (100 mg)and(10% ihexane 530 rg) in toene (3 mL) was heated in a microwave reactor at 160 'C for 40 minutes, The mixture was dilued wih dchlrorfmethane and H20 and partiioned. The aqueous layer was extracted with DCM and the organic layers were combined dred and concentrated to afford a brownish -68residue which was purifiEd on sinca gel eluting with 3% methano! containerg 10 % concentrated NHOH) in dichloromethane to provide the title compound. 1 NMR (300 MHz CD/OU 0.73(m, 1H), 0,85) t (m 1H), I 07 (in 1H), 1 13 (d, J6 Hz 3H), 1 41 (m, 1H) 1. 63 (nn 1H) 1. 76 (m, 3H), 2 0 (n, 1H) 2 28 (m, 2H), 32 (m, It): 327 m 1H) 6.65 (d: J=9 Hz, 2H). 6.83 (d, J=9 Hz, 2H) MS (DCV-NHy) m/z 231 (M+H7' Examole 24f3 N~lsobutyi-N44418 2S ([2S2 ety yroidi__etyp__hg_]r0._ A solution of the product from Example 24A (35 mg, 0, 15 mmol, 442(2S)-2 methylpy rrodin-1 -ylmethyfl(18, 28)-cyclopropyi}-phenylamrnre) and 2-nethyiV propionaldehyde (20 mL 0 23 mml) in ethanol(8 mL) was treated with borane-pyridine (30 mL) at room temperature and stirred for 16 hours. The mixture was concentrated and the residue was purified on silica gel eluting with 3% methanol (containing 10 % concentrated NH/OH) in dichloromethane to provide the title compound. 'H NMR (300 MHz. CDOD) 6 0 82 (m, 1l) 0-94 (Im. 1H, 0,95 (d: J 9 Hz, 6H), 1.17 (m, 1 H).1 26 (d J=6 Hz 3K) 1.57 (m 1 H) 1.76 (m, 2H), 1 90 (m, 3H) 2, 13 (m 1)3 27 (m, 1H), 2.75 (, 1H) 2,84 (m 3H) 3.23 (, H), 3,45 (m, 1H). 656 (d j 9 .Hz 2H), 66 (d, J= Hz, 2H) MS (DCl-NH-) m/z 287 (M+H)A N-41 2 2Jridi r methvcp yphen yrimidi n-5 A soluticr of the product from Example 24A (300 mg 1 3 mmol, 4-{2-i(2S)-2 methy-npyrrolidin-1 -yimethyl-(1 82S)cyclopropyphenyamine), 5-brompyrmidine (311 mg 1.95 mmo), r zta hloofor (40 mg), CsCO (1 g), and 1,1 '4is(diphenylphosphino)ferrocene (65 m g) in a nhydrous dioxane (8 mL) was heated to 110 C 0 for 48 hours. The mixture was cooled to room temperature. diuted with EtOAc and washed with water and brine. The organic layer was dried (MgSO4), fitered, concentrated under reduced pressure and purified on silica gei eluting with 3% methanol (containing 10 % concentrated NH/OH) indchtoromethane to provide the title compound, K NMR (300 MHz, CDOD)6 0.84 (n, 1H), 096 (n, 1H), 1.14 (d, J6 Hz, 3H), 1,20 (m 1H), 1.43 In 1H 1.5 ( m 3H), 1,88 (m, 1H), 201 (n, 1H), 2 28 (m, 1H), 2 35 (m, 1H) 3.14 (ml 1H) 3.26 (im, 1H), 7.08 (a. 4H) 844(s 2H) 8.51 (s; 1H) MS (DCWNNH 3 ) m/z 309 (M'+HK V -69- ..... .tbo Nir I Examole 26A 3k44 Bromophenvi ~po2mene 1 to a solution o ethyl trans4-bromoinnamte CAS 24393-53-1 (8 m. 42,6 mmod) in anhydrous dichlorometbane (150 mL) uUnder N2 was added dropwise diisobutylaluminum hydride in dichloromethane (128 L, 1M, 128 mmiol) at -- 78 C, Following the addteon te mixture was allowed to warm from -78 GC W -30 t over two hours. The mixture was then cooled back to -78 "C and aqueous 1 IN HCI was added. The organic layer was separated, dried with MgSO, fitered and concentrated under reduced pressure to provide the title compound H NMR (300 M D0 & 1 44 (5 J 6 Hz, 1H) 4.32 (t; J= 4,5 Hz, 2H o.37 (dt. J= 16.5 Hz, J 6 Hz, IH. 657 (dtJ=1 Hz, J =3 Hz 2H) ?.25 (d 9 Hz- 2 7,45 (d, J = 9 Hz: 2H) MS (DC-NH 3 ) mi/z 214 (M:+H )+~ 2SutviQ 3,2dioxaboroiane 2 645-dicarboxvio acid pis-dimethylamide 2(But. ,- erahydro-4H 126 2-dioxazaborocine (CAS9 1 was prepared from n-Outyioronic acid and 2(2-hydroxy-ethyiamino)-ethano[CAS 11 t1-42-2] as reported n Organic Synthesis 199$76, 86-96. This dioxazaborocine (3 g, 17,5 mmol) and (283S)-2-dihydroxy-N N Ntetramethyibutanlediamide [CAS 63126 (4-65 g) were dissolved in anhydrous dichoromethane (95 mi..) under N:. Brine (30 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The two layers were separated, and the aqueous layer was extracted with diehloromethane (30 mU The combined organic layers were washed with brine, dried over MgS.0 4 filtered and concentrated in vacuo to provide the title compound as an oil, H NMR (300 MHz, CDCl 0.82-O9 (rn 5H) 1,25-1,45 (m 4H) 2,98 Is, 6H) 3.2 (s, 6H), 552 (, 2H). MS (DCI NHt n/z 271 (M+H)t Example 26C gi24-rorn ophem ygiggropyflmithanol To a -10 solution of dimethoxyethane (1 2 mL 2 equivalents) in anhydrous -70dichormethane (30 rnO) under N 2 was added dropwise, diethyizino (12 rmi IM in fodlowed by dropwise addition of diiodomethan (1,8 mL) over 15 minutes, maintaining the temperature belw-5 "C: The mixture was stirred another 10 minutes at -10 Th after the addition, then a sotion of the dioxaborolane from Example 268 (1.8 g in 5 mL diohoromethane) was added over 6 minutes at -5 C, A solution of the akene from Example 26A (1 g in 5 mL dichloromethane) was then added dropwise. The cooling bath was removed and the mixture was stirred ovemight. The mixture was quenched with the addition of saturated aqueous NHACO, and 10% aquecus HC This mixture was extracted with ether twice. The combined organic extracts were treated wit aqueous 2N NaOH (40 mL) and 30% aqueous H)0t (5 mL) and then stirred for 5 minutes. The separated organic layer vas then washed sequentiay with 10% aqueous H, aqueous Na 2 Sy0 aqueous NaHCO 3 and brine The organic iayer was dried (MAgSO4) and filtered The filtrate was concentrated in vacuo, The residue was purified on siica gel eluting with 4.1 hexaneslethyl acetate to provide the title compound IH NMR (300 MHz, CDOl): 6 0;92 1,0 (m, 2H), 1,45-1.48 (r, 2H), 1.76-1 85 (mI H) 3.61 (d. J 7.5 Hz 2H), 695 (d J = 9 Hz, 2H9): '737 (d, J = 9 Hz, 2H). MS (DClNH 3 ) m/ 228 (M+HV. Example 26D 1R,2R).2.-(4-Sohenviedpoaetradhd DMSO (0,8 m, 3 equivalents) was added dropwise to a solution of oxaiyl chloride (0-48 mL) in anhydrous diohtromethane (50 mL) under N 2 at -78 t. A solution of the aicohfoi from Example 26C (823 mg) in dichloromethane (20 mL) was then added dropwise at 8-78 t. Stirring at ths temperature was continued for 30 minutes, then tiethylamine (2 mL 4 equivalents) was added, and the dry ice bath was removed, After stirring for 1 hour the mixture was treated vith saturated aqueous NH4tl The mixture was extracted with ether, The combined organic extracts was dried (Mg S04) and filtered. The filtrate was concentrated under reduced pressure. The residue was purnied by eluting through a pad of silica gel with hexane to provide the title compound, H NMR (300 MHz, CDCh): 6 1,48 (n, 1H 1.65 (dt. J = 9 Hz, J = 6 Hz, I H), 2.15 (in 11, 257 (rYE IH),698 (d J = 9 Hz, 2H). 7.45 (d, J = 9 Hz 2H), 9.46 (d, J 4,5 Hz, 1 H). MS (DCi NH-) m/z 226 (M+H)-. .3' 1 R~igrodd~s8k2 ycloropfbenzene A solution of the aldehyde from Example 26D (500 mg 2.22 mmDo) and ethytrihenylphosphonium iodide CAS 2065691 (1. 17 g) in anhydrous drichoromethane (50 mL) was stirred at 0 tC under N12, Potassium t-buoxide (340 mg) was added to this chilled mixture The ice bath was removed, and the mixture was stirred at room temperature for one hour. The mixture was quenched with saturated aqueous NHtL. The mixture was extracted with dichloromethane and the combined orgarnc extracts were dried (MgSQO and filtered The filtrate was concentrated under reduced Pressure and the residue was purified on s ca ge with hexanes to provide the title compound. IH NMR (300 MHz, DC)" o 1. 1-1 2 (in, 2H). 1, 6 17 (m, 1H, 1H84-1.92 (m 1H 5.05 (ddd, J 34 Hz J = 9 Hz, 1 Hz. 1 5H) 52 (ddd J 18 Hz, J 10 Hz, J 9Hz, i= H 6.9 2 J 9 Hz, 1), 76 95 d, 9Hz, 2H) MS DCVNH) m/z 224 (M+H. 21(18S,2R24-Bromophen \c ropelletano! To a solution of the alkene from Example 26E (2.25 g. 10 imol) in anhydrous THF (510 mL) under N 2 was added borane-THF (13mW I M) at 0 t2. The mixture was stirred at room temperature for two hours then chfled to 0 C, Aqueous hydrogen peroxide solution (35%; 3,5 mL) was added, the ice bath was removed the mixture was allowed to warm to room temperature and stirring was continued for 10 minutes. he mixture was quenched with saturated aqueous NHX&I and extracted with ether. The combined organic extracts were dried (MgSOA and fitered The filtrate was concentrated under reduced pressure. The redue was purified on silica ge with 4-1 hexanes/ethyi acetate to provide the: ile compound. NMR (300 MHz, CDC3): ' 0 8-0 92 (Im 2H) 021 (n 1H), 1,46 s, 1H) 1 (m, 2H) 3 75 (t, J . .6 3Hz,2H) 6.9 (d J = 9 Hz. 2K, ?.4 (d, J = 9 H z, 2H) MAS (DCi-NH 3 ) m/z 241 (MiH)t 4k1R2S22idrovthycycogr'n- 'ibihgwi 4canitrie A solution of Example 26F (1.2 g 5 mmol) 4-cyanophenylboronic acid (CAS 12674714-61 (I46 g, 2 equivalents), Pd(PPh) 2 C (350 rnc) ard s2O Q(6. 