DlARYL COMPOUNDS AND USES THEREOF

FELD OF THE INVENTION The present invention relates to diaryl derivatives that are substituted phenyl-phenyl phenyi- heteroaryl, or heteroaryl-heteroary! compounds and the uses thereof for treating diseases, conditions and/or disorders mediated by kappa opioid receptors (KORs) Specifically, the compounds are selective antagonists of KORs and are selective to KORs relative to mυ and delta (u and S) opioid receptors

BACKGROUND The compounds of the invention can be used for the treatment of CNS diseases, conditions, and/or disorders described herein atone or in combination with any other pharmaceutical agent, where the compound of formula I and/or the agent may be a pharmaceutically acceptable salt thereof The other agent includes an antimanic agent {mood stabilizers) (including Lithium, Carbamazepine {5H-dtbenz$b,fJ azepιne-5-caιboxarnιde} Depakote {divalproex sodium dissociates to the valproate ion chemically known as sodium hydrogen bιs(2-propy!pentanoate)}, and lamotπgme { 3,5-dιammo-6-(2.3-dichlorophenyl)-as- tnazine}, and Ability (also known as aπpiprazole that is an atypical antipsychotic), an atypical antipsychotic (including ztpiasidone {5-[2[-4-(1,2-beιv:ιso{hιa/of-3-yl)pipe{azιrι-1- ylJ)ethyl-]-6-chloro-1 3-dιhydro-2H-ιndol-2-one (see e g . U S Pat Nos 4,831 ,031. 6,312 295, 6.38? 904 6245.765. and 6,245.766 and European Patent application EP901781 , published Mar 17, 1999)}, olanzapine {2-methyl-4-(4-methy!-1-pιperazιnyl)-10H-thteno-[2,3-b|[1. 5|beπzodιa2epine (see, e g , U S

Pat No 5,229,382)}; clozapine {(8-ch!oro-11-{4-methy!-1-pιpera2tnyl)-5H-dιbenzo[b,el[1,4 jdιa2epιne (see, e g , U S Pat No 3,539 573, see also Hanes et al , Psychopharmacol Bull 24. 62 (1998))}, nsperidone

{3-[2-|4-{6-ftuoro-1.2-benzisoxa2Ol-3-y{)piperidtnolethyl ]-2-methyl-6.7 8,9-te^ahydro-4H-pyndo-[i.2- a]pyrtmιdιn-4-one (see e g , U S Pat No 4,804,663)}, sertιndole {1-[2-[4-(5-cnloro-1-<4-fluorophenyl)-1H- ιndol-3-yl]-1 pipeπdιnyl}ethyl3lιmιdazoi!dtn-2 one (see, e g U S Pa! Nos 4,710,500, 5,112,838 and

5,238.945)}, quetiapme {(2-|2-(4-dibenzo[b,f|π,43tπiazepιn-11-yl-1-pιperazιny! )ethoxy}ethano!, see e g.,

U S Pat No 4879288}} aπptprazole {{7-{4-(4-(2,3-dtchloropr>enyl}-1-ptpera2inyl-butoxy}-3-4 - dihydrocarbostynt or 7-{4-{4-(2,3-dιctilorophenyl)-1pιperazιnylj-butoxy}-34-d� �hydro~2(1H)-qu!nolιnone (see e g . U S Pat Nos 4,734,416 and 5,006,528)] amisulpπde {{4-amino-N-(1-ethyi-2- pyrrolιdιnyf)methyt]-5-(ethylsulfony!)-2-methoxyben2amιde (see, e g , U S Pat No 4401,822; see also P

Protais et al Neuropharmacol. 24, 861 (1985))}, mirtazepine (1 2,3,4,10.14b-hexa-hydro-2-methyl pyrazιno[2, 1-a|pyrιdo[23-c}-[2Jbenzazepιne (see, U S Pat No 4,062,848)}. and asenapine {trans-5- chloro-2-methyl-2,3,3a,12b-lelrahydro-1H-dιberiz-[2.36 7]oxepιno[4 5-c}pyrrole (see, e g , U S Pat Nos 4 145434 and 5. /63 4 /6))} or a 5-HT re-uptake inhibitor (including sertraline, paroxetine, fluoxetine, citafopram, and βscitaiopram)

US 6 974,824 discusses kappa opioid receptor antagonists that are said to yield significant improvements in functional binding assays to kappa opioid receptors relative to nor-BNi, and the use of these antagonists in treatment of disease states that are ameliorated by binding of the kappa opioid receptor such as heroin or cocaine addictions

US 6,559,159 discusses kappa opioid receptor antagonists and the use of these antagonists in treatment of disease states that are said to ameliorated by binding of the kappa opioid receptor such as heroin or cocaine addictions

US 6.548,637 discusses compounds, and pharmaceutical preparations thereof, that bind selectively to mammalian opioid receptors where the present set of compounds are said to comprise full agonists, partial agonists, and antagonists of mammalian opioid receptors

US 6.528,518 discusses the treatment of depression using kappa opioid receptor antagonists US 5.780.479 discusses a method for treating an individual afflicted with an impulse-control disorder by administering thereto an amount of one or more opioid receptor antagonists US 5,727,570 discusses a method of treatment of humans suffering from hyperlipidemia which comprises administering, by a pharmaceutically effective mode, a drug composition selected from the group consisting of opiate antagonists, and drugs which substantially equally reduce the amounts of catecholamines bound to alt catecholamine binding sites

US 5,585,348 discusses a method of preventing hyperalgesia and other undesirable side-effects associated with the administration ot growth factor, including nerve growth factor, utilizing an antagonist capable of inactivating excitatory opioid receptor-mediated functions on neurons in the nociceptive pathway. In addition, the invention relates to a composition comprising a growth factor and an antagonist capable of inactivating excitatory opioid receptor-mediated functions on neurons in the nociceptive pathway US 5,141 962 discusses compounds claimed to have dissociated antagonist affinity for kappa opiate receptor

US 5,025.018 discusses methods of inducing optate-receptor antagonistic activity in a patient suffenng from ischemic or traumatic central nervous system injury by administering to said patient an effective amount of an opiate-receptor antagonist having enhanced activity at t\\e kappa-opiate receptor suitable to permit the induction of opiate-receptor antagonistic activity.

US 4,906,637 discusses methods of inducing optate-receptor antagonistic activity in a patient suffenng from ischemic or traumatic brain injury by administering to said patient an effective amount of an opiate-receptor antagonist having enhanced activity at the kappa-opiate receptor suitable to permit the induction of opiate-receptor antagonistic activity WO 2007/100335 discusses methods of treating mood disorders, such as manic disorders, and stabilizing moods by administering a kappa agonist or partial agonist to a subject in need thereof.

The mesolimbie dopamine system, which onginates in the ventral tegmental area and projects to the nucleus accumbeπs (NAc), is involved in the pleasurable (hedontc) and rewarding effects of a variety of substrates, including drugs of abuse, food, and sexual behavior Drugs of abuse cause complex neuroadaptations in this system, some of which are associated with altered drug sensitivity. One neuroadaptation involves cAMP response element-binding protein (CREB) a transcription factor that is activated in striatal regions by psychostimulants. CREB in the NAc appears to regulate the rewarding and averstve effects of cocaine Stimulation of cAMP-dependenf protein kinase A (PKA), which activates

CREB, in the NAc decreases cocaine reward. Similarly, elevation of CREB expression in the NAc decreases cocaine reward and makes low doses of the drug aversive. Conversely, blockade of PKA activity or overexpression of a dominant-negative CREB, which functions as a CREB antagonist, in the

NAc increase cocaine reward These findings suggest that CREB activation in the NAc counteracts drug reward and increases drug aversion.

Cocaine alters neuronal excitability and neurotransmitter levels in the brain, particularly the mesoitmbfc dopamine system. Cocame withdrawal is accompanied by signs of depression and other mood disorders tn humans. The bioEogical basis of mood disorders like depression is not understood, but may be caused by genetic and environmental factors Physically and emotionally stressful events can aiso influence the etiology of depression, possibly causing subtle brain changes and alterations in gene expression. Thus, depression may have an important acquired component, caused by neuroadaptations in response to environment and expeπeoce The therapeutic actions of antidepressants appear to involve neuroadaptations. Most antidepressant treatments (including tricyclic and atypical antidepressants, selective serotonin reuptake inhibitors, electroconvulsive therapy) have common actions on components of the cAMP pathway Common actions include activation of PKA and the transcription factor CREB in the hippocampus, a brain region associated with emotion. CREB plays a critical role in the expression of numerous genes Understanding causal relations among CREB function, gene expression, and the therapeutic effects of antidepressants might provide explanations for why antidepressants require sustained treatment for effectiveness Additionally, because some genes regulated by CREB may be therapeutic while others may be pathophysiological, a more genera) understanding of the role CREB in behavior might help to elucidate the biological basis of depressive syndromes Many of the researchers studying depression are focused on the hippocampus. Many antidepressants increase the level of CRE8 in the hippocampus in this region, it is beiseved that increasing CREB activity is beneficial, because CREB controls some growth factors (e.g , BDNF) in the brain. See D ¹ Sa C. Duman RS Bipolar Disord. 2002: 4: 183-94, providing a discussion between CREB and antidepressant activity Many of the researchers studying depression are focused on the hippocampus. Many antidepressants increase the level of CREB in the hippocampus In this region, it is believed that increasing CREB activity is beneficial, because CREB controls some growth factors (e g., BDNF) in the brain. However, there is no evidence that increasing CREB in the hippocampus is associated with the therapeutic effects of antidepressants Although much research on the molecular mechanisms of depression and antidepressant actions has focused on the hippocampus, the NAc may also have relevance This basal forebrain region is innervated by dopamine neurons of the ventral tegmental area, as well as by noradrenergic and serotonergic inputs The NAc contributes importantly to the pleasurable effects of food, sexual behavior, novelty, and addictive drugs. Most current antidepressants act primarily on brain levels of noradrenaline or serotonin. There is some evidence that dopamine systems might be involved in depressive syndromes. Blocking dopamine receptors in the brain causes anhedonia (a decreased ability to experience pleasure), a defining feature of depression Nomifensine, a dopamine reuptake inhibitor, was a clinically effective antidepressant further implicating dopaminergic dysfunction in depression. Nomifensine was taken off the market because it caused lethal allergic reactions in some people

