US 2011 000.9465A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/00094.65 A1 Stangeland et al. (43) Pub. Date: Jan. 13, 2011

(54) 3-PHENOXYMETHYLPYRROLIDINE A6IP 29/00 (2006.01) COMPOUNDS A6IP 25/28 (2006.01) A6IP 25/08 (2006.01) (76) Inventors: Eric Stangeland, Pacifica, CA A6IP 43/00 (2006.01) (US); Daisuke Roland Saito, Burlingame, CA (US); Adam (52) U.S. Cl...... 514/428: 548/570 Hughes, Belmont, CA (US); Jane (57) ABSTRACT Schmidt, San Francisco, CA (US); Priscilla Van Dyke, San Francisco, In one aspect, the invention relates to compounds of formula CA (US); Lori Jean Patterson, San I: Francisco, CA (US)

Correspondence Address: (I) THERAVANCE, INC. 901 GATEWAY BOULEVARD SOUTH SAN FRANCISCO, CA 94080 (US) (21) Appl. No.: 12/834,128 (22) Filed: Jul. 12, 2010 Related U.S. Application Data (60) Provisional application No. 61/225,074, filed on Jul. 13, 2009. N Publication Classification where R'' are as defined in the specification, or a pharma (51) Int. Cl. ceutically acceptable salt thereof. The compounds of formula A6 IK3I/40 (2006.01) I are serotonin and norepinephrine reuptake inhibitors. In C07D 207/08 (2006.01) another aspect, the invention relates to pharmaceutical com A6IP 25/24 (2006.01) positions comprising Such compounds; methods of using A6IP 25/00 (2006.01) Such compounds; and process and intermediates for prepar A6IP 25/04 (2006.01) ing Such compounds. US 2011/00094.65 A1 Jan. 13, 2011

3-PHENOXYMETHYLPYRROLIDNE agents having more balanced SERT and NET affinity or COMPOUNDS slightly higher NET affinity are expected to be particularly useful for treating chronic pain while producing fewer side CROSS-REFERENCE TO RELATED effects, such as nausea. 0009. Thus, a need exists for novel compounds that are APPLICATIONS useful for treating chronic pain, Such as neuropathic pain. In 0001. This application claims the benefit of U.S. Provi particular, a need exists for novel compounds that are useful for treating chronic pain and that have reduced side effects, sional Application No. 61/225,074, filed on Jul. 13, 2009; the Such as nausea. A need also exists for novel dual-acting com entire disclosure of which is incorporated herein by reference. pounds that inhibit both SERT and NET with high affinity (e.g., pICsoe8.0 or Ks 10 nM) and balanced inhibition (e.g., BACKGROUND OF THE INVENTION a SERT/NET binding K, ratio of 0.1 to 100). 0002 1. Field of the Invention SUMMARY OF THE INVENTION 0003. The present invention relates to 3-phenoxymeth 0010. The present invention provides novel compounds ylpyrrolidine compounds having activity as serotonin (5-HT) that have been found to possess serotonin reuptake inhibitory and norepinephrine (NE) reuptake inhibitors. The invention activity and norepinephrine reuptake inhibitory activity. also relates to pharmaceutical compositions comprising Such Accordingly, compounds of the invention are expected to be compounds, processes and intermediates for preparing Such useful and advantageous as therapeutic agents for those dis eases and disorders that can be treated