5 g in sopropanoi (80 mL) under N2 was stirred at reflux overnight. The mixture was paritioned between ethyl acetate and H 2 O The organic layer was washed with saturated aqueous NaHCO 1 and then with brine, The organic layer was then dried (MgSO 4 ) and filtered The -72filtrate was concentrated in vacuo and the resulting residue was purified by hrmatgraphy on siflca geieluted with 41 hexanesethyl acetate to provide the ti le compound, H NMR (300 MHz, CDC,): 8 0,85 -1.03 (m, 2H'. 112-1.2 (m, 1H) 65 1.7 (m, 3HK) 3.78 (t J = 6 Hz, 2H), 7.15 (d, J = 9 Hz 2H) 7.48 (d, J 9 Hz, 2H), 768 qsJ = 9 Hz, 4H). MS (DU-NHH) m/ 264 (M+H), Examte 26H Methanesulforic acid 2(18,2 4 in beccopro pyhl ester To a solution of Exanple 26G (560 mg, 2,13 mmol) and methanesufonyl chloride (0 22 mL, 1 2 equivalents) in dichloromethane (10 mL) under N, was added tnethyamine (O.42 Li A eqivalents) at 0 . 'The mixture was strred at room temperature for 5 hours, The mixture was treated with H20, and the organic layer was washed with brine, then dried (MgS0 and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluted with 4:1 hexanesethyl acetate to provide the title compound. 'H NMR (300 MHz, CDc)0 9 -1 08 (m, 2H) 1.1-2 (m, 2H), 3.0 (s 3H 4,35 (t J = 6 Hz. 2H), 7,1 (d . 9 Hz, 2H) 7.46 (d, 3 9 Hz. 2K), 7.68 ( J = 9 Hz. 2H). S (DC..4tH 3 ) rn/z 342 (M+H)+ Example 261 4-U1R,2_2QQ@7')ehyipyrrojjdijr -y]getyovrpcighuny To a solution of the nesylate from Example 26H (500 mg 1.47 mmol) and potassium carbonate (0.446 g; 3.24 mmcl) in DMF (10 mL) was added (R)-2 methgipyrrondine rydrobromide [CA S 117607-1 3-3] (300 ng 1 81 mmol). The mixture was stirred at 50 0 overnight. The mixture was partitioned between ethyl acetate and H20 The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purfed by chromatography on silca ge eluted with 7,5/20/70 MeCH/EtGAc/iCHCi 3 to provide the title compound. 1 H NMR (300 MHz CDCI fre base); 0,85 -0 9 (m, 1H); i.031 0 i, 1H) 1. 14 (d, J= 6 Hz 3H) 1.42 24 (I 11H), 2 9 (m1. I H1 3.15-3.23 (mI 1H) 7 15 (d J 9 Hz, 2 H) 7.47 (d, J = 9 Hz , 2H), 7,66 qJ = 9 Hz, 4H) MS (DCl-NH) riz 331.2 (M+H)* Anal. Cac. for CKHa N

C.H

0 1025 H2G (L-tartaric acid salt): C 64 46; H 6,.91 N, 5.57, Found C, 64 46: H, 6.91 N 5. 57. -73- (fz2Jt1 52R24VBromIophenylicopropvlethv!)2Cne ylgrahilr amrie 27A (S 2PMethanesulfonic acid 24244-bromophen2Iy-mjoeth vj estr The alcohol from Example 26F 2-[(1 S2R)-2-(4bromophenycyclopro -1 yfltethanol 'was o r to (18C .2R) inmethanesufonic acidbromopheny cyclopropyl]-ethyl ester according to the methods outlined in Exampe 26H, Exajm gje 278 (2R92Z(1S 2R 2 4Brmohev yc1pwo±ehy) r-mthlprrAiQn The fite compound was prepared according to the methods outlined in Example 261 subsUting the product from Example 27A (1R2R)-methanesulfonic acid 2[2-4 bromo-phenyclopropy}thylester, for the product from Examnple 26H H NMR (300 MHz C DC Ifree base) 0, 7 5-0.9 (, 2H 0 97-1 04 (in, 1H 1.15 (d, J =6 Hz, 3 H); ,65 i m, H185235 (m, H 2 852-95 (m, 1H), 312320 (- . 1 H) 6. 9 (d; J= 9 Hz, 2H), 7.33 (d, J 9 Hz 2H). MS (DC-NH 3 ) rinS/z 310(M+)> n(1A~/42 /ehiyrol ~lehlccorop- vP-I 1<bphenyV4 carborntrile Examo~e26A 2-Buty141 C dxaboroianej3R5di4 carboxv acd bis-dimethyamide 2-(Buty-tetrahydro-4H136 2ioxazaborone [CAS 9252 34) ( ,1 imoh, which wvs prepared from n-butylboronic acid and 2 (?-hydsoxyamina) ethanol [CAS 11-42 21 as reported in Organic Synthesis, 1998 76 86 96, and (2R 'R) 2/3-dShydroxy-NN N N Mtetramethybutanediarnide (CAS 26549~65-5) (9 85 g) were dissolved in anhydrous dwchloromnethane (10m)udrN-rn (2$ mL) was added. The resulting mixture was stirred at room temperature for about 16 hours. The two layers were separated, and the aqueous layer was extracted with dichlromethane. The 74combined organic layers were washed with 50 mL brine, dried over MgSO filtered and concentrated in vacuo to provide the title compound as an oil Exarol 2813 (1 8.2SJ2trornophen v1cyocroylmethanoi To a -10 "0 solution of dimethoxyethane ( .2 ro) in anhydrous dichioromethane (200 mL) under N 2 was added dropwise. dethylzino (62 6 nL, 1 M in dichloromethane) followed by dropwise addition of diiodomethane (10 1 m) maintaining the temperature below -5 "C. The mixture was strred another 10 minutes at -10 'C after the addition, then a soktion of the dioxaborolane uRR)-4t5dicarboxyic amd bis-dimethylamide) (8.8 g in 40 mL dichoromethane) was added at -5 "C. A solution of the aikene from Exampie 26A (3-(4bromophenyi)prop2~1, 5 3 g in 50 mL dichloromethane) was then added dropwise The cooling bath was removed and the mixture was stirred overnight. The mixture was quenched with the addition of saturated aqueous NHACI. and 10% aqueous HCI This mixture was extracted with ether twice. The combined organc extracts were treated with aqueous 2N NaOH (250 mL) and 30% aqueous HJ% (35 mL) and then stirred for 5 minutes, The organic layer was then washed sequentiaIly with 10% aqueous HC aqueous N aS aqueous NaHCO, and brine, The organic layer was dried (MgSoQ) and filtered. The filtrate was concentrated in vacuo. The residue was purified on silica gel eluting with hexaneslethyl acetate to provide the title compound. Exarnjpa2C0 (13 ,2Sh244Bromoohenv~clopopanecarbaidehyde DMSO (3 equivaents) was added dropwise to a solution of oxaiyi chloride in anhydrous dichoromethane under N at -78 cC, A solution of the alcohol from Example 2BB (( 12 S 244-bromophenyl)cyclopropylmethanol) in dichloromethare was then added dropIwise at -7' C. Stirring at this temperature was continued for 30 minutes, then tnethyamine (4 equivalents) was added and the dry ice bath was removed. After stirring for 1 hour the nture was treated with saturated aqueous NHgCL. The mixture was extracted with ether. The combined organic extracts was dried (MgSO 4 ) and filtered The filtrate was concentrated under reduced pressure, The residue was purified by eluting through a pad of silica gel with hexane to provide the title compound. -75~ I Bromo-4 3 2R2-vinytgvoprpybenzene A sotion of the aldehyde from Example 28C ((1S,2SY2J44 bromophenyl)cycopropanecarbadehyde] and methyltrphenylphosphontum iodide [CAS 2065-669 in anhydrous dichioromethane was stirred at 0 t under N 2 . Potassium t butoxide was added to this chided mixture. The ice bath was removed and the mixture was stirred at room temperature for one hour The mixture was quenched with saturated aqueous Nti The mixture was extracted with dichioromethare and the sned organic extracts were dried (MgS) and filtered. The filtrte was Ooncentrated under reduced pressure and the residue was purfied on silica gel with hexanes to provide the titlecompond. Examoe 28E 2- i1R, 2S6214-B ro mophenv -cyclor -- Ilethano To a solution of the aikene from Example 28D (bromo-4-1 .2R)-2 vinykyciopropylbenzene) in anhydrous THF (50 mL} under N, was added barane-THF at o 'C The mixture was stirred at room temperature for two hours and then chilled to 0 0Q, Aqueous hydrogen peroxide (30 %) solution was added, the ice bath was removed, and the mixture was allowed to warm to room temperature with continued stirring for 10 minutes. The mixture was quenched with saturated aqueous NH0Ci and extracted with ether The combined organic extracts were dried (MgS4) and filtered, The filtrate was concentrated under reduced pressure. The residue was purified on silica gel with 4:1 hexanes/ethyl acetate to provide the title compound. Exampe28F 4(IS 2R)-2- 2-Hydroxvethviclopro- 1-ylibioheny4-carbonitrile A solution of the product of Example 28E (2(1R2Y)244bromophenyyioprop- 1-y]ethanol). 