Buprenorphine (8UP), a partial mu agonist/weak parttat kappa agonist, was reported to be effective in the pharmacoiogicai treatment of affective disorders A double blind investigation showed BUP to induce strong antidepressant effects in patients with endogenous depression (Emrich, et ai . Ann NY Acad Set, 1982. v398, p108) Additionally, depressive symptoms were found to be significantly decreased with BUP treatment in heroin addicted patients who were depressed at intake {Kosten. J Sυbst Abuse Treat. 1990, v1 , p51)

Recently, Gerra et ai. (Gerra et al, Prog. Neuropsychopharmacol Biol. Psychiatry, 2006. v30, p265) reported a better outcome m heroin addicts co-morbid for depression, as a result of the improvement of depressive symptoms that was tentatively attributed to the specific pharmacoiogicai profile of BUP In contrast to antagonists, kappa receptor agonists, such as butorphanoi and enadoiine have been reported to increase dysphoria, confusion, sedation and to produce feelings of depersonalisation in humans (Greenwafd and Stiteer, Drug Alcohol Depend , 1998, v1, p17, and Walsh et al., Psychopharmacology 2001, v157, p151). thus supporting the use of antagonists ot partial agonists in depressed subjects. Preclinical^, immobilization stress, forced swim, or induction ot teamed helplessness (LH) increase dynorphin (endogenous ligand for kappa receptors) immunoreactivity in specific subregions of the hippocampus, as weii as NAc Conversely, KOR antagonists to these regions produces an antidepressant response in the LH model of depression (Shirayama et al., J. Neurochem., 2004, v90. p1258). consistent with antidepressant effects observed after systemic administration of kappa receptor antagonists

Changes in dynorphin ieveis in the NAc in response to stress may also be noteworthy Most depressed patients exhibit a reduced ability to experience pleasure (anhedonia) and loss of motivation Reward is mediated by the dopaminergic neurons located in the ventral tegmenta! area (VTA) that project to the NAc and is modulated (inhibited) by the kappa receptors located directly on dopamine cells. Thus blockade of kappa receptors m the NAc has antidepressant activity in several animal models and likely to blunt the decreased reward associated with excessive stimulation of kappa receptors Dynorphin upregulation in the NAc shell has been shown to be stimulated by stress and various drugs of abuse, and to cause anhedonia-like effects (Newton et at J Neurosci . 2002,v22, p10833)

Depressed patients perform significantly worse than controls in learning and memory tasks (Hasier et al.. Neuropsychopharm.. 2004 v 29 p1765 and Zakzanis, Neuropsychiatry Neυropsychol. Behav Neurol , 1998 V11. p11i) consistent with imaging studies suggesting decreased hippocampai volume Hippocampai changes are also observed in bipolar disorder (Frey. et al Ben Pharmacol VoI 18(5-6), pp 419-430) wiβi some evidence of reduced glutamatergic transmission that may contribute to impairments in learning and memory observed in bipolar patients Interestingly, dynorphin is co-localized with glutamate in granule cells of the hippocampus and exerts a potent inhibitory control over giutamate release in the hippocampus Furthermore, a kappa receptor antagonist can potentiate LTP induced by prolonged stimulation (Terman et al, J Neurosci. 2000. v20, p437θ) suggesting that a kappa antagonist may facilitate learning and memory

Although many opioid receptor antagonists are known, there remains a need to identify compounds having improved selectivity at file KOR over other receptors

SUMMARY

Compounds of Formula (I) have been found to act as selective antagonists at the KOR, and, therefore, may be used In the treatment of diseases, conditions and/or disorders that benefit from such antagonism (e.g., diseases/disorders/conditions related to obesity and obesity-related co-morbidities in addition to those related to the centra! nervous system) In particular, the compounds of Formula (I) provide selectivity at the KOR.

formula (I) wherein the variables are described herein.

In an embodiment of the present invention, a method for treating, or preparing a medicament to treat, a disease, condition and/or disorder that is mediated by selectively antagonizing the KOR over the mu and delta opioid receptors in animals that include the step of administering to an animal (preferably, a human) in need of such treatment a therapeutically effective amount of a compound of the present invention (or a pharmaceutical composition thereof) to treat any disease, condition, or disorder mediated by antagonizing the kappa opioid receptor.

Diseases, conditions, and/or disorders mediated by selectively antagonizing the kappa opioid receptor include any one individually or combination of any of the following: schizophrenia including negative symptoms; schizophreniform disorder; schizoaffective disorder including of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder; personality disorder of the paranoid type; personality disorder of the schizoid type; panic disorder: phobias; obsessive- compulsive disorder; stress disorders; generalized anxiety disorder: movement disorders involving Huntington's disease; dyskinesia associated with dopamine agonist therapy: Parkinson s disease, restless leg syndrome; disorders comprising as a symptom thereof a deficiency in cognition; dementias; mood disorders and episodes in a mammal; anxiety or psychotic disorders including schizophrenia, of the paranoid, disorganized, catatonic, undifferentiated, or residual type: delusional disorder; personality disorder of the paranoid type, of the schizoid type, or agoraphobia; post-traumatic stress disorder; acute stress disorder; chemical dependencies including alcohol, amphetamine, cocaine, heroin, phenobarbital, opiate, nicotine and benzodiazepines addiction; deficiency in memory, intellect, or learning and logic ability; reduction in any particular individual's functioning in one or more cognitive aspects; age-related cognitive decline; dementia: Alzheimer's disease; multi-mfarct dementia; alcoholic dementia or other drug-related dementia: dementia associated with intracranial tumors or cerebral trauma; dementia

associated with Huntmgtαn's disease or Parkinsons disease, AfDS-related dementia, deiiπum amnestic disorder, mental retardation, a learning disorder including reading disorder, mathematics disorder, or a disorder of written expression attention-deficit/hyperactivity disorder; mood disorders or mood episodes, a manic or mixed mood episode, a hypomawc mood episode, a depressive episode with atypical features, a depressive episode With melancholic features, a depressive episode with catatonic features, a mood episode with postpartum onset, post-stroke depression, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder, delusional disorder or schizophrenia, a bipolar disorder including bipolar I disorder bipolar tl disorder, cyclothymic disorder, hypertension, and depression, depression in cancer patients, Parkinson's patients, infertile women, and pediatrics depression as a single episode depression or recurrent episodes, including depression associated with postmyocardial infarction subsyndromal symptomatic depression, induced by child abuse, post partum depression, and major depression of the miid, moderate or severe type avoidant personality disorder, premature ejaculation, eating disorders including anorexia nervosa and bulimia nervosa, obesity, cluster headache, migraine, pain neuroiepttc-induced parkinsonism and tardive dyskinestas, endocrine disorders, hyperprolaetinaemia, vasospasm, vasospasm in the cerebral vasculature, cerebellar ataxia, gastrointestinal tract disorders involving changes in motility and secretion, mania, premenstrual syndrome, fibromyalgia syndrome, stress incontinence Tourette's syndrome, trichotillomania, kleptomania; male impotence cancer, small cell iung carcinoma, chronic paroxysmal hemicrania, and headache associated with vascular disorders Of most particular interest is schizophrenia, using the compounds of formula in combination with an atypical antipsychotic and also depression and/or bipolar using the compounds of formula I as monotherapy or in combination with an antimanic agent (mood stabilizers, including Lithium, Carbamazepine Valproate, Lamotngine, and Abilify), or with a 5-HT reuptake inhibitor (including sertraline) The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (ι) treats or prevents the particular disease, condition or disorder (iι) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (m) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein The term "animal" refers to humans (male or female), companion animals (e g dogs, cats and horses), food-source animals, 200 animals manne animals, birds and other similar animal species 'Edible animals' refers to food-source animals such as cows, pigs, sheep and poultry

The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically. with the other ingredients compπsing a formulation, and/or the mammal being treated therewith

The teims 'treating', "treat", or 'treatment' embrace both pieventative. ι e , piophyiactic. and palliative treatment

The terms "modulating opioid receptor activity" or "optoid-mediated" iefers to the activation or deactivation of the mu, kappa and/or delta opioid receptors The term "compounds of the present invention" refer, unless specifically identified otherwise, to compounds of formula (I) and pharmaceutically acceptable salts of the compounds and hydrates of the

compounds thereof and salts thereof, as well as, all stereoisomers {including diastereomers and enantiomers) tautomers and isotopically iabeied compounds.