by inhibition of the compounds and methods of using Such compounds to treat a serotonin and/or norepinephrine transporter, Such as neuro pain disorder, Such as neuropathic pain, and other ailments. pathic pain. 0004 2. State of the Art 0011. One aspect of the invention relates to a compound of 0005 Pain is an unpleasant sensory and emotional expe formula I: rience associated with actual or potential tissue damage, or described interms of such damage (International Association for the Study of Pain, Pain Terminology). Chronic pain per (I) sists beyond acute pain or beyond the expected time for an R3 injury to heal (American Pain Society. “Pain Control in the Primary Care Setting.” 2006:15). Neuropathic pain is pain R R2 initiated or caused by a primary lesion or dysfunction in the nervous system. Peripheral neuropathic pain occurs when the lesion or dysfunction affects the peripheral nervous system R5 O RI and central neuropathic pain when the lesion or dysfunction R6 affects the central nervous system (IASP). 0006. Several types of therapeutic agents are currently used to treat neuropathic pain including, for example, tricy N clic antidepressants (TCAS), serotonin and norepinephrine H reuptake inhibitors (SNRIs), calcium channel ligands (e.g., gabapentin and pregabalin), topical lidocaine, and opioid where: agonists (e.g., morphine, oxycodone, methadone, levorpha (0012) R' is selected from Calkyl, -Clscycloalkyl nol and tramadol). However, neuropathic pain can be very optionally substituted with 1 or 2 fluoro atoms, —Calk difficult to treat with no more than 40-60% of patients achiev enyl, and - C-alkynyl; ing, at best, partial relief of their pain (R. H. Dworkin et al. (0013 R’ through R are independently selected from (2007) Pain 132:237-251 at 247). Moreover, all of the thera hydrogen, halo. —Calkyl, -CF, -O-C-alkyl, —CN. peutic agents currently used to treat neuropathic pain have —C(O)—Calkyl, —S Calkyl, -C scycloalkyl, and NO; or R and R are taken together to form various side effects (e.g., nausea, sedation, dizziness and -CH=CH-CH=CH-; or RandR are taken together to Somnolence) that can limit their effectiveness in some form - CH-CH=CH-CH ; patients (Dworkin et al. Supra. at 241). 0014 with the proviso that when R is ethyl, R is fluoro, 0007 SNRIs, such as dulloxetine and Venlafaxine, are R" is chloro, R is hydrogen, and R is hydrogen, then R is not often used as first line therapy for treating neuropathic pain. fluoro or chloro; These agents inhibit the reuptake of both serotonin (5-hy 00.15 or a pharmaceutically acceptable salt thereof. droxytrypamine, 5-HT) and norepinephrine (NE) by binding 0016. Another aspect of the invention relates to com to the serotonin and norepinephrine transporters (SERT and pounds of formula I having a configuration selected from: NET, respectively). However, both duloxetine and Venlafax ine have higher affinity for SERT relative to NET (Vaishnavi R3 R3 et al. (2004) Biol. Psychiatry 55(3):320-322). R R2 R R2 0008 Preclinical studies suggest that inhibition of both