4-cyano phenyiboronic acid [CAS 126747-14-6] 2 equivalents) Pd(PPhs'Cl2 and saCO n 'sropropanoi under.N 2 was stirred at reflux overnight. The mixture was partitioned between ethyl acetate and H 2 ,0 The organic layer was washed with saturated aqueous NaHOC> and then with brine. The organic layer was then dried (MgSO 4 ) and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluted with 4:1 hexanes/ethyl acetate to provide the title compound. Example 2G Methainesulfonic acid. 2+1 R2S)-244tyano-biphenyl-4-y)cyclopropvikeihy ester -76- To a solution of the product of Exampe 28F (4iS 2R)-2-(2 hydroxyethy)cycloprop~1-yflbiphenyi4carbonitrile) and methanesufonyi chloride (1.2 equivalents) in dichlorornethane under N2 was added tethym 4 equivalents) at ,C. The mixture was stirred at room temperature overnight, and then the mixture was treated vth H, The separated organic layer was washed with brine, dried (Mg .04) and filtered. The fitrate was concentrated in vacuo and the resulting residue was purified by chrormatography on silica gel eluted with 4:1 hexanesethy acetate to provide the titde compound, Example 28H 4 S2R)-222R2- Mtvpyrrod in -ylethy}coproovi,1-,iphenV4 carbonitrile To a solution of the mesviate from Exampie 28G (metanesulfoic acid, 2 [(1R, 25)-2- 1 4'-cyano-iphenyey)-cyclopropyl]-ethy ester) and potassium carbonate in DMF was added (R)2ethylpyrroidine hydrobromide [CAS 11760713] The mixture was stirred at 50 C ovemight. The mixture was partitioned between ethyl acetate and HO. The organic layer was washed wth bone, dried (MgSO4 and centrated in vacu. The rescuing residue was purified by chromatography on silca gel eluted with 7520/70 MeOHEtf CH 2 to provide the tile compound H NMR (300 MHz, CDCI free base): 6S 0,88-10 (, 2H) 1.10 (d. 6 Hz 3H) 142.4 (m 11H) 2.9 (mn 1 HY 3.15-3.23 (in. IH) 7.15 (d, J 9 Hz, 2H) 7.47 (d. J 9 Hz, 2H 7.- (p J=9 z, 4H). MS (DCNH 3 ) m/z 331,2 (M+HV Ana Calo, for C94N.CHr0s 1.25 HGO (LV tartaric acid salt). C 6446: H, 6.91 N. 5.57. Found: C, 64 46 H, 6,91 N 657. Example 29 4tf1R F251-242-J2R) 24Methvlpyrrolidin-1ilethyl}cycloprop&Q1.1 biphenyL4 carbonitriie Exaole 29A 344l3romochenNthoxvnethviarlyiamde A soution of oxaiyM chloride In dichioromethane (2 M, 100 mL, 200 mmol) was added dropwise to a stirred solution of trans4-romocinnamic acid [CAS 1200-07-3] -77- (25.0 g 110 mmol) and DMF (05 mL) in dchloromethane (300 mL at 0 'C under a dry nitrogen atmosphere, The nitrogen line and coming bath were removed and the mixture was stirred at room temperature until gas evolution had ceased Volatiieswere removed ) under reduced pressure. and the residue was redissolved in dichoromethane (200 mL) The resulting solution was added dropwise to a stirred solution of N,O0 dimethylhydroxylamine hydrochloride (25 g 22C) mol) and triethylamine (61.4 mL. 440 mmcl) in dichioromethane 5 mL) at 0 "C. When the addition was complete, the cooling bath was removed and the mixture was stirred ovemight at room temperature. insoluble material was removed by fitration and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous 10% citric acid. The organic iayer was successively washed with aqueous 10% citric acid, aqueous 3 N sodium hydroxide and Orine: The ethyl acetate solution was then dried (MgSO2 and filtered The filtrate was concentrated under redu ced pressure, and the residue was purified by column chromatography (6 :35 hexane/ethyl acetate) to provide the title compound. H NMR (300 MHz, CDCi) 623 31s (H), 3.76 (s, 3H) 702 (d, J 15 Hz, 1H) 7 43 (i J = 9 Hz, 2H), 7,51 (d J 9 Hz, 2H11) 7 (d, J = 9 Hz 1) MS (DCl--NH3 mfz 270 (u+-) mz 287 (M+NH4)* 2U4Bomchenyitrnsycyloorocaneoarboxyicacid, N methoxQNmeltyamfide fracemic} A stirred solution of trimethylsuifoxonium odide (26 7g, 119mmo) in DMS0 100 mL) at 0 "C was treated with sodi urn hyd ride (60% oil dispersion. 4.57 g, 114 mmcl) in small portions. When the addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 46 minutes. A soution of the alikene intermediate from Example 29A (26. 85 g 99 mmdo) in DMSO (1O0 mL) was added dropwise to the mixture and stirring was continued overnight, The mixture was diluted with saturated aqueous amomum chloride arid the mixture was extracted with diethyl ether '4 X 100 mL), .T combined extracts were dried (MgSO 4 ) and filtered. The filtrate was concentrated under reduced pressure to provide an oil that was purified by column Chromatography (70:30 hexane/ethy acetate) to provide the title compound. H NMR (300 MHz, CDC 3 ): 8 1.23-131 (m 1H), 1.60-1 67 (m. 1H) 2 32-2.42 (m, 1H) 2,42-2.50 (m, 1H), 3.23 (s, 3H) 3.69 (s, 3H): 7,00 (d J = 9 Hz 2H). 7.39 (d, J 9JHz, 2H) MS -78- (DCNH miz 284 (M+H)* m/z 301 (M+NH4)* Example 290 A solution of the product from Example 298 (24.3 g7 86 mol) and potassium t butoxide (80.8 g, 684 mmo1) in diethyl ether (900 mL and water (10 m was stirred at room temperature for three days. The mixture was then slowly acidified by the additon of concentrated hydrochloric acid The ether layer was washed 'th brine and the acidic aqueous layer was extracted with ethyl acetate (2 X 100 mL), The ether layer and the e-hyl ate extracts were combined, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure to provide the title compound. * H NMR (300 MHz, CDO2): 8 1 3 A2 (m1, 1 H), .3<71 (m 1H 1.84-1. 1 (m, I H), 2.51~ -60 (rr. I H), 6.98 (d, J 9 Hz& 2H), 7A1 (d, j 9 Hz. 21h, 11 08 (br S I H). MS (DDb44H 3 ) rniz 258 (M+N H 4 ) Example 29D [(1R 2IRI2 47BromnoPhenvlevdlprovfH(1,5R L 7 1 10-dirnethy!33dioxo-3A thia 4 .azatricio{5 .2.1 .0>9dec 4 vl~iethanone d [(14mohen ydrv 18R7R10 10-dimethy dioxo-3tha 4-azatricvdic f.2t10'dec-4 vimetha3none A stirred solutin nf the racemic trans-cyclopoy intermediate n Example 290 (20.5 g, 85 mni) n DM,- (100 mL was treated with 1,1tarbonyldimidazole (15.2 g. 94 mmch under a dr nirogen atmosphere The mixture wis stirred at 40 "C for hour and then (1 ))92.10c-anphorsultarn ([CAS 9459490-8), Aldrich catalog number 29,8352) (25 82 g. 120 mmiol and DBU (12.7 mL 85 nmo) were added. The mixture was stirred at 40 %0 for 6 hours and then at room temperature ovenight, The mixture was then partitioned between ethyl acetate and aqueous 2 N hydrochloric acid. The organic layer was washed with saturated aqueous sodium bicarbonate and then with brine, The ethyl acetate solution was then dried (MgSO 4 ). and filtered. The fttrate was concentrated under reduced pressure, and the residue was purified by column chromatography (90:5:5 hexane/dichloronethanelisoproanoL Drying under high vacuum supplied a mixture of diastereoniers. The diastereomers were separated by elution through a chir olumn 79- (Chiraicel CJ @ 90 10 hexane/ethanob) The first iastereomer to elute (retention time 11.8 minutes) was identified by x-ray crystallography as possessing the S: S absolute configuration at the cydopropyl carbons The later-eluting diastereomer (retention time: 19 minutes was assigned' the R, R absolute configuration at the cyclopropyi carbons. Earlyveluting diastereomer (S, S-cyclopropyl), [(1IS2)-2-(4 bromophenyl)cydiopropyl]-{( 1 3 SR? 7R)J(1010-dinmethye33-dioxoy3%thia-4 azatricycl5,2i 06]dec-yl)}methanone 'H NMR (300 MHz, DC;): 6 0 97 (s, 3H) 1.17 (s 3H), 1 30-17 (n, 3H) 1.611,69 (in 1) 1.83-1.99 (n 3H) 2,01-2,19 (n 2H), 2.53-2 61 (rm 1 H) 2.63-2.71 (n, iHi. 342-3.56 (m, 2H), 3,86-3 92 (mn, 1H) 7 10 (d J 9 Hz, 21H), 740 (d J = 9 Hz 2H). MS (DCkNH-) m/z 455 (M+NHt. . Late-euting diastereomer (R, R cydopropyi [(1R2R)-2-M bromophenyi)cyclopropyl]-{{1 Ry atricycl[5,2.1,0"!decN4-yl)}mehanone: H NMR (300 MHz, CDC1 6 0 98 (s, 3H) 1.20 (S3..H) 1.29147 (m, 3H), 11,7381 83 (rn, 1H), 1 83400 (. 3H 2 001-2 8 (m 2H). 2 46-259 (n 2H) 3.39-3,5 (m, 2H) 366-4. 96 (m 1H) 7.09 (d. J 9 Hz 2H) 7. 39 (d, J 9 Hz, 2H). MS (DC1NH) mh455 (M+NH 4 )*. I R'2- (4 -Srom ophenyi)cyclooronanecarbaldehyde A solution of the later-eluting. R R-diastereomer ([( R,2R)-2-(4 bromophenyl~cyclopl>{(1,5RF 7R)-(1 0,10-dimethyl.3,3dioxo3X.tia-4 azatricycio(52 1 04]dec-4jl)}methanorne) described in Example 29D (5.2 g. 11.86 mnmol) n dichoromethane (100 mL was stirred under a dry nitrogen atmosphere at -78 oC. A 1 M solution of diisobutylaiumninum hydride in dichioromethane (26.1 ml., 26 1 mmcl) was added dropwise to the mixture. When the addition was complete, the mixture was stirred at -78 T for 3 hour. Methanol (27 nL) was then added dropwise at -78 *O The dry ice bath was then replaced with an ice water bath and saturated aqueous amnonium chloride was added to quench e mixture After 10 minutes, the insoluble material was removed by fltration and the organic layer was s dried (MgSOj: and filtered The filtrate was concentrated under reduced pressure to provide a coloress oil that was purified by column chromatography (9:1 hexaneethy acetate). Fractions containing product were combined and concentrated under reduced pressure to provide the title compound. IH NMR (300 MH D)z,-0 & 1.45I57 (m 1K) 1.704.78 (m, 1H) 2.1 -80* 2 19 (n 1H) 2.55-2.63 (. 