DETAILED DESCRIPTION One aspect of the present invention is a compound of formula I,

formula I, or a pharmaceutically acceptable sait thereof, wherein

R ¹ is Ci^afkyf C^alkyl-O-Ci.^aikyl a ?-, 8-, or 9-membered bridged bicydic carbocyclic ring, a fused bicydic carbocyclic πng. (CH^ phenyi, (CH ₂ ) _a »heteroaryl, or (CH^beterocycloalkyl. wherein the bridged ong, the fused πng, phenyl, heteroaryl, or heterocycloalky! is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, OH. Ci _? alkyt, O-C< ₃ alkyl, NH ₂ , NHC^alkyl. or N(C, <alkyl),

R ^? is H or C, ^alkyl, or

R' and R ⁷ are taken together with the nitrogen to which they are attached to form a mono- or bicydic N-nng. where said N-nng is a 4- to 7-membered mono-cyclic heterocyctoalkyl ring; a fused bicyclic heterocyclic πng. or a 7-. 8-. or 9-membered bridged bicychc heterocyclic ring, wherein said N-πng is unsubstituted or substituted with 1 2, or 3 substituents independently selected from halogen. OH. -CN, Ci. ₃ alKyl, C^alkyl-OH O-C^alkyl, Ct^alkyl-O-d.saikyl, NH^. NHC^alkyl. or N(C ₁ .,alkyl)/. a is O ₁ 1. or 2;

R ³ is H. or Ci salkyl, or when X ^f or X ³ is >{C(R ⁵ )}-, R ^-1 may be taken together with R ^fl of one of X ¹ or X ^a and the carbon atoms to which they are attached to form a 5- or 6-membered saturated, or partially saturated πng, wherein one carbon atom in said 5- or 6-membered ring may be a heteroatom selected from -O-, -N(H)-, •N(C*alkyl}-, and >N-, and wherein said ring is unsubstituted or substituted where valency permits with 1 substrtuent selected from halogen, -CN. or -Ct ^alkyl,

R* is H. halogen. CN, Cj _$ alky!, or OC ₁ jalkyl.

R ^s is H. halogen. CN. Ci ^alkyi, or OC, ₃ alkyl.

R ^1* is Ci^alkyl. or C^alkyl-O-C^alkyl:

R ^? is H. or C^alkyi; or

R ^δ and R ⁷ are taken together with the nitrogen to which they are attached to form a mono- or bicyclic SN-ring. where said SN-ring is a 4- to 7-rnembered mono-cyclic heterocyclic ring containing 0 or 1 additional heteroatom selected from O, NH, or NC« jalkyl, or a 7-, 8-, or 9-membered bridged bicycSic heterocyclic ring, wherein said SN-ring is unsubstituted or substituted wtth 1 or 2 substittients independently selected from halogen, OH, -CN, C, _s alkyl. C, .alkyl-OH, 0-C. ₃ alkyi, C, _% alkyl-O-C,. ₅ aikyl. HHz. NHd-salkyi, or NCC^alky!)^

X ^! , X ^? , X*, X*. X ^$ , and X ^β are independently >(C(R ^iS ))- or >N-, and each R ^? is independently H, halogen, -CN, -C _h alky), -0Cκ _S alkyl. provided that when X ¹ or X ^? is >{C(R' ⁱ ))- one R ^s of X ₁ or X ₃ may be taken together with R ^s and the carbon atoms to which they are attached to form said 5- or 6-roembered saturated, or partially saturated ring

In the invention, it ss preferable that X ¹ , X ² , X ^J , and X ⁴ are >(C(R ^$ ))- wherein R* is selected from any definition discussed herein, and also include wherein each R ^E is independently H. haiogen, -CN. -C,. • _? a!kyf. Qr -OC ₁ . _s alkyl

Another aspect of the invention is where R ^δ and R ^? are taken together with the nitrogen to which they are attached to form the monocyclic SN-rtng wherein said SN-nng is unsυbstituted or substituted with C» ,-,alkyl Preferred monocyclic moieties making this SN-nng include pyrrolidinyl or morpholinyl wherein said SN ring is unsubststuted or substituted with methyl.

Another aspect of the invention is wherein R ¹ is C<. _s a)kyi or the ?-membβr«d bridged bicyciic carbocycSic ring, and R ^" is H Yet, another aspect of the invention is wherein R ¹ and R° are taken together with the nitrogen to which they are attached to form the 5- to 6-membered mono-heterocycloalkyl ring, or the 8-membered bridged bicyclic heterocyclic ring, wherein said N-ring is unsubstituted or substituted with 1 or 2 substitutents independently selected from OH, methyl, or metboxy

Another aspect of the invention is wherein X ^s is <N- and X ^' , X ² , X*. X ⁴ , and X ^$ are >(C(R ^S )K or. alternatively y? is >N- and X', X\ X ³ . X ⁴ , and X ^$ are >(C(R ⁸ ))-, wherein R* is independently H. halogen, - CN, -C,. ₅ alkyi, or -OC^alky!

Another aspect of the invention is wherein X ^; or X ⁱ are both >{C(R*)}- and oniy one R* of X ¹ and X ³ is H and the other R* is halogen, -CN, -C^alkyl, or -OC _t ^alkyl Another aspect of the invention is wherein at least one of X ¹ or X ^J is >(C(R*))- and R* of formula I forms a πng with R ⁸ of X ^! or' X ^s and the carbon atoms to which they are attached to form a 5- or 6-membered saturated, or partially saturated ring, wherein one carbon atom in said 5- or 6-membered nng may be a heteroatom selected from -O-, -N(H)-, -N(C^ _s alkyl)- and >N-, and wherein said ring is unsubstituted or substituted where valency permits with 1 substituent selected from halogen, CN, or -C _h alky!.

The invention includes the free base or a pharmaceutically acceptable salt of every example of compounds of formula I, by itself or in a group of any combination of the compounds of formula I prepared herein

"Halogen ^"1 and 'halo" and the like include fluoro, chloro. bromo and todo.

The term "alky! ^* , as used herein, unless indicated otherwise, includes straight or branched alkyl groups of C ₈ ^ number of carbons where e is the least number of carbon atoms and g is the largest number of carbon atoms possible When an alkyl moiety contains at least 3 carbon atoms, said alky! includes cycioalkyl moieties Each alkyl moiety may be substituted with up to three substttuents

independently selected from halogen. OH, -CN, O-Ci ₃ alkyl, NH.>, NHC^alkyl. or N(C,. _s alkyl) ₂ , wherein the alky! moieties that are substituents are not further substituted unless otherwise indicated. Therefore, non-limiting examples of Ci^aikyi include methyl, trifiuoromethyf. ethyl, n-propyl, i-propyl. cyciopropyl, methyl-cyciαpropyl, t-butyl, and cyclobutyl. The term "heterocycloalkyi" as used herein, unless indicated otherwise, includes a 4- to 7- membered saturated cycloaSky! moiety in which up to two carbon atoms are replaced with a nitrogen, O, or S atom or any combination thereof. When nitrogen replaces an atom, to satisfy velancy requirements, the nitrogen is substituted with H or C _h alky! or is a point of attachment when heterocycloalkyi is a substituent or is created by two substituents combining to form a heterocycloalkyi moiety, e g , when R ¹ and R ² are taken together with the atom to which they are attached to make pyrrolidinyf. Non-ftmiting examples of heterocycloalkyi include oxetanyl. tetrahydrofuranyl, tetrahydropyran, azetidinyl, pyrrolidinyl, pyrazolidinyf. piperidinyl. dtoxanyi, morpholinyf, thiomorpholinyl, and piperazinyl.

The term "aryl" refers to carbocyclic aromatic moieties having a single ring (e.g., phenyl).

The term "heteroaryl" as used herein, unless indicated otherwise, is a 5- to 6-membered ring that is aromatic or partially saturated, where at least one heteroatom is present and no more that three heteroatoms are present, wherein the heteroatom is nitrogen. O, or S or any combination thereof. When nitrogen replaces an atom, to satisfy velancy requirements, the nitrogen is substituted with H or C ₁ ^ alky! or is the point of attachment when heteroaryi is a substituent or is formed by two substituents combining to form a heteroaryi moiety. Non-iimlting examples of heteroaryi include pyridyl, pyrimidyl, pyridazyl pyrazinyl. furanyl, thiophenyl, pyrrolyl. pyrrolinyl. oxazolyl. isoxazolyl, thiazolyl, isothiazolyl, imtdazolyl, irmdazolinyl, pyrazolyl, pyrazolsnyt. pyranyl, and azapmyl.

A fused bicyclic carbocyclic ring as used herein, unless indicated otherwise, has the two rings that share adjacent carbon atoms. The fused rings form a 5-6 or 6-6 fused bicyclic ring. In the fused ring, unless otherwise specified, either ring may be aromatic, or partially or fully saturated. A non-limiting example of a fused aromatic ring moiety is naphthyl. A non-limiting example of a saturated or partially saturated fused ring moiety ss decahydronaphthyf and tetrahydronaphthyl, respectively. Other non- limiting examples include indanyt.

A fused bicyclic heterocyclic ring as used herein, unless indicated otherwise, is a bicyclic fused ring where up to 3 atoms are independently selected from O, nitrogen, or S or any combination thereof in either ring, including the atom where the rings are fused where valency permits. When nitrogen ts the heteroatom, to satisfy valency requirements, it is substituted wtth H or Ct^alkyi. or is a point of attachment when a fused bicyclic heterocyclic ring is a substituent or is the point of attachment when formed by two substituents combining to form a fused bicyclic heterocyclic moiety.

A bridged bicycϋc carbocyctic ring as used herein, unless indicated otherwise, is formed when two rings do not share adjacent carbon atoms to make the bicyclic ring. The bridged nng contains from 7 to 9 carbon atoms. Non-limtting examples include bιcyclo(2.2.1]heptaoy! and bicyclo{3.i.i)heptanyl.

A bridged bicyclic heterocyclic ring as used herein, unless indicated otherwise, is a bridged bicyclic carbocyclic ring where 1 to 2 carbon atoms are replaced by a nitrogen atom that is substituted where valency requires by H or C _h alky! or provides the point of attachment for the ring when the ring is a substituent or is formed, for example, when R' and R ³ or R ^β and R* combine to form a bridged bicyclic heterocyclic ring. Non-limiting examples include quinudidinyl. 6-aza-[3.2.13-octanyl, 2-

azabicycioβ 2 1)heptaπyl, 3-azabιcycJo{3 3 2jdecanyl, 2-azabtcyc!o(2 22]octanyi, and 3- azabιcyc!o[3 2 1]octanyf

Another aspect of the present invention is a pharmaceutical composition that comprises (i) a compound of the present invention, and (2) a pharmaceutically acceptable excipient. diluent or earner Preferably the composition comprises a therapeutically effective amount of a compound of the present invention The composition may also contain at least one additional pharmaceutical agent {described herein) in yet another embodiment of the present invention a method for treating, or preparing a medicament to treat a disease, condition and/or disorder that is mediated by selectively antagonizing the KOR over the mu and delta opioid receptors tn animals that include the step of administering to an anima! (preferably a human) in need of such treatment a therapeutically effective amount of a compound of the present invention (or a pharmaceutical composition thereof) to treat any disease, condition or disorder mediated by antagonizing the kappa opioid receptor

Diseases conditions, and/or disorders mediated by selectively antagonizing the kappa opioid receptor incfude any one individually or combination of any of the diseases discussed herein

Compounds of the present invention may be administered in combination with other pharmaceutical agents The combination therapy may be administered as (a) a single pharmaceutical composition which composes a compound of the present invention, at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable exαpient, diluent, or carrier, or (b) two separate pharmaceutical compositions compnsmg (ι) a first composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or earner, and (it) a second composition comprising at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient diluent, or earner The pharmaceutical compositions may be administered simultaneously or sequentially and in any order Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts particularly in light of the description contained herein The starting matenais are generally commercially available or are readily prepared using methods well known to those skilled in the art (e g , prepared by methods generally described in Louis F Fieser and Mary Fieser, Reagents foi Organic Synthesis, v 1-19, Wiley, New York (1967-1999 ed ), or Beilstems Haπdbuch der orqanischen Chemie 4, Aufl ed Spπnger-Verlag Berlin, including supplements (also available via the Beiistem onfine database))

For illustrative purposes the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates For a more detailed description of the individual reaction steps, see the Examples section below Those skilled m the art wiii appreciate that other synthetic routes may be used to synthesize the inventive compounds Although specific starting materials and reagents aie depicted in the schemes and discussed below, other starting matenais and reagents can be easily substituted to provide a variety of denvatrves and/or reaction conditions In addition, many of the compounds prepared by *he methods descπbed below can be further modified in light of this disclosure using conventional chemistry well known to those skied m the art In the preparation of compounds of the present invention, protection of remote functionality (e g , pnmary or secondary amine) of intermediates may be necessary The need for such protection will vary

depending on the nature of the remote functionality and the conditions of the preparation methods Suitable amino-protecting groups (NH-Pg) include acetyl, trtfJuoroacetyl. f-butoxycarbonyl (BOC), benzyloxycarbonyl (CSz) and 9-fluorenyimethyleneoxycarbonyi (Fmoc) The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene. Protective Groups in Organic Synthesis. John Wiley & Sons. New York, 1991

The following schemes outhne the general procedures one could use to provide compounds of the present invention.

The compounds of this invention can be prepared starting from the aryl sulphonyl chloride with a group ortho that can be utilized to couple in a palladium-catalyzed reaction such as a Suzuki coupling (see for example Miyaura, N ; et a! Chem Rev. 1995, 95, 2457) Standard ortho groups for R ¹⁰ are a chloride, bromide, iodide or boronic acid These compounds are commercially available or can be prepared by one who is skilled in the art

Scheme 1

Treatment of the sulphonyl chloride with an organic tertiary amine base in organic solvent such as tetrahydrofuran followed by the addition of the secondary or primary amine readily affords the sulfonamide.

When X" ss >N- and R ^1t is H, the halogenated intermediate 2(8) can be prepared as outlined in Scheme 2: Scheme 2

The sulfonamide can be treated with LDA in tetrahydrofuran or potentially an alternative organic aprotic solvent and the anion quenched with bromine to provide the Suzuki coupling partner 2(ii). If either R ^δ or R ⁷ are a proton, an additional equivalent of base (LOA) will be required to carry out this sequence. Suzuki couplings are well precendented in the literature (see for example ivfeyaura, N ; et ai

Chem Rev 1995, 95, 2457) and are very effective in coupling aryl halides with aryi boronic acids This can be accomplished with a variety of palladium catalysts and itgands which can improve the coupling or aryl chlorides (Buchwald et a!.. Angwandte Chemie, International addition. 1999, 38(16) 2413-2416). One of these ligands and palladium catalysts is DPPF (IM'- Bιs(d)phenylphosphιno)ferrocene)dιchtoropalladtum (H).

Scheme 3

Compounds like 3(t) (Scheme 3) can be coupled to compounds like 3(«) utilizing DPPF as the catalyst'ϊigand source TNs can be conducted in a variety of organic solvents with one such being dimethyiacetamide or ethylene gioco!. These reactions can be conducted at ambient temperature or may require heating, either condition readily being determined by one of ordinary skill in the art

Compounds like 3(«i) can be converted to compounds of Formula I through a standard reductive amination (Scheme 4). Treatment of aldehyde 3(1») with a secondary or primary amine in an organic solvent such as tetrahyrdofuran in the presence of catalytic aαd (e g , acetic acid) followed by addition of a reducing reagent affords the desired compounds of formula I. The variety of reducing agents can be utilized, one such reagent is sodium tnacetoxy borohydrtde

Scheme 4

When one of X ¹ -X* is H, the pyndyi borontc acid aidehyde is commercially available and coupled as described in Scheme 4

The compounds of the present invention may be isolated and used per $β or in the form of any pharmaceutically acceptable salt The term 'salts ^* refers to inorganic and organic salts of a compound of the present invention. These salts can be prepared in situ dunng the final isolation and purification of a compound, or by separately reacting the compound with a suitable organic or inorganic acid or base and isolating the sait thus formed Representative salts include the hydrobromide, hydrochloride, hydrαodide, sulfate, bisulfate, nitrate, acetate, tnfluoroacetate. oxalate, besylate, palmitate, pamoate, malonate, stearate, laurate, malate, borate, benzoate. lactate phosphate, hexafluorophosphate, benzene suifonate, tosylate, fomnate. citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate lactobionate, and iaurylsulphonate salts, and the like. These may include cations based on the alkali and

alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to. ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethyfamtne. tπmethytamine, triethylamine, ethylamine. and the like. See, e.g., Berge, et at, J. Pharm. Set., 66, 1-19 (1977). The compounds of the present invention may contain asymmetric or chiral centers, and. therefore, exist in different stereoisomer^ forms. It is intended that all stereoisomers forms of the compounds of the present invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of the present invention incorporates a double bond or a fused ring, both the OS- and trans- forms, as well as mixtures, are embraced within the scope of the invention.

Diastereomeπc mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art. such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomenc mixture by reaction with an appropriate optically active compound (e.g.. chirai auxiliary such as a chirai alcohol or Moshers acid chloride), separating the diastereomers and converting (e.g , bydroiyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chirat HPLC column. It is also possible that the intennediates and compounds of the present invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term ' iautomer" or 'tautomeric form" refers to structural isomers of different energies which are interconvertible v/a a low energy barrier. For example, proton tautomers (also known as prototropic tautomers} include interconversions via migration of a proton, such as keto-enol and imtne-enamme tsomerizattons. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens Valence tautomers include interconversions by reorganization of some of the bonding electrons.

The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlonne. such as ² H, ⁵ H. ¹¹ C, "C, ^W C, ¹³ N, ^K η, " ⁵ 0, ¹⁷ O. ^1S O, ³¹ P ₁ ³² P, «S. ' ⁸ F. ^1ϊ3 l. ¹²⁵ I and ^?6 CI, respectively.

Certain isotopieally-labeled compounds of the present invention (e.g.. those labeled with ³ H and ^U C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e . ^a H) and carbon~i4 (i.e.. ¹⁴ C) isotopes ate particularly preferred for their ease of preparation and detectabiiity. Further, substitution with heavier isotopes such as deuterium (i.e., 'H) may afford certain therapeutic advantages resulting from greater metabolic stability (e g , increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as ^ib Q, ¹³ N, ¹¹ C, and ^" '*F are useful for positron emission tomography (PET) studies to examine substrate occupancy lsotopicaily labeled compounds of the present invention can generally be prepared by following

procedures analogous to those disclosed in the Schemes and/or in the Examples herein belovv, by substituting an isotopicaliy labeled reagent for a non-isotopicaity labeled reagent

Compounds of the present Invention are useful for treating diseases conditions and/or disorders modulated by the mu, kappa and/or delta opioid receptors, therefore, another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable exαpient, difuent or earner The compounds of the present invention (including the compositions and processes used therein) may also be used m the manufacture of a medicament for the therapeutic applications described herein

A typical formulation is prepared by mixing a compound of the present invention and a carrier diluent or exciptent Suitable carriers diluents and exciptents are well known io those skilled in the art and include mateπals such as carbohydrates waxes water soluble and/or swellabte polymers, hydrophific or hydrophobic materials gelatin, oils solvents, water, and the like The particular carrier, diluent or exαplent used wili depend upon the means and purpose fot which the compound of the present invention is being applied Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GKAS) to be administered to a mammal In general, sate solvents are norvtoxtc aqueous solvents such as water and other non-toxic solvents that are soluble or misαble in water Suitable aqueous solvents include water, ethanol propylene glycol, polyethylene glycols (e g , PEG400, PEG3Q0), etc and mixtures thereof The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents lubncating agents, emuisifiers, suspending agents, preservatives antioxidants, opaquing agents glidants processing aids, colorants, sweeteners, perfuming agents flavoring agents and other known additives to provide an elegant presentation of the drug (ι e , a compound of the present invention or pharmaceutical composition thereof) or aid in the manufactunng of the pharmaceutical product (ι e medicament)