1H) 6.99 (d J = 9 Hz, 2H) 742 (d J = 9 H Hz, 2H)35 (d, J 4.5 H , 1 H) MS (DC-NN r mz 225 (M+H)* nz 242 (M+NH 4 )t Example 29i 1-Bomo440R,442viym<cloro)vibenen The aldehyde intermediate from Example 2SE (2,35g, 10,44 mo) was converted to the alkene by the methods outlned in Example 26E followed by chromatography (100% hexane) provided the tale compound. H NMR (300 MHz, CIDCl): 6 1.07-1.19 (m, 2K 1,60-1 71 (n 1H 183- 191 (im, IH), 4.91-4,7 (m, 1H), 5,05-5.14 (mr. 1H 5 .4&559 (min H) 6.93 (d, J = -Hz2H), 7.36 (d, 9 Hz, 2H). MS (DCL. NH 1 ) mz 241 (MNH 4 Y. .. arh 259G 2 1 R2(-rmohn ylpo-vilethanoi The alkene intermediate from Example 29F (1.64 g, 7.35 mmol) was converted to the aloohol by the method of Example 26F. followed by chromatography (7:3 hexane/ethy acetate) provided the title compound, H NMR (300 MHz, CDC,: 6 0.96 0.79 (im, 2H). 1.00A, 14 (m, 1H), 1 54-1 .76 (m, 3H), 49144 97 (m, I H), 376 t, J 6 Hz, 2H, 6.12 (d, J 9 Hz, 2H), 7.35 (d. J 9 Hz, 2H). MS (DCl-NH) m/z 258 (M+NHts t Example 2th 4t(1R2 2%K Hdoxethyklvcvooprop -f vibiphenvi-4-ca~rboni The bromophenyl intermediate from Examiple 29G (0.83 gt 3.44 nmol) was converted to the biphenyi intermediate by the method of Example 26G, but with a total reaction tme of 45 minutes, followed by chromatography (7:3 hexane/ethyi acetate) provided the tie compound. H NMR ('300 MHz, CDC): S 0,8 0.95(nn iH) 0,971,04 (i, 1H), "11-1.24 (, IH) 1.61-1 79 (m 3H), 3,79 (t, 6 Hz 2H), 715 (d, J = 9 Hz, 2H) 7,48 (d J 9 Hz, 2H). 7,67 (q, J 9 Hz 4H). MS (DCl-NHj) mz 281 (WNH4 Example 291 -841- Methanesunc acid2, 1 2 methyl ester The acoho~l ntermediate from Example 29H (0 31 g 8 118 mmo) was converted to the mesylte intermediate by the method of Example 26H to provide the hdle compound H (300 MHz, CDG): 6 0,89-096 (I 1H), 1 0008 m I 1H) 1 131, 24 (m, 1H): 1 .76-1.93 (m 3H), 2.98 (s, 3H), 436 (t J 6 Hz, 2H), 716 (d. J9 Hz 2H),7,49 (d; J 9 Hz, 2H) 7 68 ( J = 9 Hz, 4H), MS (DOVNH 3 ) mNz 359 (M+NH,)t 4 R 2MethroLn ethvciopyj1$bpheny-4 carbongtne The mesylate intermediate from Example 291 (0 37 g, 1,08 mmol) was converted to the final product by the method of Example 261, The tile compound was obtained after column chromatography (95 5:trace dichioromethanelnethanoiammornum hydroxide). The title compound was diesoived in methanol. To this stirred solution was added a section of one equivalent of L:artric acid in methanol, After stirring for 15 minutes, the solution was concentrated to haf volume and treated with ethyi ether to induce crystaiization of the title compound as the mono L-tartaric ackd sat 1 H NMR (300 MHz. CD30), L-tartaric acid salt): 6 0 93<110 (i, 2H, 1 13-1 24 (n, 1). 1.44 (, J = 5 Hz; 3H), 1.71-1.85 2H),1;S5~199 (inm 2H 202-2 15 (m, 2H) 225-2.49 (iM 1H), 3,06u 3 19 (m, 2H) 3 41-356 (m 2H) 359-372 (im, 1H) 439 (s, 2H), 7,21 (d = 9 Hz, 2H), 7.58 d. J =9 Hz, 2H), 7.77 is 4H). MS (D H) m/z 331 (M+H E xam ole 30 4 -013. 2RW2 {-R2Mtyproii-7 tyccorpk ihnl Exampol A Sr rrn .arbajd shvd e A solution of the early-eluting S, S-diastereomer ([(1 S,2S)-2-(4 bronophenv)cyclopropy{1 6R7 ,104meth3 -oxo-3tthia-4 azatricyclo[5 2..03dec-4-y)}methanone) described n Example 29D in dichloromethane was stirred under a dry nitrogen atmosphere at -78 C. A 1 Mut solution of -82d aumn hydrid n dihrthne was added dropwise to the mixture, When he addition was complete, the mixture was stirred atS 78"C for 3 hours Meh anol was then added dropwise at -78 C. The dry ice bath was then replaced with an ice water bath and saturated aqueous ammonimm chloride was added to quench the mixture. After 10 mInutes. the inso;ube material was removed by filtration and the organic layer was separated dried (Mg SO) and filtered, The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (9.1 hexaneiethy acetate). Fractions containing product were combined and concentrated under reduced pressure to provide the title compound. Example 3B 1-Brorno-41iS;2R2-vin vcyclopro1-lbenzene Te product from Example 30A vas subject to the conditons outlined in in Example 26E. followed by chromatography (100% hexane) to provide the title e compound. Exa2m2leamie 36E.C The Product from Example 30B was subjected to the conditions outbined in Example 26Fofollowed by chromatography (7:3 hexane/ethy acetate) to provide the tie compound. E xampilD0 Methhic::i idvxyinas9m:M jhenwl4-crboith The product from Example 30C was subjected to the conditions outline in Example 26G, followed by chromatography (7:3 hexanelethy acetate) to provide the title compound. E "xample 30E Metansifoiaig d 2 + 2,5 tL :2§ygrogbigohn4-cdooyrogvylethyl ester The product from Example 30D was subjected to the conditions outlined in Example 26H to provide the title compound Example 3F~ 441,2R 24 #2) 2metylprroidi-1 ilehy~yclproy0-1j,'bUphen4 The product from Example 30E (methanesulfonic acid, 2[(1 R,2S)-2(4-cyano 8-to biphenyl4-yrcyciopropy-ethyf ester) 0,40 g 1.17 mmo) ws further converted to 4 ((1,2P)~2-{2 2R) -2 methylpyrrodin- I yflethyI)cyclopropyl>,i ,i-phenyl-4mcarbonitrie through the the procedure described in Example 29J. Column chromatography (9&4:trace dichlororethanernethanoammonium hydroxide) provided the title cornound. The title compound was dissolved in ethyl ether and anhydrrous HCi gas was butled nto the solution to provide the hydrochoride salt of the title compound that was crystaibzed from methanollethyl ether H NMR (300 MHz, 00OD hydrochloride salt) 6 0,95-12 (m 2H). 1,14-1.24 (m 1H, 1.45 (d1 J = 5 Hz 3H 66-. 81 (m1H) 1.814 93 (m 3H) 2.00 2217 (m 2H). 2.27241 (m, 1H) 3.073.26 (m 2H) 3,4 -3.56 (m, 2H), 3 64-37 5 Cm, 1H) 7.21 (d, J 9Hz 2 7H),58 (7,5 d: = 9 Hz: 2H) 7.7? (, 4H MS (DC0 NH) m,'"z 33'1 (M+H) 4 Example 31 Mitrns>429rroiidintletHylcyclopropvi ihenyidarbo__tle Example 31A A stirred, 0 "C solution of homoproparyi alcohol (10g. 0.14 mci) and tert butyidimethyisily chloride (21.5 g 0.14 mol) in dichoromethane (50 mL) was treated with triethylamine (22.8 mL, 0-168 mo). The mixture was then stirred overnight at room temperature. The mixture was washed with water and the organic layer was dried (MgS'4 and filtered. The tNtrate was concentrated under reduced pressure and the residue was purified by chromatography (95:5 hexaneethyl acetate) to provide the tile compound. 'H NMR 300 MHz, C001) 6 0.08 (s, H), 0.90 (s 9H) 1.9 6 (t = 3 Hz, 1H 2.41 (d J = 6 Hz, J 3Hz, 2H), 3 75 (d J =6 H., 21) E example 31B Te __buvdmem 4-tibuvisannnvut_-enyoxsiiane A solution of Example 31A (1.08 g, 5.87 mmol), trnnuty!tin hydride (1,43 mL 5,31 mmol), and AIBN (Cat) )n benzene 10 mL) was stirred at 80 KC for 3 hours. Volaties were removed under reduced pressure to provide the title compound As a colorless oil (>95% E-isomer). H NMR (300 MHz, CDCl): 6 0 05 (s3 H), 0 80 -098 (in 15H), 0.90 9 , 1 23-1 38 ( ) 1.42-1.53 (In, 6H) 2 34-240 (m, 2H), 3,66 (d, J -84- Hz. 2H) C\45 8(m 2H) "rjeltbEtampje 314 A solution of Example 311 (4 0.4 mmi) 4 cyanobipheny trifIate (3 1 g: 9,48 mmol prepared from 4Thydroxybheny4-carbonitrie by standard methods) and Pd(P2h~ 0 ~332 g. 0.47 mmoh in rMF (20 m was stirred at 80 C overnight The mixture was cooled to room temperature and parvtiioned between ethyl acetate and water. The organic layer was dried (MgSO) and filtered The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (97.52 hexane/eth acetate) to provide the title compound. 1 H NR (300 MOHz CDC): 0.07 (s. H)1 .91 (s, 9H)2.48 (q J 6 Hz, 2H), 3,75 (', J = Hz, 2H) 632 (d, J 16 Hz, 1H),4 6 (dJ = 16 Hz, i 1) 7.4 (d J = 9 Hz, 2H), 7.54 (d: J 9 Hz, 2H) 7.65474 (m. 4H. MS (D0NHz) mfz 364 (M±H)t mz 35'9 (M+NHj)r Trnf 4ietpdjehislniX tviylp oovjlhen viA4carbonitri Ie fracemfic) The cyclopropanation reaction was conducted according to the rnocedure in Tetrahedron Letters 1998 393 8621-8624. A stirred solulior, of diethyl zinc (1 M in hexane, 4 41 mL 4.1 mmol) i dichloromethane (10 mL) was chiled to 0 .C. A solution of trifluoroacetic acid (0,32 mL, 4.1 mmol in dichiromethane (2 mL) was added dropwise to the coid mixture. Stirring at 0 c was continued for 20 minutes andthen a solution of diiodomethane (0.4 mL, 4.9 mmol) in dichlrnmethane (2 mL was added dropwise to the cold mixture. After 20 minutes, a solution of Example 310 (06 g, 65 mmfl) in dichioromethane (5 mL) was added to the rnixture and the ice bath was removed. The mixture was irred at romi temperature for 3 hous. diluted with 0.1 N aqueous HC and extracted vith hexane. The crude product was purified by preparaive thin layer chromatography (97:3 hexaneiethyl acetate) to provide the title compound. H NMR (300 MHz, CDC1 6 0.04 (s, 3H), 0.05 (s, 3H) 0.84-0.97 (m 2H) 0.89 ( 3H) L,56-1 75 (m, 3H) 3,74 (t, J 6Hz. 2H), 714 (, J = 9 Hz, 2, 7.48 (d, J 9 Hz,2H) 7.65 (dJ 9 Hz 2H) 7.71 (d, J = 9 Hz, 2H). MS (DC NH,) m/z 378 (M- H)t z 359 (M+NH4)W -85- A I M solution of tetrabutylamrnoniun fluoride in THF (31 mL, 3.1 mnoi) was added to a stirred room temperature solution of Example 31D (0:585 g, 1 55 mmol) in THF (5 mL), The mixture was stirred for 2 hours, parttioned between ethyl acetate and water. The organic layer vas dried (MgSO4) and filtered, The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (65:35 hexane/ethyl acetate) to provide the tife compound. 