The formulations may be prepared using conventional dissolution and mixing procedures For example, the bulk drug substance (ι e compound of the present invention or stabilized form of the compound (e g complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropnate form Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package In addition, the container has deposited thereon a label mat describes the contents of the container The label may also include appropriate warnings

The present invention further provides a method of treating diseases, conditions and'or disorders modulated by the opioid receptor(s) in an animal that includes administering to an animal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention and a

pharmaceutically acceptable excφtent diluent or earner The method is particularly useful for treating diseases conditions and/or disorders that benefit from antagonizing the mu, kappa and/or delta opioid receptors

For a normal adult human having a body weight of about 100 kg a dosage m the range of from about 0001 mg to about 10 mg per kilogram body weight is typically sufficient preferably from about 0005 mg/kg to about 50 mg/kg, more preferably from about 0 01 mg/kg to about 3 mg/kg However, some variability in the general dosage range may be required depending upon the age and weight of the subject being treated, trie intended route of administration trie particular compound being administered and the iike The determination of dosage ranges and optimal dosages for a particular patient is weil within the ability of one of ordinary skill in the art having the benefit of the instant disclosure It is aϊso noted that the compounds of the present invention can be used in sustained release, controlled release, and delayed release formulations which forms are also well known to one of ordinary skill in the art

The compounds of this invention may also be used in conjunction wfth other pharmaceutical agents for the treatment of lhe diseases, conditions and/or disorders described herein Therefore methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention include anti obesity agents

Another aspect of the present invention is the treatment of central nervous system diseases disorders, and/or conditions as discussed herein Embodiments of the present invention are illustrated by the following Examples It is to be understood, however, that the embodiments of the invention are not limited to the specific details of these Examples, as other variations thereof wilt be known or apparent m light of the instant disclosure, to one of ordinary skill in the art

EXAMPLES Unless specified otherwise, starting materials are generally available from commercial sources such as AJdrich Chemicals Co (Milwaukee, Wl), Lancaster Synthesis, lnc (Windham, NH), Acros Organics (Fairlawn, NJ) Maybndge Chemical Company, Ltd (Cornwall, England), Tyger Scientific (Pnnceton, NJ) and AstraZeneca Pharmaceuticals (London, England)

PHARMACOLOGtCAL TESTING The practice of the instant invention for treating the diseases or conditions discussed herein can be evidenced by activity in at feast one ot the protocols described hereinbelow

In Vitro Biological Assays Binding Assay

Binding assays on membranes from CHO celts expressing either human kappa, mu or delta opioid receptors were performed according to standard procedures Briefly, fro?en cell paste (70-80-mgs per 96 welt plate) is homogenized in 50 mM Tris HCI buffer (pH 74 @ 4 degrees C) containing 2 0 mM

MgCl2 using a Polytron and spun in a centnfuge at 4000Og for ten minutes The final pellet is resuspended in assay buffer (50 mM Tris HCI buffer (pH 74) containing 1 mM EOTA. 5 mM MgCU.)

Incubations were initiated by the addition of tissue to 96-well plates containing test drugs and 04-1 nM (3H]diprenorphιne in a final volume of 250 ul) Non-specific binding was determined by radioligand

binding in the presence of a saturating concentration of naltrexone (10 uM) After one hour incubation penod at room temperature, assay sampfes were rapidly filtered through Whatman GF/B filters and nnsed with ice-cold 50 mM Iris buffer (pH 74) Membrane bound [3H]dtprenorphine levels were determined by liquid scintillation counting of the filters in BetaScint The ICw value (concentration at which 50% inhibition of specific binding occurs) was calculated by linear regression of the concentration-response data. Ki values were calculated according to the Cheng Prusoff equation, Ki = !Cac'{1 ⁺ (UKa)), where L is the concentration of the radioligand used in the experiment and the Kd value ts the dissociation constant for the radioligand {determined previously by saturation analysis)

Compounds not exemplified but ptepared making non-critical changes to conditions provided herein were tested in the kappa assay discussed above and had a Ki value within the range of 02 nM and 10,00O nM

The compounds of the present invention tested in the kappa assay discussed above had the following specific Ki value(s)/ranges with ranges being provided when there is more than one date point"

General Experimental Procedures

NMR spectra were recorded on a Vartan Unity™ 400 (available from Vanan Inc., Palo Alto, CA) at room temperature at 400 MHz for proton. Chemical shifts are expressed in parts per million (δ) relative to residua! solvent as an internal reference The peak shapes are denoted as follows' s, singlet; d, doublet, t, tnpfet q, quartet; m, multiple!, bs broad singlet, 2s. two singlets Atmosphenc pressure chemical ionization mass spectra (APCI) were obtained on a Fisons™ Platform If Spectrometer (carrier gas acetonitnSe available from Micromass Ltd. Manchester, UK) Chemical ionization mass spectra (Cl) were obtained on a Hewlett-Packard™ 5989 instrument (ammonia ionization. PBMS available from Hewlett-Packard Company Palo Alto, CA). Electrospray ionization mass spectra (ES) were obtained on a Waters™ ZMD instrument (carrier gas acetonitnle: available from Waters Corp., Milford, MA). Where the intensity of chlorine or bromine-containing ions are described, the expected intensity ratio was observed (approximately 3 1 for ^3: Cl/ ¹⁷ Cl-contaιning ions and 1.1 tor ^Br/^Br-containtng tons) and the intensity of only the lower mass ion is given. In some cases only representative ⁵ H NMR peaks are given. MS peaks are reported for aii examples Optical rotations were determined on a Perkm£lmer ^rM 241 poianmeter (available from PerkinElmer lnc , Wellesley. MA) using the sodium D tine (λ - 589 nm) at the indicated temperature and are reported as follows (αjo'T concentration (c - g/100 mi), and solvent.

Column chromatography was performed with either Baker™ silica gel (40 urn; J T Baker, Phiflipsbufg, NJ) or Silica Gel 50 (EM Sciences ¹ * ¹ , Gibbstown, NJ) in glass columns or in Flash 40 Biotage™ columns (ISC Inc., Shelton, CT) under low nitrogen pressure. Preparation of intermediates KH):

To a solution of amine of formula HNR ¹ R ⁷ (198 mmol) in anhydrous dichloromethane (CH ₂ CI;) (80 mL) was added triethylamine (2.0 g, 19.8 mmol). This was followed by dropwise addition of bromobenzene sulfonyl chloride (4.21 g. 16 5 romol) and was stirred overnight at room temperature The reaction was washed with IN HCI (2 x 30 mL), the aqueous layer was extracted with CH-Ct and dπed over MgSO^, that was removed by filtration and the filtrate was concentrated and the intermediate was taken on to next step without further purification, intermediates made by this process

(ft)-1-(2-Bromo-benzenesulfonyi}-2Hrriethyl-pyrrofιdιr� �e (i(ιι)<a)) 84% yield, MS (APCI) (M+1) m/z

305.

{SH-(2-Broπv3-benzenesυtfonyl)-3-methyf-moφholιne <1(n)(b)) 64% yield . MS (APCI) (M+1) m/z 321

2-(Pyrrolιdιne-1-sulfonyi)-pyridιne (i{ιt)<c»- 36% yield, MS (APCI) (M+1) m/z 213. 2-chloro-3-(pyrrolidine-1yi-sulfony!)pyπdιne (1<H>(d». 96% yield. MS (APCI) (M> 1) m/z 246 Preparation of intermediates 2uή

3-8romo-2-{pyrro8dιne-1-su!fofiyl)-pyridιne (2(«), where -NR ⁶ R' is pyrrolidinyl). 21% yield, MS (APCi) (M+1) m/z 292

To a solution of lithium diisopropylamide mono THF in cyclohexane (? 54 mL, 11 3 mmol) in tetrahydfofuran (5mL) at -60C was added a solution of the 1c (12 g, 5.7 mmol) in tetrahydrofuran (10 mL) at -60C and was allowed to stir for 1-1.5 hrs Bromine (1.8 g. 11.3 mmol) was added dropwise and stirred at -60C for 1 hr The reaction was quenched with water at -60C and warmed to room temperature The solution was extracted with ethyl acetate, dneά and concentrated to give crude oil Chromatographed on silica using a 0-50% ethyl acetate/heptane gradient Preparation of intermediates 30») Method III:

To 16.4 ml of a 2M aq sodium carbonate solution was added a solution of 25 mL of dimethyiacetamide/dimethy! ethylene glycol, bromo or chloro sulfonamide (2 g. 6.6mmol) and boronic acid (1 48g. θ ββmmol) FinaHy, (1.1'-Bιs(dιphenylphospNno)ferrocene}dichloropalladιum (II) (537 mg,

00657 mmoi) was added and then heated overnight at 1OO°C. Reaction was filtered through a fritted

funnel and «nsed with water and copious amounts of ethyl acetate The filtrate was concentrated to 1/4 the volume and poured into seperarory funnel The aqueous phase was extracted wrth ethyl acetate (3 x 25 mi.) and me organic phase was dried over sodium sulfate filtered and concentrated The crude product was chromatographed on siltca ge! using 10-40% ethyl acetate/heptane gradient

Method )V

To 1 95 ml of a 2M aq sodium carbonate solution was added a solution of 2 ml of dιmethy!acetamιde/d»methyl ethylene glycol, bromo sulfonamide (500 mg, 1 56 mmol) and boronic acid (351 mg. 2 34 mmo!) Finally, [1,i -Bιs{dφhenylphosphino)ferrocene]dιchloropaffadium (If) (12 δ mg, 00156 mmol) was added and then the reaction was microwaved at 100-140C for 20-40 minutes Reaction was filtered through a fritted funnel and rinsed with water and copious amounts of ethyl acetate The filtrate was concentrated to 1/4 the volume and poured into seperarory funnel The aqueous phase was extracted wrth ethyl acetate (3 x 25 mL) and the organic phase was ύned over sodium sulfate, filtered and concentrated The crude pjoduct was chromatographed on stlica gel using 10-40% ethyl acetate/heptane gradient

2M(R)-2-Methylψytτoitdine~1-sulfonyf)-bipr»eny!-4^rbal dehyde (3(HfKa)) <99% yiekl, MS (APCI) (M+1 ) m/z 329

2'-({R)-3-(Vtetriyi-moφrioiιne-4-suffony{)-t)tphenyl-4- carbaωehycie {3<ιιt)(b) ) 92 7% yield, MS (APCi) (M+1) m/z 346

4-[2κPyrroi(dme~1-suifonyl)-pyridin-3-y!]~benzaldehyde (3(Ht)(C)) 854 % yield, MS (APCI) (M+ 1 ) m/z 317

3-Fluoro-2'-((R)-3-methyl-morpholine-4-sulfonyl)-biphenyl -4-carbaldehyde (3(»ι)(d)) <99% yield, MS (APCI) (M+1 ) m/Z 364 3-Metrtoxy-2'-(pyfrolιdιrte-1-suifonyl)-btphenyl-4-carbald ehydβ (3(κι)(e)) 74 0% yield. MS (APCI)

(M+1) m/z 346

2'-(Pytτolιdfne-1-sulfonyl)-bfphenyl-4-carbaidehyde (3(m)(f)> 97 5% yield, MS (APCI) (M+1) m/2

316

4-[3-(pyyrrolιdtn-1-y!su!fonyl)-pyπdin-2-yl3benzaldehyd e 3(ifi)(g) 28% yield, MS (APCI) (M+1) m/z 317

Preparation of compounds of formula I. Method V

Aldehyde (3(w)) (50 mg. 0 159 mmol) was dissolved in 2 ml of anhydrous tetrohydrofuran or dichloromethane followed by {he addition of amine (29 5 mg 0 200 mmol) Catalytic acettc acid (5υL) and 4A molecular sieves were added to the solution and allowed to shake for 15-30 minutes After winch time was added MP-tnacetoxyborohydπde (180 mg, 0 396 mmol) The reaction was shaken overnight at room temperature MP-carbonate (300 mg, 0 765 mmol) was added to scavenge excess acefec acid along with 5eq of the respective scavenging agent (PS-tsocyanate resin fot secondary amines ot PS- benzafdehyde for primary amines) and let shake overnight Reaction was loaded onto a pre-equilibrated (with methanol) Waters Oasts 500 mg MCX cartndge and washed with methanol (10 x 2mL) Compounds of formula I were released from the column using IN ammonia in methanol solution (5 x 2mL) Product was isolated and chromatographed on silica gel using 1-10% methanol/dichloromelriane giadient

Method Vl

Aldehyde (3{i»» (20 mg. 0.063 mrnol) was dissolved in 2 mL of dichloromethane followed by addition of amine (96 mg, 0 0950mmol). and the reaction was stirred for about 30 minutes, after which time was added sodium tnacetoxyborohydnde (26.7 mg, 0 126 mmol) and stirred overnight at room temperature The reaction was quenched with ethyt acetate (3mL) and water (3mL) and allowed to stir for (en minutes after which time the aqueous layer was made basic by adding 10% ammonium hydroxide solution The solution was extracted with ethyl acetate (3 x 5 mL) The organic layer was dried over sodium sulfate, filtered and concentrated. Compounds of formula I were chromatographed on silica get using 5-20% methanol/dfchioromethane gradtent Examples:

4(a): (IR^Si-Bicyclo^^.ijhept^-yl-P'^pyrroiidtne-i-sulfonyD-bii^en yi-φ-ylmethylJ-amme

Prepared by Method V starting with 3(niχf) and bicyclo(22 1βiep!an-2-amine, giving 4(a) in 63 4% yield ¹ H NMR (400 MHz. CHLOROFORM-cQ ppm 1.08 - 1.18 (m. 1 H), 1.22 {br. S . 2 H), 1.25 - 1 32 (m, 1 H),

1 38 • 1 49 (m, 2 H), 1 48 • 1 54 (m, 4 H), 1 59 - 1 70 (m. 1 H). 1 74 - 1 86 (m. 1 H). 202 - 2.09 (m. 1 H) 2.19 - 2.26 <m. 1 H). 2.62 - 2J4 (m. 4 H), 2.91 - 301 (m, 1 H). 363 (t, 2 H), 7.13 - 7.21 (m. 2 H) ₁ 7 32 -

7 39 (m, 2 H) 740 - 749 (m, 2 H). 799 - 806 <m, 2 H) MS (APCI) (M+1) m/2411

4(b): (IS.δRj-€-^' ξPyrroiidine-i sulfonylJ btphenyl ^ ylmethyll-e aza bicyclop 2 1]octane

Prepared by Method Vl starting with 3{iii)(f) and 6-azabicycio{3,2.13octane, giving 4(b) in 37.8% yield. ¹ H

NMR (400 MHZ, METHANOL-Cf ₄ ) ppm 1 13 - 1 22 (m, 1 H). 1 64 - 1 98 (m, 8 H), 227 - 239 (m, 2 H) 263 - 2 77 (m, 2 H), 2.82 - 2 94 (m, 4 H), 3.36 - 3.44 (m. 2 H). 3.45 - 3.54 (m 1 H). 3 56 - 3.64 (m, 2 H),

395 - 4.03 (m 2 H), 442 (s, 2 H) 7.31 - 739 (m. 2 H), 7.52 (d, 2 H) _x 7 56 - 7.72 (m. 2 H), 8 02 - 8.10 (m,

2 H) MS (APCI) (M+1 ) m/2 411

4(c): 4-Methyl-1-[2'-(pyrrolfdine-1-sulfonyi)-bιphenyl-4-ylmethyl j-pιperidιn-4-o} Prepared by

Method V starting with 3(m)(f) and 4-methylpιpeπdιn-4-ol, giving 4(c) tn 75 3% yield ¹ H NMR (400 MHz CHLOROFORM-d) ppm 1 15 (s, 3 H), 1 42 - 1.55 (m. 6 H), 1 57 {dd. J=10 17. 3.94 Hz, 2 H), 224 -

2 36 (m, 2 H), 241 - 253 (m. 2 H), 260 - 2 72 (m, 4 H), 347 (s, 2 H), 7 17 - 7.23 (m, 2 H). 7 34 - 740 (m,

2 H). 7.43 - 7 50 (m. 2 H). 8.01 - 8 09 (m. 2 H). MS (APCi) (M+1) m/z 415

4(d): lsobutyl-(2'-(pyrrotιdfne-1-sulfonyl)-fc«phenyl-4-ylmethyf ]-amine Prepared by Method Vi starting with 3(ιιι)(f) and 2-methylpropan-i -amine, giving 4(d) in 82.1% yield ¹ H NMR (400 MHz, CHLOROFORM-d) ppm 1 03 - 1.15 (m. 6 H), 1 59 - 1.76 (m, 4 H) 2.21 - 2.35 (m, 1 H), 2.64 (br. s., 2

H), 279 - 289 <m. 4 H), 424 (br s , 2 H), 7 22 - 7 27 (m 1 H), 7 43 - 760 (m, 4 H), 767 - 7 7? (m. 2 H).

808 - 8 14 (m, 1 H) MS (APCI) (M+1) m'z 373

4(e): 3,3- Dimethyl λ \Z- (pyrrolidine- 1 sulfonyl) biphenyl-4 ylmethylj piperidine. Prepared by

Method V starting with 3(nt){f) and 3,3-dimethyipιperidine giving 4(e) in 840% yield. 1H NMR (400 MHz, CHLOROFORMS) ppm 084 (s, 6 H), 1.08 - 1 20 (m, 2 H), 1 41 - 1 5S (m. 6 H). 1 93 (br. s . 2 H), 2.25

(br. s.. 2 H). 2.59 - 2.72 <m, 4 H), 3.38 (s. 2 H), 7.21 (d, J=747 Hz 2 H), 7.37 (d, J=1.66 Hz, 2 H), 7 45

(dd. J=747. 1 66 Hz. 2 H), 8.07 (d, J=788 Hz 2 H) MS (APCI) (M+1) m/z 413.

4<f): (3-Mefhyl-oxetan-3-y!methyl)-[2'-(pyriOiidιne-1-suifonyl)-b iphenyi-4-ytmethytj-amine

Prepared by Method Vl starting with 3(ιiι)(f) and 1~(3-metbyloxetan-3-yl)methanamme, giving 4(f) in 38 0% yield *H NMR (400 MHz ₁ CHLOROFORM-d) ppm 1 33 (s. 3 H), 1 59 - 1 68 (m, 4 H), 278 - 286 (m. 4

H) ₁ 3.84 (S, 2 H), 3.89 (S, 2 H), 4.38 (d, 2 H) _: 4.48 <d, 2 H), 7.28 - 7.43 (m, 4 H), 7.45 - 7.52 (m. 1 H), 7.54 - 7.61 (m, 1 H), 8.11 - 8.17 (m, 1 H). MS (APCf) (M-M) m/2401.