1 NMR (300 MHz! CDC): 5 0.87 0 97 (m; 1H) 0.97-1.05 (mI 1H), 112-121 (m, IH). 164-179 (m, 2H), 3.76-3,84 (m, 2H 7.15 (d. J =9 Hz 2) 7.48 (d J = 9 Hz, 2H4> 7.68 (q J = 9 Hz, 4H) MS (DCVNH 3 ) m/z 2i (M+Hie. Methanesuoon acid trans-2 4-vnobiphen4ycycorop et'"ester Triethylamine (0. 18 i 1.29 mmol) was added to a stirred: room temperature solution of Example 31E (0.24g, 0.91 mmol) and nethanesulfonychlnde (0092 mL, 1 19 mmol) in dichloromethane (10 mL) After stirring for 30 minutes the mixture was washed with water The organic layer was dried (MgSO.). and filtered. The filtrate was concentrated under reduced pressure to provide the crude title compound. H NMR (300 MHz. CDC,): 6 0 89-0 96 (m. 1H); 1.01-1:08 (m; 1H), 1.13-1 23 (im IH), 1.76-1 83 (m, 1H), 1.83-193 (in, 2H), 2.99 (s. 3H) 435 t, J = 6 Hz., 2,) 7,16 (d, J = 9 Hz 2H); 749 (d, J = 9 Hz. 2H]), 7.68 (qo J 9 Hz 4H) MS (DCI-NH) m/z 359 'M+NH,)+ Exanle 310 4 trans 22yroldnYthllyLoQropyLK . biphe l.4-cabonitie A solution of Example 31F (0054 g, 0:158 nmol) in pyrrolidine (5 mL) was stirred at reflux overnight. Volatiies were removed under reduced pressure, and the residue was purified by column chromatography (95:5 dichloromethanemethanoi) topoide the title compound. H NMR (300 MHz CDC): 5 0.84-1.91 (m: I H), 0.92-1.0 (mn. 1H), 1 05 116 m, 1H) 15-1 9 (m 8H) .2 48-2.75 (m, 5H) 714 (d J 9 Hz 2H), 7,48-(d, J= 9 Hz, 2H) 765 (q J -9 Hz, 4H). MS (DC-NH-) m/z 317 (M+H)V Example -86- N{4(1iS 2.2methvVoojdin-1 vilmethyljcyclopropylbphenvl5 trifluopromneth.''Y thin i3'2 b pyridine carboxamide E:xarmpe 32A 481,2 24?-((S 3 '2-methyipvr rolidi n4 1-vimethvi)yclorocyflaniline A solution of the product from Example ID (1.72 g, 5,85 mroiL lithium bis(trimethyisiyamide (1 5i g, 878 mmol) Pd2(dba) (268 mg. 029 mmi) and tri t butylphosphine (1.42 g, 10% ir hexane. 0 702 mrnol in anhydrous tolene 0 mL) was heated to 120 "G in a sealed tube for 16 hours. The mixture was cooled to ambient temperature. treated with HC1 (1 M) and extracted with ethyl acetate (2 x 75 mL.). The organic layers were combined, washed with H)O and brine, and dried with magnesium sulfate. After filtration, the organic laer was concentrated under reduced pressure and the resulting oil was buried onsilica gel with 1% to 3% methan(containing 10 % concentrated NH..OH) in dichloromethane to provide the titie compound. 'H N MR (300 MHz. CDsOD) t5 0.70-076 (m, 1H), Q82088 (m,, IH). 1 13 (d.=6 Hz, 3H). 1,03-11 m iH), 1 35-1 48 (n, 1H) 1-60 -1.66 (m. i). 1 694 87 (m 3H), 1,922,04 (m 1H), 227(dd, J=12 Hz, J=9Hz 1 H), 2-32240 (m 1H 3 12 (rdd Jr 12 Hz, J3 Hz 1H) 3. 23-3. 29 (m, 1H), 6.64 (d, J9 Hz, 2H): 6,84 (d, J=9 Hz, 2H). MS (DOL-NHs) mtz 231 (M4H) _Emple 32B Nd4 (1S 28) 2At23L 2 meth virrlidin 1 y rmethvjtygpopylpenyjIb5 (trifluoromethylithienc(j3,2-bip ridinn43-zarboxanide A soutdon of the product from Example 32A (50 ig, 0,22 rmol), 5 (tril u oornethyl)thieno3,2-b.pyridine-6-carboxvc acid ( 10 mg, 0A 4 mmoi) and N-(3 dimnhylaminopropy-ethyicarbodiimide hydrochloide (55 mg, 0.28 mmo ) in DCM (10 mL) was treated with triethylairie (0.061 m,, 044 mmol), and stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified on sica ge with 1% to 3% methanol (containing 10 % concentrated NHf0H) in dichlorornethar e to provide the title compound. "H NMR (300 MHz, C03D) 5 0.86-1.92 (n, 1H 0.99-1. 05 (m H) 1.17 (d J=6 Hz, 3H) 1.20-1.29 (m, 1H), 142-1 .52 (m, IH). 1.73-1.83 (m, 3H), 1.94-2.08 (m 2H) 2,32-2,51 (m, 2H) 3.17 (dd. J=12 Hz, J=3 H; 1H). 3.26-3.30 (m 1H), 7.10 (d. J=9 Hz, 1H), .555 ( 9 Hz 2H). 7.70 (d J6 Hz. 2H) 8 30 (d, J =6Hz, 1H), 874 (a, i H) MS (DCNH) m/z 460 (M+H). Example 33 -87 it(J__ S__{___-mehypyrondn_ vrmtyccoropyvlVpensonicatnamide A solution of the pruct om Exarnpe 32A (50 mg, 0.22 mmol) isonicotinovi chloride hydochiorde (62 m, 0.31 mmoi), and 4-0diethtminopyrdine (5 mg,0 04 mmoL in DCM (10 mL) was treated with tnethylamine (0.12 mL. 0.86 mmo) and stirred at ambient temperature itr 16 hours The mixture was concentrated under reduced pressure and the residue was purified on silica gel with 1% to 3% nethano containing 10 % concentrated NH 4 0H) in dichloromethane to provide the title compound H NMR (300 M ZCD D 104-,10 (m, 1H) 1S1-1 23 (mr 1H, 39 (d. J6 Hz, 3H), 137-442 (im: IH), 1 66-177 (m, IH), 2 01 08 (n, 3H) 2 25-2.36 (m, 1 H)r 294 (dd, J 6 Hz. J3 Hz, 1H), 3 153.21 (m, 1H) 3.40 (dd J=6 Hz, j=3 Hz, 1H: 3.61-3.70 (m, 1H) 716 (d J=9 Hz. 1H), 7.63 (d; J=9 Hz, 2H) 7,86 (d J=6 Hz. 2H), 3 (d, J=3 Hz, I H), 8.03 (m, 1H). MS (DC LNH;) n/z 336 (M+H)* ExampIle 34 21 4- 1"S 2 S) 2 ethylpyrridin~1vlm t opropy p nlpyid one Exarnpie34A t }4oiOhrWl o 2--I ,-cl ,T .oiinDM 30' To a solution of (E)-ethy 3-(4-brorrophenyjacrylate (25 g, 96 mmoi) in DOM (300 mt under nitrogen and cooled to -78 *C was added dro pwise DBAL-H (240 ml, IM in DCM, 240 mmol) in about 20 minutes, The mixture was stirred at -78 0O for 2 hours. Then, the dry ice bath was removed. The reaction was diluted with DOM (500 mL), quenched vith HCi (IN), and partitioned The combined organic phases were washed with H 20, dried and concentrated under reduced pressure to provide the title compound. iH NMR (300 MHZ CDt).5 1.43 (t J =6 Hz, IH) 4.32 (. J = 4.5 Hz, 2H),6.37 (dt J= 16.5 Hz, J = 6 Hz. IH). 6 57 (d,3 =J5Hz IH) 7.25 (d, J 9 Hz, 2H) 745 (d J = 9 Hz. 2H). MS N m/z 214 (M+H)* 2u 3,-oer348 a To a solution of 2,2.azanedyidiethanol (26.12 g, 24$ mmcl) in DOM (250 ml) and ether (500 mL) vwas added nbutyiboronic acd (25,4 g, 242 mmol) and molecular aieves (SA, 4-6 mesh 65 g). It was stirred at ambient temperature for 2 hours. The mixture was filtered, and the fitrate was concentrated under reduced pressure. The resulting white solid was recrystallized with DCM/ether to provide white crystals as the title product, NMR (300 MHz. CDCL). 0 47 t J = 9 Hz, 2H, 0.88 (t, J = 6 Hz, 3H), i.20-1.37 (in, 4H), 282 (br, 2 ,24 (br 2H), 39 (br, 4H), 4.27 (br, 11H, MS (DClNH) m/ 172 (M +H) Emple 34 4R5R2-butyL-NNN5 tetrametyl4 i dcoxa1b4nie A sottion of the product from Example 34B (31.3 g, 183 mmol) and (2R,3R)-2,3 dihydroxy"N1 N1 N4 N4itetramethysuccinamnide (31 g, 149 mml) in DCM (600 nL) was treated with brine (1 20 mLI) and stirred at ambient temperature for 30 nmnutes. The organic layer was separate, and the aqueous layer was extracted with additional DCM, The organic ayrwere combined and washed with brine(700 mL), dried with MgSO, and concentrated under reduced pressure to provide the title product. NMR (300 MHz, CDC,) 5 O183- 90 (rn 6H), 1 26-1.42 (m, 5H) 2,98 (6H), 3:20 (s,6H) MS (DCNH) m/;z 205 (M+H) (13,2 S)12 4-Bromophenlicvcopropylmethanol A solution of DME (24 39 ml 235 mmol in DM (700 under nitrogen atmosphere was cooled to -10 eand diethylzino (235 mL 1M In hexane, 235 mmol) was added over 5-10 minutes followed by diodomethane (37.9 mL, 469 mmc), The product from Exarn-ie 34C (33.f g 122 mmcl) in 100 mL DCM was added in 5-10 mirntes The temperature was maintained from -5* to -10" C throughout the additons. The product from Example 34A, (E)13-(4-bromophenylprop2-en-1ol (20 g. 94 mmol) in DCM (150 nL) was added dropwise, and the reaction rmixture was stirred at ambient temperature for 16 hours, t was quenched with saturated aqueous NH 4 CI (300 mLt HCI (1 N, 480 mL) and dilted with ether (900 mL). The organic layer was separated. The aqueous layer was extracted with additional ether The organic avers were combined and treated with NaOH (2N 880 rm). To the solution, H (30% 136 niL) was added dropwise while the reaction was cooled with an ice bath. The solution was stirred for 5-10 minutes The organic layer was separated, washed with Had (1 N). saturated aqueous 89- Na 2