4(9)- ({S)-2-Methoxy-i-methy!-etbyl)-I2 ^< -(ρyrrolictlr>e-1-suffonyi)-biphenyi-4-y}meth^}-amine

Prepared by Method Vl starting with 3(iii){f) and (2S)-1methoxypropan-2-amine. giving 4(g) in 47.0% yield. ¹ H NMR (400 MHz, CHLOROFORM-cf) .. ^; ppm 1.46 (s. 3 H), 1.66 (s. 4 H), 2.82 (s, 4 H). 3.27 (br. s ., 1 H). 3.42 (s _t 3 H), 3.60 (br. s., 1 H), 3.85 {br. s ., 1 H). 4.11 - 4.49 (m _: 2 H), 7.15 - 7.24 (m, 1 H), 7.38 -

7.60 (m, 4 H) ₁ 7.75 (br. s., 2 H), 8.10 (d. 1 H). MS (APCI) (M+1) m/z 389.

4(tι): [2'-(Pyrrolκ3fne-i-su!fonyl)-bipher»yl-4-ylmethyl]-(tetrah ydro-pyfan-4-yi)-amine. Prepared by

Method Vl starting with 3{iii)(f) and tetrahydro-2H-pyran-4-amine, giving 4(h) in 87 0% yield. ¹ H NMR (400 MH2, METHANOL-^) : ppm 1.63 - 1.84 (m, 4 H), 2.06 - 2.19 (m, 2 H) ₁ 2.87 - 2.99 (m, 3 H), 3.24 -

3.36 (m, 4 H), 3.39 - 3.54 (m. 2 H), 4.00 - 4 12 (m, 2 H), 4.31 (s, 2 H), 7.30 - 7.36 (m. 1 H). 7.46 - 7.63 (m,

5 H), 7.63 - 7.71 (m, 1 H) ₁ 8.03 (d. 1 H). MS (APCl) (M+1) m/z 400.

4(1): {2-(Pyrrolidirte-1-sulfonyi)-biphenyl-4-ylm6thylJ-(tetrahydr o-furatv3-yl)-amirte. Prepared by

Method Vl starting with 3(tii)(f) and tetrahydrofuraπ-3-amine, giving 4(j) in 27.1% yield. ¹ H NMR (400 MHz, CHLOROFORM-d) : ppm 1.42 - 1.58 (m, 4 H), 1.63 - 1.79 (m. 1 H), 1.94 - 2.09 (m, 1 H). 2.59 -

2.79 (m, 4 H). 3.25 - 3.44 (m, 1 H), 3.50 - 3.62 (m, 1 H), 3.62 - 3.78 (m, 4 H), 3.79 - 3.92 (m, 1 H) ₁ 7.11 -

7.21 (m, 2 H) _s 7.32 • 7.39 (m, 2 H), 7.41 • 7.48 (m, 2 H), 7 97 •• 8.04 (m, 2 H). MS (APCI) (M+1) m/2 387.

4{|): lsobυlyl-[2'-((f?)-2-methyi-pyrroiidine-1-sulfor»yl)-biphe nyl-4-ylmethyf]-amine. Prepared by

Method Vl starting with 3(itt)(a) and 2-methylρroρan-i-amine, giving 4(j) in 77.9% yield. ^'' H NMR (400 MHz, METHANOLS) ^; Ppm 0.96 (d. 3 H). 1.05 (d, 6 H). 1.40 - 1.52 (m, 2 H), 1.60 - 1.71 (m. 1 H), 1.73 -

1.92 (m, 2 H), 2.00 - 2.12 (m. 1 H), 2.85 - 3.04 (m, 3 H), 3.53 - 3.61 (m, 1 H), 4.28 (br. s... 2 H), 7.33 (dd, 2

H), 7.45 - 7.76 (m _: 4 H), 8.05 (d, 2 H). MS (APCI) (M+1) rn/z 387

4(k): (S.S-Dirnethyi-butylvp'^^-S-methyl-morpholine^-suffonyl^biph enyW-ylrnethylJ-arriine. Prepared by Method V starting with 3(»i)(b) and 3,3-dimethylbutan-i-amine, giving 4(k) in 36 1% yield. ¹ H NMR (400 MHz. CHLOROFORM-d) ;:: ppm 0.82 - 0.96 (m. 9 H), 1.06 - 1.19 (m. 3 H). 1.58 - 1.71 (m. 2 H), 2.67 - 2.79 (m, 1 H), 2.85 - 3.03 (m, 3 H), 3.03 - 3.16 (m. 2 H). 3.30 - 3.40 (m _t 2 H), 3.50 - 3.61 (m. 1 H), 4.10 (s _: 2 H), 7.19 - 7.26 (m, 1 H), 7.41 - 7.52 (m, 4 H), 7.53 - 7.61 (m, 1 H). 8.10 - 8.15 (m, 1 H), 8.39 (s. 1 H). MS (APCf) (M+1) m/z 431.

4(1): lsobυtyl42'-((S)-3-metriyl-morpholine-4-suffonyi)-biphenyl- 4-ylrnethySJ-afriine. Prepared by Method Vi starting with 3(iii)(b) and 2-methylpropan-i-amine, giving 4(1) in 42.2% yield. ¹ H NMR (400

MHZ. METHANOL-**,) : ppm 1.03 (d. 6 H), 1.16 (d, 3 H), 1.97 - 2.15 (m. 1 H), 2.72 - 2.83 (m, 1 H), 2.87 -

2.97 (m, 2 H). 2.98 - 3.10 (m, 1 H), 3 10 - 3.23 (m, 2 H), 3 23 - 3.45 (m, 2 H).. 3.53 - 3.65 (m, 1 H). 4.29 (s,

2 H). 7.36 (d, 1 H). 7.51 • 7.64 (m, 5 H), 7.66 •• 7.76 (m. 1 H), 8.14 (d, 1 H). MS (APCI) (M+1) m/2403.

4(m): (1 S,5/?)-6-(3-Fluoro-2'-(pyrroltdine-1-sυlfonyl)-biphenyM-ylm ethyl]-6-aza- bicyclo[3.2.1 Joctane. Prepared by Method Vl starting with 3(iii)(f) and 6-azabicyclo(3.2.1]octane, in 58.1 % yield. ¹ H NMR (400 MHz, METHANOL-^) ^; ppm 1.10 - 1.25 (m, 1 H), 1.60 - 2.01 (m, 8 H). 2.06 - 2.40 (tn, 1 H) _: 2.62 - 2.84 (m, 2 H), 2.87 - 3.05 (m. 4 H). 3.38 - 3.62 (m, 1 H), 3.63 - 3.76 (m, 1 H). 3.97 (br. s.. 1 H), 4.43 - 4.68 (m. 3 H), 7.30 - 7.42 <m _; 3 H), 7.58 - 7.82 (m, 3 H), 8.00 - 8.08 (m, 1 H). MS (APCi) (M+1 ) m/z 429. 4(n): 2-{1-[2'-(2-Hydroxymethyf-piperidine-1 -sulfonyf)-biphenyl-4-ylmethyS}-pipertdin-4-yl}-ethanol.

Prepared by Method Vi, starting with 2'-{[2-(hydroxymethyl)piperidtn-1-yij$utfonyf}-biphenyi-4~

carbaldehyde and 2-piperidin-4~yiethanoi, giving 4(n) in 67.0% yield ¹ H NMR (400 MHz, METHANOL d,) ppm 1.09 - 1.27 (m. 2 H), 1.35 - 1.58 (m. 6 H), 1.64 - 1.88 (m. 2 H), 1.94 - 2.08 (m, 2 H), 2.64 - 2.79 (m,

1 H), 2.97 - 3.12 (m, 3 H) _; 3.38 - 3.58 (m, 5 H), 3.56 - 3.69 (m. 3 H), 4.37 (br S., 2 H), 7.34 (d. 1 H), 7.54 - 7.63 (m. 5 H). 7.64 - 7.71 (m, 1 H). 8.14 (d. 1 H). MS (APCI) (M+1) m/z 473. 4(o}: BicydolS.S.Ilhept^-yi-lS^uoro-SM^ffJ-a-methyl-moφholtne^-su lfonyO-biphenyM- ylmethyl}-amine. Prepared by Method V starting with 3{iii}(d) and 3,3-dimetnyibutan-i -amine, giving 4{o) in 26.0% yield. ¹ H NMR (400 MHz. CHLOROFORM-^ ppm 0.91 (s, 9 H), 1.17 (d. 3 H) ₁ 1.60 - 1.71 (m,

2 H). 2.77 - 2.87 <m. 1 H), 2.89 - 2.99 (m, 1 H), 3.01 - 3.11 <m, 1 H), 3.13 - 3.26 (m, 2 H) ₁ 3.38 - 3.49 (m, 2 H). 3.59 - 3.69 (m. 1 H). 4 19 (s, 2 H), 7 21 - 7 33 (rα 2 H) ₁ 7.52 (dd. 1 H), 7.60 (dd _: 2 H), 8.12 <dd, 1 H), 8.39 (S, 2 H). MS (APCl) (M+1) m/z 449.

4(p): B(cydo(2.2.1]hept-2-yK3-ftuotO-2 ^* -({f?)-3-niethy{-morpholfne-4-sulfbnyl)-biphenyl-4- ylmethylj-amine. Prepared by Method V starting with 3(iii)(d) and bicyclo[2.2.1]heptan-2-amine. giving 4(p) in 35.1% yield. ⁵ H NMR (400 MHz, CHLOROFORM-tf) ppm 0.66 - 0.80 <m _: 1 H). 1.16 (d, 3 H), 1.19 • 1 28 (m, 1 H), 1.28 - 1 51 (m, 2 H), 1.52 - 1 66 (m. 1 H). 1 72 - 1.83 (m. 1 H). 1.88 - 2.01 (m, 2 H), 2.00 - 2.14 (m, 1 H), 2.17 - 2.31 (m, 2 H), 2.40 - 2.48 (m, 1 H), 2.57 (br. s., 1 H), 2.63 (S, 1 H). 2.81 «3. 1 H), 2.99 - 3.11 (m. 1 H), 3.15 - 3.26 (m, 2 H), 3.33 • 3.49 (m, 3 H), 3.60 - 3 69 (m, 1 H), 4.06 - 4 22 <rn. 3 H), 7.19 • 7.32 (m, 1 H). 7.48 •• 7.55 (m, 1 H), 7.56 • 7.65 (m. 2 H), 8.08 • 8.15 (m, 1 H). 8.34 (s, 2 H). MS (APCi) (M+ 1) m/z 459.

4(q): [3-FJuoro-2'-((S)-3-metnyl-moφho!ine-4-su(fonyf)-btphenyt-4 -yimethyfHsobutyi-amJne Prepared by Method Vl starting with 3(«iχd) and 2-methylpropan-1 -amine., starting with 3(ιii)(d) giving 4(q) in 45.6% yield. ¹ H NMR (400 MHz, METHANOL-d.) ppm 1.06 (d, 6 H), 1.18 (d, 3 H), 2.02 - 2.17 (m. 1 H), 2.81 - 2.90 (rn. 1 H), 2.93 - 3.01 (m. 2 H). 3.05 - 3.16 (m. 1 H), 3.17 - 3.28 (m, 2 H), 3.39 - 3.50 (m, 2 H), 3.60 - 3.70 (m, 1 H), 4.37 (s, 2 H), 7.35 - 743 (m. 3 H), 7.59 - 7.67 <m, 2 H). 7.69 - 7.76 (m, 1 H). 8.11 - 8.16 (m, 1 H). MS (APCi) (M+1) m/z 421. 4(r): [3-Fiuoro-2'-<(R)-2-rnethyl-pyrroiidme- 1 -sulfonyl)-biphenyl-4-yimethyl)-isobutyl-amine.

Prepared by Method Vl starting with 3(HtKa) and 2-methyfpropan-1 -amine, giving 4(r) in 95.0% yield. ¹ H NMR (400 MHz, METHANOL-*) ppm 1.01 (d, 4 H), 1.08 ((J. 7 H), 1.46 - 1.58 (m, 1 H), 1.64 - 1.77 (m, 1 H), 1.78 - 2.00 (m, 3 H), 2.00 - 2.15 (m, 1 H), 2.87 - 3.14 (m. 5 H), 3.57 - 3.77 (m, 1 H), 4.35 (S, 2 H). 7.30 - 7.39 (m, 3 H), 7.57 - 7.66 (m, 2 H). 7.66 - 7.74 (m, 1 H). 8.02 - 8.07 (m, 1 H). MS (APCI) (M+1) m/z 405.

4(s): (3,3-Oimethy!-butyf)-{4-l2-(pyrrolidine-i-suffonyl)-ρyπdι n-3-yll-benzyl>-amine. Prepared by Method V starting with 3(iii)(c) and 3,3-dimethylbutan-1-amtne, giving 4(s) in 64.0% yield ¹ H NMR (400 MHz. CHLOROFORM (S) ppm 0.89 (S, 9 H), 1.45 • 1.56 (m. 2 H), 1.95 • 2.04 (m, 4 H), 2.67 • 2.78 (m, 2 H), 3.45 - 3.56 (m, 4 H), 3.89 (s, 2 H). 7.40 - 7.53 (m, 5 H), 7.70 - 7.77 (m, 1 H), 8.49 - 8.57 (m, 1 H). MS (APCi) (M+1) mlz 402.

4(t): (5S,6R)-Bιcycio{2.2.i}tøpt-2-yl-{4-}2-(pyffθiιd(ne-i-sul fonyi)-pyrκ}ιn-3-yl3-benzyf}-amine. Prepared by Method V starting with 3(iii)(c) and bicycio[2.2.1]heptan-2~amine. giving 4(t) in 17 0% yield. ¹ H NMR (400 MHz, CHLOROFORM S) ppm 0.67 - 0.77 (m, 1 H), 1.18 - 1.29 (m, 1 H), 129 - 1.44 (m, 1 H), 1.48 - 1.61 (m _; 1 H), 1.66 - 1.81 (m, 3 H), 1.88 - 1.98 (m, 1 H). 1.98 - 2.04 (m, 4 H), 2.13 - 2,21 (m. 1 H), 2.30 - 2.40 (m, 1 H), 3.07 - 3.17 (m. 1 H), 3.45 - 3.56 (m, 4 H), 3.76 (dd. 2 H), 7.40 - 7.51 (m. 5 H). 7.72 - 7.79 (m, 1 H), 8.49 - 8.57 (m, 1 H) MS (APCi) (M+1) m/z 412.

4<u): 4^Cyclopentylaminomethyl biphenyl-2 su}fonic acid isopropyl methy ⁾ amide. Prepared by Method Vi starting with 4 ^> -fcrTOyt-N-isopropyM\l-methytbiphenyl-2-sulfonamide and cydopentanamine. giving 4(u) In 40.0% yield. 1H NMR (400 MHz.. CHLOROFORM-d) ; .: ppm 0.88 <d, 6 H), 1.32 - 1.63 (m, 4 H). 1.66 - 1.78 (m, 2 H), 1.81 - 1.94 (m, 2 H), 2.20 (s. 3 H), 3.09 - 3.20 (m. 1 H). 3.64 - 3.76 <m, 1 H). 3.82 {s. 2 H). 7.25 - 7.32 (ro. 1 H). 7.32 - 7.43 (m, 4 H), 7.42 - 7.50 (m, 1 H) ₁ 7.51 - 7.59 <m. 1 H), 8.10 - 8.18 (ro. 1 H). MS (APCl) (M+1) m/z 387.

4(v): 4'-0sobutylamino-methyl)-btphenyt-2~sutfonic acid isopropyf-methyl-amide. Prepared by

Method Vl starting with starting with 3(iiiKg) and 2-methyipropan-i -amine, giving 4<v) in 24.3% yield. ¹ H

NMR (400 MHz. METHANOL-(Z ₄ ) ppm 0.90 - 0.98 (m, 6 H), 0.98 - 1.11 (m. 6 H). 1.93 - 2.15 (m, 1 H), 2.26 - 2.41 (m, 3 H), 2.82 - 2.98 (m. 2 H), 3.62 - 3.83 (m, 1 H), 4.27 {br. s., 2 H). 7.27 - 7.36 (m, 1 H), 7.45

- 7.63 {m, 5 H), 7.63 - 7.73 (m, 1 H), 8.02 - 8.11 (m, 1 H). MS (APCI) (M+1 ) m/z 375.

4(w): (3,3-Dimethy)-butyl)-{4-{3-(pyrro!idtne-1-sulfonyl)-pyridiπ -2-yf]-benzyl}-amtne. Prepared by

Method V stalling with 3(iii)(g) and 3.3-dlmethyibutan-1-amine, giving 4(w) in 52.0% yield. ¹ H NMR (400

MHz. CHLOROFORM-d) J ppm 0.91 (s, 9 H), 1.52 - 1.59 (m, 2 H), 1.60 - 1.65 (m, 4 H), 2.67 - 2.74 (m, 2 H), 2.78 - 2.86 (m, 4 H), 3.96 (S, 2 H). 7.42 - 7.47 (nr 1 H). 7.49 - 7.54 (m, 2 H), 7.58 - 7.63 (m. 2 H), 8.46

(dd, 1 H), 8.80 (dd, 1 H). MS (APCI) (M+1) m/z 402.

4(x): (1S.4R)-8icycio{2.2.13hept-2-yl {4 J3 (pyιτofidine-1 suifonyi>pyridin-2 yl3 benzy^ amine. Prepared by Method V starting Yi'ith4-(3-(pyyrrotidin-1-y|$ulfonyl)-pyridin-2-yi]benzaldeh yde and bicycio^.iJheptan-σ-amine, giving 4<x) in 67 0% yield. ¹ H NMR (400 MHz, CHLOROFORM-cf) : ppm 0.63 - 0.74 (ro, 1 H), 1.16 - 1.26 (m, 1 H), 1.27 - 1.42 (m, 3 H), 1.46 - 1.65 (m. 5 H), 1.67 - 1.78 (m, 1 H), 1.81 - 1.93 (m, 1 H), 2.10 - 2.18 (m, 1 H), 2.24 - 2.33 (m, 1 H), 2.73 - 2.85 (m _: 4 H), 2.98 - 3.07 (m, 1 H), 3.75 (dd, 2 H), 7.37 - 7.45 (rn. 3 H), 7.55 (d. 2 H), 8.40 - 8.48 (m _: 1 H), 8 74 - 8.82 (m, 1 H). MS (APC!) (M+1) m/z 412.

4(y): lsobutyi-{3-methoxy-2 ^> -(pyrroSdine-1-sυ!fonyl)-bipheπyl-4-ylmethyl]-amine. Prepared by Method Vi starting with 3(iti)(f) and 2-methylpfopan-1-amine, giving 4(y) in 72.0% yield. ¹ H NMR (400

MHz, METHANOL-Cf ₄ ) : ppm 0.96 - 1.14 (m. 4 H), 1.15 - 1.47 (m. 3 H), 1.60 - 1.90 (m, 4 H), 1.97 - 2.19

(m, 1 H), 2.76 - 3.05 (m, 5 H), 3.94 (s, 3 H), 4.28 (s, 2 H). 7.04 (d, 1 H), 7.20 (br. s., 1 H), 7.32 - 7 50 (m, 2

H), 7.54 - 7.74 (m, 2 H). 8.05 (d, 1 H). MS (APCI) (M+1) m/z 403.

Ail of the above recited U.S. patents and publications are incorporated herein by reference.