S

2 0 saturated aqueous NaHCO 3 . and brine, dried and concentrated. The residue was chromatsoraphed nlica gel ekuting with 5-5% EtDAc/Hexane to provide the title compound. 'H NMR (300 MHz CDC)4. 60.92-10 (r 2H), 1.45-148 (m 2H), 1,76 1.85 (m, 1), 3.61 (d, J 75 Hz, 2H), 695 (d J Hz, 2H): 737 (d, J = 9 Hz, 2H) MS (DCINH) miz 228 (M+H). (ee 94%), Exanmnle 343 ( S.28V g4pr h gea eorbaldehyde To a solution of oxay! chIoride (17,50 iL, 2 M in DCM, 35 0 mmoJ) in DCM (150 mL) under itrogen atmosphere and coed I 8 0C was added dro wise DMSO (4,97 mL. 70 0 mmnol), foowed with the dropwise addition of a solution of the product from Example 34D, ((1.2S15(4roopheny5cydopropy)methanP (5,3 g, 23,34 mmol) in DOM (100 r) The mixture was stirred 30 innutes at -78 OC. Then the mixture was treated with trethylamiine (13.01 mL 93 mmol), and then the reaction temperature was raised to ambient teiperature, The mixture was partitioned between DCM (400 mL) and H 4 0 0 rganic layer was separated, washed wth water. dried and concentrated under reduced pressure to provide the title product H NMR (300 MHz, CDCI ) 1 48 (, tn H), 1 65 (dt, J 9 Hz, J = 6 Hz H), 2.15 (m, 1H) 2.57 (m 1H), G.98 (d, J 9 Hz, 2H), 7 45 (dJ = 9 Hz, 2H, 9A6 (d, j= 4.5 Hz; 1H), MS (DCilNH) m/z 226 (M+Hf Examole 34F 14(1S,2S)j2n44bromophenylhyclopopy-ethv}2S2-methyl.yrrolidine A solution of the product from Example 34E 18 2S)2- (4 bromnophenyi)cyclopropanecarbaldehyde (5.7g 25.3 mmoi) in DCM (20 mI) and MeOH (300 mL) was treated with (S)>2-methyVrroidine tar rate (8 94 g, 38.0 mmo)at ambient temperature, and the mixture was stirred for 5-10 minutes. Then, the mixture was cooled tos0 " and a sation of NaCNBH 2,51 g, 38.0 mmoi) in MeOH (50 mL) was added dropwise. After addition the reaction mixture was raised to room temperature and strred overnight. The reaction rnixture was treated with NaOH (1N) till basic, extracted with DCM thrice (500 mL x 3), dried and concentrated under reduced pressure. The crude product was leaded onto a silica gei column and eluted with 1% to 3% methanol (containing 10% concentrated NHOH) in dichoromethane to provide the title product. H' NMR (300 Mzt CDC1), 0 87-092(m,1 097-1 02 (n, 1H), 1.16 (d J= Hz. 2H): 1,22 (I, 1H) 1.39-1 49(m' Ki), 1 73- 81(m. 3H 20 (m., 2H): 2.36(i J=6 Hz, IH), -90- 2,45 (n, 1H), 3.13 (dd, J=12 Hz. =6 Hz, 1H), 3.25 (m, 1H) 7,00 (d J=8 Hz, 2H), 7.37 (d. J=6 Hz, 2H) MS (DC[NH 3 ) m/z 294 (MtH. Eampk 34( 2 41}$% ) ethlrldn-1mtv~ccorplyhrdazirH3(2H> one A solution of the product from Example 34F 1-{[(1 S2S)2-(4 br(100 mg, 0.340 mmot pyridazin-3(2H)-one (52.3 mcg, 0.544 mnmo),N1,N2 dimethylemane-1 2-diamine (0:088 nL. 0.816 mmo) and copper(l) odide (78 mg, 0.40 mmol) in pyridine (2 rnL) under a nitrogen atmosphere in a sealed vial was heated in an o bath to 135 *>C for 16 hours The reactionr mixture was coled and diluted with DCM (10mL), filtered through d atomaceous earth and washed with DCM. The fitrate was washed sequentiaiy with H 28-30% NH 4 0H (10 mL x 2, and H-cit dried with MgSO .and concentrated under reduced pressure The residue was chromatographed on stca gel eiuting with concentrated concentrated NHOH/MeOH!DCM (0.4/96) to provide the title compound H NMR (300 MHz, CDOD) 3 0.90-09W (H, -( 1.03 1H09 (in, i 1 1 15 (d j=6 Hz, 3H) 123-133 m, H) 39149 (rm 1H), 170-1 80 (rn. 2H), 132 -2.05 (m 3H) 2.26 2.42 (m 2H) 3. 16 (dd, J=12 Hz J= H., H, 3.21-3.2 (n 1H) 7,07 (d, J=6 Hz, 2H) 7,21 (dd, J= Hz, J= 1,5 Hz, 2H). 7.43 (d, J=% Hz, 2H): 7.47 (dd J=9 Hz, =3 Hz, 1H), 8 02 (dd J, Hz, J=1 5 Hz, 1H), MS (DCINH,) m/z 310 (M+H)* 2d [41 S 2S 2(22-Meth ylpyrroljdin-1-yirneth y cycroy e ]ordazn-3(2H A solution of the product from Exampie 34G ( 3.25 g, 10.5 mmol) mn ethanol (20 ml) was treated with L-artaric acid (1 577 g, 10.5 mmci) and stirred at ambient temperature for i hour. The mixture was concentrated under reduced pressure, and the resulting solid was recrystalkzed from isopropyl alcohol/acetone to provide the titled cormpound as the L4artrate. H NMR (300 MHz, CDOD) 5 1,12-i.19 (n, 1H1. 1.23-1-30 (imh: 1H). 1.43 (d, J6 Hz, 3H), 1 47-1 56 (in 1H), 1. 2-1.81 (m 1 H), 2.02-2.19 (m, 3H), 2 28 -2.39 (m, 1H) 3.043 11 (m, 1 H), 3.43-355 (Im 2H)3 .64-3 75 (n. 1H)1 4. 38 (s, 2H) 7.03 (ddJ J6 Hz, J=2 Hz, 1H), 7.28 (d =6 Hz, 2H), 7.44 -7 50 (Im, 3H), 8.03 (m. 1K), MS (QD-NH) maz 310 (M+H)+ Anal. Calcd, For C23H29N307: C, 012: .36; N, 9.14. Found: 60.07; 5.76;N ,8,82, -91 - Exampe 354 onIe R~j(S S24brmnenin lorcuethiyy2-inethylpv ncgdne The tte compound was prepared using the procedure described in Example 34F suosttuting (R)-2nethylpyrroldire tartrate for (S);2-methylpyrroidine trtrate. 'H NMR (300 MHz, CDCk) 60 88-094(m 1H) 0,9541.02 (IN, 1H) 1.12 (d, J6 Hz 2H). 1,19 1.29 (, 1H) 1.37-49(m, 1H) 171 -1.81(m, 3H), 1.93205 ( 1 H) 2. 12 (dd, J=12 Hz, J=6 Hz, 1H, 2.29 (q, J=6 Hz 1H), 2362.45 (n, 1H), 2 93 (dd, J=12 Hz,=6 Hz, 1H) 3.25 (mI 1H), 7.00 (d J=6 Hz, 2W. 7.37(d J=6 Hz., 2H) MS (D CVNH) m/z 294 (M + H)t 2 2 2 2 tyvrln1-yjimethyfcycioo opylphenylpvridaziri3(2H one The title compourd was prepared using the procedure described in Example 34G substitubng the product from Example 35A for the product from Example 34F, 1 1p2S)244 yrrodire H NMR (300 MHz. CD-,OD) 6 0.94-0.98 (m, 1H), 1.05-1,09 (m. 1H" 113 (d, J3 Hz, 3H) 1,30-1 36 (m, IH), 14-1,48 (m, 1H), 172-181 (rn, 2H), 1 6,4 -1.188 (m, 1 H), 2.16 (dd, J=-6 Hiz, J=3 1Hz, IH), 2,31 (q, J=6 Hz 1H) 2.41-2.45 (m, 1H)2,942,98 (q, J-3 Hz, 1H) 325-3,29 (, 1H), 707 (d, J=6 Hz 2H) 7,21 (d, J=6 Hz, 2H): 7.41 (d J=6 Hz, 2H), 746 (dd, J6 Hz, J=3 Hz 1H) 8,02 ,03 (m, 1H), MS (DCKNH 3 ) mmz 310 (M+H)* :41 2SN22R)-2 .methvipvrroiirymethycvr1ropyh lpiperidin-2-one The title compound was prepared using the procedure decribed in E xample 34G substutirg pieridin-2-one for Pyridazin-3(2H) one0 and substituting the product from Example 35A for the product from Example 34F 'H NMR (300 MHz, CD 3 OD) 8 1 08 1.21 (m, 2H). 1 39 (d, J6 Hz, 3H), 1431.48 (m, 1H): 1.68 -1.78 (n. 1H), 1.92-1 96 rn. 3), 2.01-2 08 (m, 3H): 223-2,35 (Km 1H) 250 (t, J=6 Hz, 2H), 3.03 (dd. j=12 Hz, J=6 HzIH), 3.13-3.22Km 1H) 3.32-3.36 (n, 1H), 3,39-3,47 (n, 1H)7 358-3.67(m 3H), 717 -92- (d. J3 Hz, 4H), MS (DC-NH) m/z 313 (M+H)V (4(1 824R'-mtv ridirn1 -V methylcymopropy!) ohenylapanfrov The title compound was prepared using the p described in Example 35B substiuting azepan2-one for pyridzin-3(2H);one and subsitufing the product fram Example 35.A fr the product from Example 34F. H NMR (300 MHt, CDJOD) 6 1.02 108 (m; 1) 1.13419 n 1H) 1 36 (d J=6 Hz, 3H) 1.35-138 (m, ,H), 164-1 71 (m f H) 1.84 (broad, EHI 1.97-2.05m, 3H, 2.21-232 (rt 1H), 2,67-2.71 (n., 2782 85 (m, 1H), 30523.15 (,n 1H), 3.23-3.28 r 1 H). 3. 35-3.41 (m, IH) 3,54-3 ,63 (m, 1H) 3.75-3.78 (In. 1H 7. 13 (d. 3 Hz 4H). MS (DCl-NH 3 ) mMz 327 (M+H). -4 2 k $) i:Lf2DE2-methytpyrrlin 1v2mtycyclproavhermwrapyrrdirone The le compound was prepared using the procedure described in Exampie 35B substitng pyrreidcin-2one far pyridazin3(2He and sulbsdtiing the product from Example 35A for the product from Example 34F. 'H NMR (300 MHz C D, OD) 0-9 0. 96 ( 1H) 1 01-1 .08 (m, 1) 1.22 (d, J=6 Hz 3H) 1 214 3 (m, 1 K) 4- 1.55 ,( 1H), 1.8 1 839 (, 4W. 2.03-2.27 (m, 4H, 2-57 (t, J=6 Hz, 2H), 2.t5-2.74 (m 1H <32 (q, J=6 Hz 1H), 3,33-3,40 (n, 1H). 3.89 (t J=6 Hz, 2H 7.10 (d, J=9 Hz 2H) 7.46 (d, J=9 Hz, 2H) MS (DCI NH.) m/z 299 (M+HJ. Exam-le 39 1f4(18,252t(2Ri2'rethyly 'raliin. 1-vlmcthv cyopr o.vlhenrflazetidin-2-one The title compound was prepared ui the procedure descrbed in Example .35 substituting azetidin-22-ne for pyndazir-3(2H)-one and substituting the product from Example 35A for the product from Exampk 34F. NMR (300 MHz, COD) u.98 1.04 (m 1H), 1 08-4 15 (m H 1 34 (d J= Hz 3H), 1 35 (m H), 1 .591.72 (m 1H) 1 94 -2.04 (rr 3H) 2 182.29 (m, 1H) 2.75 J=6 Hz, 1H), 2,983,07 in (m ) H', 3 08 it J6 Hz, 2H), 3,16,26 (na, 1H), 3.2- 336 (m. 1H) 3.52-362 (m 1K) 3.65 (t J=6 Hz, 2H), 7,11 (d J9 Hz, 2H), 7,30 (d, J=9 Hz, 2H). MS (DCikNH 3 ) m/z 299 M+Hyt Ezxamale 40 14U 1S92S2(2Sj2-methyayrroinire1 viymethy!ycxopropyi ph enyflazetidtn e -93-.

The title comnpoundvwas prepared using the procedure described in Example 34G substituting azetidin-2-one for pyr:dazi-3(2H)one H NMR (300 MHz; CD)OD) 6 0,97~ 1 031( 1H) 108-1 14 (m 1H), 133 (d J=6 H3). 1 35 (m, 1'H 1.60 1 68 (m 1H), 1. 94-2.04 m, 3H 2 17-2.29 (m, H) 2 71 (q J=6 Hz; 1H) 2.9653.03 (m, 1H), 3 .08 (t J=6 Hz, 2H), 313-3 22 (m -) 3 51459 (n, 1H), 3 6 (t, J6 Hz, 2 ). 7. (d J= Hz 2H). 730 (d, =9 Hz 2H) MS (DCl-NH) m/z 285 (MjH) H *44-1U;S 32(22S)2-methviyrrouin1-l 2etviov oprop§LShAnXazSa++' mrg The title compound was prepared using the procedure described in Example 34G substituting azepan-2-one for pyridazin(2H)-one, H NMR (300 MHz, OrtoD) S 0.98 1.05 (mI 1H) 1 09116 ( rH)I t ( J HzJ 9 3K) 1.36-1,39 (im, 1H), 1.59-1.69 (m, 1H), 1 83 (broad, 6H), 1 94-2 0 (m 3H) 2,6-2.27 (n, 1H), 2.61-2.71 (m, 2H 2,90-2,98 (m, 1H), 307-3,14 (m, 1K) 3.32-2.37 (m, H), 348-3 58 (m, 1K 375-378 (im 1H) 7.13 (d, J=3 Hz, 4H). MS (DC-NH) mz 327 (M4H3 i-1.2S2>-2%2 2:{ methrylpyrfofjdin-1 li ethyv <loproppherylpperinn2-or The title compound was prepared using the procedure described in Example 34G substituting piperidin--2-cne for pyridazin-3(2H)-one. H NMR (300 MHz, COD0D) A 0,97 1 03 (m, 1H. 1.08-1 15 (m1, 1 1.30 (d J6 H z 3H) 1,31-1.38 (im, 1H): 1 56 -163 (m, 1H): 1,92-1.99 (rn 3H), 2,14-2,24 (m 3H), 2.49 (t 6 Hz, 2H), 2.52-2,59 (m, 1H), 2:31 2 90 (mi),2 96-3 04 (m 1H) 3.44-3.54 (m, 1H) 3.61-3.65 (2m), 7.17 (d L J=3 Hz, 4-) MS (DO NH mz 313 (M+Hj. Example 43 1L.4d(t1822512S22-meth'jybyrpro&Ldnerirnjty vdpovlhnlproii rn The title compound was prepared using the procedure described in Example 34G substitutin pyrrolidin-2-one for pyridazin-3(2H)-one, 'H NMR (300 MHz CDOD) t; 0.99 (5(, 1H). 1.10-1 16 (in 1H), 1,34 (d, J6 Hz, 3H) 135-140 (I 1H), 1 59 -1. 71 (n 1H), 1 95-2,04 (i. 3H), 2,1 2-2,27 (m 3H) 258 (t J-6 Hz. 2H) 2.67-2.76 (in, 1H), 302 (. J=6 Hz, 1H) 315-3.22 (mn 1H), 331-3.37 m, 1H). 3,51-359 m 1H): 389 (t, J 6 Hz 2H), 713 (d, J=9 Hz% 2H), 7.49 (: J=9 Hz, 2H). MS (DO[NHn m/z 299 (M.H) -94- Example 44 1MS {2n lmethylc c propyphenyllactaide The title compound was prepared using the procedure deserbed in Example 34G substituting acetamide for pyridazmn3(2H)nne H NMR (300 MHz, CD0D) 6 0.98-1.04 (In, 110-116 (m, 1H) 1. 36 (d, J=6 Hz, 3H) 1,29-1.40 (m, 1H) 1 61 -1.74 im, 1H), 1 94-2,06 (m, 3H) 2 0(s, 3H) 2.20-2.32 (n, H), 2.77-2,84 (ni, I H), 304-3.14 (m. 1H) 3,2143.27 (m, 1H), 33-339 'm, IdH. 3.55-3,63 (rn IH), 7.06 (d, J=9 Hz 2H. 7.44 (d J=9 Hz, 2H). MS (DOIWH 3 ) m/z 273 (MH. vi-hIyloopS),hen- yrr-d idon-e The tWe compound was prepared using the procedure described in Example 34G substitting (S)-3-hydroxypyrroidin.2-one (CAS# 34368-52-)) for pyridazin-3(2H-one 1H NMR (300 MHz, CHLOROFOR1-D) d ppm 08G0 88 (m, I H) 0.9- 0 96 (m 1 H) 1 11 (t 3 H) 11 - 1,31 (m 1 H) 1 5 1 50 (m 1 H) 1 -173 ('m. 3 H) 1 8.3 - 1 .9 ( 2 H) 2,031-2 18 2 H) 2 19- 231 (m 1 H) 2.53 - 2.66 (rn 1 H) 3.00 - 3.14 i(rn 2 H) 3.25 (dd, I Hi) 3.76 (dd, 2 H) 4.45 (dd I H) 7,06 (d, 2 H) 7.51 I'd, 2 H) MS (DCi-NH) m/z 315 (M+rHJ. Example 46 one 2S.3S)2,3-dhydroxv-succinik acAd A solution of the moduc fromthe Example 34G. 2-(4-((1,2S)-2-(((S) 2 methylpyrroiidin- 1-yl)meth)ycyclopropyl phenyi)pyridazir-3(2H)-one (615 mng 0.5 0 in methan-l (10 mL) was treated with Dtartani acid (350 mg) and stirred at ambient temperature for 30 minutes. The mixture was concentrated under the reduced pressure and the residue was crystaizedin 2-propanollacetone to provide the title produCt as white crystalline solid. MRP 145-1471 "G. Ana Gala, for C 3 HNC-Hs ,: C, 60.12: H, 6 36: N, 9 14. Found: 5 9 94; H, i57 N, 9.17. Determination of BiolooicaiActviy To determine the effectiveness of representative compounds of this invention as 9'S histamir3 receptor ligands (Hreceptor ligands), the fcHowing tests were conducted according tor methods previously described (European Joumal of Pharmacology, 188219-227 (1990) Journal of Pharmacology and Experimentai Therapeutics, 275:598 ) 60411995); Journal of Pharmacology and Experimental Therapeutics 276:1009-1015 (1996). and Biochemical Pharmacoiogyl 22:3099-3108 (1973)) Briefly, maie Sprague-Dawley rat brain cortices were homogezed tissue10 ML buffern 50 mM Tris~Hil5 rM EDTA containing protease inhibitor cocktail (Calbiochem) using a polytron set at 20,500 rpm. Homogenates were centrifuged for 20 minutes at 40,000<g The supernatant w'as decanted. and pelets were weighed. The pelet was resuspended by polytron homogenization in 40 rL 50 mM Tri<-HCU5 mM EDTA with protease inhibitors and centrifuged for 20 minutes at 40.000xg. The membrane pelet was resuspended in 6.25 volumes per oram wet weight of pellet) of 50 mM TrisHC/5 mM EDTA with protease inhibitors and aliquots flash frozen in liquid N and stored at 70 'C untl used in assays. Rat cortcal membranes (12 mg wet weight/tube) were incubated with (H -rmmethvhstamine (O 6 nM) with or without H, receptor antagonists in a total incubation volume of 0,5 mL of 50 mM Tris-HCUl5 mM EDTA (pH 7 7 Test compounds were dissolved in DMSO to provide a 20 mM solution serially diluted and then added to the incubation mixtures prior to initiating thencubation assay by addition of the membranes. Thioperamide (3 pMN) was used to deternmne nonsoecific binding.. Binding incubations were conducted for 30 minutes at 25 and terninated by addition of 2 mL of ice cold 50 mM' Tris-'HCi (pH 7.7) and filtration through 0.3% polyetyleniminesoaked Unifilter plates (Packard). These filters were washed 4 additional times with 2 rL of ice-cold 50 mM Tris-HCI and dried for I hour, Radioactivity was determined using liquid scintilation counting techniques Results were analyzed by Hil transformation and K values were determined using the Cheng P rusoff equation, As an alternative to the use of cortical membranes from rats as a source of histamine H receptors. membranes prepared from celis expressing H3 receptors are also suitable For this. the rat histamine H receptor; oLoned and expressed in cells was used, and subsequently competition binding assays were carried out according to methods previously described (see Esbenshade, et a. Journal of Pharmacology and Ex perimental Therapeutics vol. 313:165-175, 2005: Esbenshade et al. biochemical Pharmacology vol 68 2004) 933-945; Krueger, et al, Journal of Pharmacology and Experimenta Therapeutics vol. 314271-281, 2005.) Membranes were prepared from C6 cr HEK293 cells expressing the rat histamine H receptor, by homogenization on ice in TE buffer (50 mM Tris -HCI buffer; pH 7.4 containing 5 mM EDTA), 1 mM benzamidine, 2 pug/mi aprotinin I pginl leupeptir and I . g/mi pepstafin. The homogenate was centrifuged at 40000g, for 20 minutes at 4 .C This step was repeated and the resulting pelet was resuspended in TE buffer, Aliquots were frozen at 70*1 until needed, On the day of assay, membranes were thawed and di!uted with TE buffer Membrane preparations were incubated with [H4Vxmethvhstamine (0.5<0 nM) in the presence or absence of increasing concentrations of ligands for H receptor cornpetiton binding. The binding incubations were conducted in a- fnal volume of 0.5 ml TE buffer at 25 *- and were termnated after $0 minu Thioperamide (30 cM) was used to define nonepecific binding, All binding resotioris were terminated by filtration under vacuum onto polyethyenimine (02%) presoaked Uniffilters (Perkin Eirer Life Sciences) or Whatman GF/B filters followed by three brief washes with 2 mi of ice-cold TE buffer Bound radiolabei was determined by iquid scintilation counting For all of the radioligand competition binding assays lC values and Hli slopes were determined by Hill transformation of the data and pK. values were detemined by the Cheng-Prusoff equation. Generally, representative compounds of the invenfion demonstrated binding affinities in the above assays from about 0.05 nM to about 1000 nM. Preferred compounds of the invention bound to histamine-3 receptors with binding affinities from about 0.05 nM to about 250 nMl More preferred compounds of the invention bound to histamine-3 receptors with binding affinities from about 0.05 rM to about 10 nM. in addition to the utility of in vitro methods for cha rizing the H binding affinity of compounds, there are animal models of human disease availabe which demonstrate the utility of compounds of the invention for treating human disease. One animal modei of the human disease ADHD (attention deficit hyperactivty disorder) and related human disorders of attention is an inhibitory avdancle test in SHR rat pups (a Spontaneously Hypertensive strain of rat pups) This model has also been alternatively termed a PAR (passive avoidance response) model. The methodology and utility of this test has been described in the literature, for example in Komater, V A., et al Psychopharmacology (Berlin, Germany (2003). 167(4: 363-372 in Two novel and selective nonimidazoie H, receptor antagonists A30412i and A317920.: I in vivo behavioral and neurophysiological characterization, Fox, G. , etal. Journal of Pharmacokgy and Experimental Therapeutics (2003), 3053, 897-90; in Cowart, et al. Med Che7 2005, 48, 3&55 in Fox, 6B, et al. "Pharmacological Properties of ABT-239: H, Neurophysiological Characterization and Broad Preclinical Efficacy in Cognition and Schizophrenia of a Potent and Selective Histamine H, Receptor Antagonist. Journal of -97 Pharmacology and Experimenta Therapeutics (2005) 313 176190; in "Effects of histamine H-, receptor ligands GT-2331 and ciproxian in a repeated acquisition avodance response in the spcntaneousy hypertensive rat pup. Fox G B., et al Behavioural Brain Research (2002) 131(12) 15161. Representative compounds are active in this model with preferred compounds of the invention active in the model at doses of ranging about 0.001-3 mgkg of body weight. Compounds of the inventor ar hs ine3 receptor lgands that modulate the function of the histamine- receptor. The compounds may be inverse agonists that nhibit tne basal activity of the receptor or they may be antagonists that block the action of receptor-activatng agonists. it is understood that the foregoing detailed description and acconpanying examples are merely ibiustrative and are not to be taken as imitations upon the scope of the invention, which is defined solely by the appended daims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitaton those relating to the chemical structures, substituents, derivatives intermediates, syntheses. formulations o methods, or any combination of such changes and modification of use of the invention, may be made without departing from the spirit and scope thereof, 2918-

Claims

1. Use of an effective amount of a compound in the manufacture of a medicament for the treatment of a condition or disorder selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome, the compound having the structure of:

2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1-yl]methyl} cyclopropyl)phenyl]pyridazin-3(21-) one L-bitartrate monohydrate; 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1-yl]methyl} cyclopropyl)phenyl]pyridazin-3(21H) one L-bitartrate anhydrate; 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1-yl]methyl} cyclopropyl)phenyl]pyridazin-3(21-) one D-bitartrate dehydrate; or 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1-yl]methyl} cyclopropyl)phenyl]pyridazin-3(21H) one D-bitartrate anhydrate. 2. Use of an effective amount of a compound in the manufacture of a medicament for the treatment of a condition or disorder selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, (7728955 1):GGG 100 obesity, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome, the compound selected from: a crystalline salt of 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1 yl]methyl} cyclopropyl)phenyl]pyridazin-3(21-) -one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2- {4-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl} -2H-pyridazin-3-one L-bitartrate monohydrate demonstrating at least one characteristic peak in the PXRD at values of two-theta of 7.157.+-.0.20, 10.064.+-.0.20, 14.356.+ .0.20, 16.727.+-.0.20, 19.198.+-.0.20, 20.119.+-.0.20, 21.222.+-.0.20, 22.146.+-.0.20, 24.048.+ .0.20, and 24.574.+-.0.20; a crystalline salt of 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1 yl]methyl} cyclopropyl)phenyl]pyridazin-3(21-) -one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2- {4-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl} -2H-pyridazin-3-one L-bitartrate anhydrate demonstrating at least one characteristic peak in the PXRD at values of two-theta of 4.589.+-.0.20, 9.206.+-.0.20, 13.85.+ .0.20, 14.335.+-.0.20, 15.824.+-.0.20, 16.272.+-.0.20, 16.825.+-.0.20, 18.083.+-.0.20, 18.514.+ .0.20, 19.588.+-.0.20, and 20.551.+-.0.20; a crystalline salt of 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1 yl]methyl} cyclopropyl)phenyl]pyridazin-3(21-) -one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2- {4-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl} -2H-pyridazin-3-one D-bitartrate dehydrate demonstrating at least one characteristic peak in the PXRD at values of two-theta of 4.387.+-.0.20, 8.788.+-.0.20, 10.326.+ .0.20, 12.056.+-.0.20, 13.192.+-.0.20, 14.089.+-.0.20, 16.194.+-.0.20, 19.502.+-.0.20, 19.877.+ .0.20, 20.271.+-.0.20, 20.736.+-.0.20, 21.313.+-.0.20, 23.103.+-.0.20, and 23.937.+-.0.20; and a crystalline salt of 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1 yl]methyl} cyclopropyl)phenyl]pyridazin-3(21-I) -one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2- {4-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) (7728955 1):GGG 101 cyclopropyl]-phenyl} -2H-pyridazin-3-one D-bitartrate anhydrate demonstrating at least one characteristic peak in the PXRD at values of two theta of 5.004.+-.0.20, 10.590.+-.0.20, 13.548.+ .0.20, 14.219.+-.0.20, 15.279.+-.0.20, 15.723.+-.0.20, 16.990.+-.0.20, 18.723.+-.0.20, 19.052.+ .0.20, 20.827.+-.0.20, 21.293.+-.0.20, and 22.826.+-.0.20.

3. A method for the treatment of a condition or disorder selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome, wherein said method comprises administering an effective amount of a compound having the structure of: 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1-yl]methyl} cyclopropyl)phenyl]pyridazin 3(21-1)-one L-bitartrate monohydrate; 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1-yl]methyl} cyclopropyl)phenyl]pyridazin-3(21) one L-bitartrate anhydrate; 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1-yl]methyl} cyclopropyl)phenyl]pyridazin-3(211) one D-bitartrate dehydrate; or 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1-yl]methyl} cyclopropyl)phenyl]pyridazin-3(211) one D-bitartrate anhydrate.

4. A method for the treatment of a condition or disorder selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, asthma, motion sickness, dizziness, Meniere's disease, vestibular (7728955 1):GGG 102 disorders, vertigo, obesity, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome, wherein said method comprises administering an effective amount of a compound selected from: a crystalline salt of 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1 yl]methyl} cyclopropyl)phenyl]pyridazin-3(21-) -one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2- {4-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl} -2H-pyridazin-3-one L-bitartrate monohydrate demonstrating at least one characteristic peak in the PXRD at values of two-theta of 7.157.+-.0.20, 10.064.+-.0.20, 14.356.+ .0.20, 16.727.+-.0.20, 19.198.+-.0.20, 20.119.+-.0.20, 21.222.+-.0.20, 22.146.+-.0.20, 24.048.+ .0.20, and 24.574.+-.0.20; a crystalline salt of 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1 yl]methyl} cyclopropyl)phenyl]pyridazin-3(21-) -one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2- {4-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl} -2H-pyridazin-3-one L-bitartrate anhydrate demonstrating at least one characteristic peak in the PXRD at values of two-theta of 4.589.+-.0.20, 9.206.+-.0.20, 13.85.+ .0.20, 14.335.+-.0.20, 15.824.+-.0.20, 16.272.+-.0.20, 16.825.+-.0.20, 18.083.+-.0.20, 18.514.+ .0.20, 19.588.+-.0.20, and 20.551.+-.0.20; a crystalline salt of 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1 yl]methyl} cyclopropyl)phenyl]pyridazin-3(21-) -one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2- {4-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) cyclopropyl]-phenyl} -2H-pyridazin-3-one D-bitartrate dehydrate demonstrating at least one characteristic peak in the PXRD at values of two-theta of 4.387.+-.0.20, 8.788.+-.0.20, 10.326.+ .0.20, 12.056.+-.0.20, 13.192.+-.0.20, 14.089.+-.0.20, 16.194.+-.0.20, 19.502.+-.0.20, 19.877.+ .0.20, 20.271.+-.0.20, 20.736.+-.0.20, 21.313.+-.0.20, 23.103.+-.0.20, and 23.937.+-.0.20; and a crystalline salt of 2-[4-((1S,2S)-2- { [(2S)-2-methylpyrrolidin-1 yl]methyl} cyclopropyl)phenyl]pyridazin-3(21-I) -one, identified by powder X-ray diffraction (PXRD) wherein the salt is: crystalline 2- {4-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl) (7728955 1):GGG 103 cyclopropyl]-phenyl} -2H-pyridazin-3-one D-bitartrate anhydrate demonstrating at least one characteristic peak in the PXRD at values of two theta of 5.004.+-.0.20, 10.590.+-.0.20, 13.548.+ .0.20, 14.219.+-.0.20, 15.279.+-.0.20, 15.723.+-.0.20, 16.990.+-.0.20, 18.723.+-.0.20, 19.052.+ .0.20, 20.827.+-.0.20, 21.293.+-.0.20, and 22.826.+-.0.20.

5. A compound selected from the group consisting of: (S)-3-hydroxy-1-(4-((1S,2S)-2-(((S)-2-methylpyrrolidin-1 yl)methyl)cyclopropyl)phenyl)pyrrolidin-2-one; and 2- {4-[(1S,2S)-2-((S)-2-methyl-pyrrolidin-1-ylmethyl)-cyclopropyl]-phenyl)-2H-pyridazin-3 one (2S,3S)-2,3-dihydroxy-succinic acid; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 5 in combination with a pharmaceutically acceptable carrier.

7. Use of an effective amount of a compound of claim 5 in the manufacture of a medicament for the treatment of a condition or disorder selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome.

8. A method for the treatment of a condition or disorder selected from the group consisting of attention-deficit hyperactivity disorder (ADHD), deficits in attention, dementia, diseases with deficits of memory, learning, schizophrenia, cognitive deficits of schizophrenia, cognitive deficits (7728955 1):GGG 104 and dysfunction in psychiatric disorders, Alzheimer's disease, mild cognitive impairment, epilepsy, seizures, allergic rhinitis, asthma, motion sickness, dizziness, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type II diabetes, Syndrome X, insulin resistance syndrome, metabolic syndrome, pain, neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, jet lag, drug abuse, mood alteration, bipolar disorder, depression, obsessive compulsive disorder, Tourette's syndrome, Parkinson's disease, medullary thyroid carcinoma, melanoma, and polycystic ovary syndrome, wherein said method comprises administering an effective amount of a compound of claim 5. AbbVie Bahamas Ltd. Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON (7728955 1):GGG