SERT and NET may be necessary for maximally effective treatment of neuropathic and other chronic pain states (Jones et al. (2006) Neuropharmacology 51 (7-8): 1172-1180: Vick ers et al. (2008) Bioorg. Med. Chem. Lett. 18:3230-3235: Fishbain et al. (2000) Pain Med. 1(4):310-316; and Mochi Zucki (2004) Human Psychopharmacology 19:S15-S19). However, in clinical studies, the inhibition of SERT has been reported to be related to nausea and other side effects (Greist et al. (2004) Clin. Ther. 26(9): 1446-1455). Thus, therapeutic US 2011/00094.65 A1 Jan. 13, 2011

iting norepinephrine reuptake in a mammal comprising -continued administering to the mammal, a norepinephrine transporter R3 R3 inhibiting amount of a compound of the invention. And another aspect of the invention relates to a method for inhib R R2 R R2 iting serotonin reuptake and norepinephrine reuptake in a mammal comprising administering to the mammal, a seroto nin transporter- and norepinephrine transporter-inhibiting R5 R, and R amount of a compound of the invention. 0020 Since compounds of the invention possess serotonin R6 H R6 reuptake inhibitory activity and norepinephrine reuptake inhibitory activity, Such compounds are also useful as research tools. Accordingly, one aspect of the invention relates to a method of using a compound of the invention as a research tool, comprising conducting a biological assay using or enriched in a stereoisomeric form having Such configura a compound of the invention. Compounds of the invention tion. can also be used to evaluate new chemical compounds. Thus 0017. Yet another aspect of the invention relates to phar another aspect of the invention relates to a method of evalu maceutical compositions comprising a pharmaceutically ating a test compound in a biological assay, comprising: (a) acceptable carrier and a compound of the invention. Such conducting a biological assay with a test compound to pro compositions may optionally contain other active agents such vide a first assay value; (b) conducting the biological assay as anti-Alzheimer's agents, anticonvulsants, antidepressants, with a compound of the invention to provide a second assay anti-Parkinson's agents, dual serotonin-norepinephrine value; wherein step (a) is conducted either before, after or reuptake inhibitors, non-steroidal anti-inflammatory agents, concurrently with step (b); and (c) comparing the first assay norepinephrine reuptake inhibitors, opioid agonists, selective value from step (a) with the second assay value from step (b). serotonin reuptake inhibitors, Sodium channel blockers, sym Exemplary biological assays include a serotonin reuptake patholytics, and combinations thereof. Accordingly, in yet assay and a norepinephrine reuptake assay. Still another another aspect of the invention, a pharmaceutical composi aspect of the invention relates to a method of studying a tion comprises a compound of the invention, a second active biological system or sample comprising serotonin transport agent, and a pharmaceutically acceptable carrier. Another ers, norepinephrine transporters, or both, the method com aspect of the invention relates to a combination of active prising: (a) contacting the biological system or sample with a agents, comprising a compound of the invention and a second compound of the invention; and (b) determining the effects active agent. The compound of the invention can be formu caused by the compound on the biological system or sample. lated together or separately from the additional agent(s). 0021. The invention also relates to processes and interme When formulated separately, a pharmaceutically acceptable diates useful for preparing compounds of the invention. carrier may be included with the additional agent(s). Thus, yet Accordingly, one aspect of the invention relates to a process another aspect of the invention relates to a combination of for preparing compounds of formula I, the process compris pharmaceutical compositions, the combination comprising: a ing deprotecting a compound of formula XI: first pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a first pharmaceutically acceptable carrier; and a second phar (XI) maceutical composition comprising a second active agent and a second pharmaceutically acceptable carrier. The invention also relates to a kit containing Such pharmaceutical compo sitions, for example where the first and second pharmaceuti cal compositions are separate pharmaceutical compositions. 0018 Compounds of the invention possess serotonin reuptake inhibitory activity and norepinephrine reuptake inhibitory activity, and are therefore expected to be useful as therapeutic agents for treating patients Suffering from a dis ease or disorder that is treated by the inhibition of the sero tonin and/or the norepinephrine transporter. Thus, one aspect of the invention relates to a method of treating: a pain disorder Such as neuropathic pain; a depressive disorder Such as major depression; an affective disorder Such as an anxiety disorder; or a salt thereof, where P is an amino-protecting group to attention deficit hyperactivity disorder, a cognitive disorder provide compounds of formula I, where R' and R are as Such as dementia; stress urinary incontinence; obesity; or defined for formula I. In other aspects, the invention relates to vasomotor symptoms associated with menopause, compris novel intermediates used in Such processes. ing administering to a patient a therapeutically effective 0022. Yet another aspect of the invention relates to the use amount of a compound of the invention. of a compound of the invention for the manufacture of a 0019. Still another aspect of the invention relates to a medicament, especially for the manufacture of a medicament method for inhibiting serotonin reuptake in a mammal com useful for treating pain disorders, depressive disorders, affec prising administering to the mammal, a serotonin transporter tive disorders, attention deficit hyperactivity disorder, cogni inhibiting amount of a compound of the invention. Yet tive disorders, stressurinary incontinence, for inhibiting sero another aspect of the invention relates to a method for inhib tonin reuptake in a mammal, or for inhibiting norepinephrine US 2011/00094.65 A1 Jan. 13, 2011

reuptake in a mammal. Still another aspect of the invention where applicable, all cis-trans or E/Z isomers (geometric relates to the use of a compound of the invention as a research isomers), tautomeric forms and topoisomeric forms of the tool. Other aspects and embodiments of the invention are compounds of the invention are included within the scope of disclosed herein. the invention unless otherwise specified. 0026. More specifically, compounds of formula I contain DETAILED DESCRIPTION OF THE INVENTION at least two chiral centers indicated by the symbols * and ** 0023. In one aspect, this invention relates to novel com in the following formula: pounds of formula I:

(I)

::::::

N H N H 0027. In one stereoisomer, both carbonatoms identified by the * and * symbols have the (R) configuration. This or a pharmaceutically acceptable salt thereof. embodiment of the invention is shown in formula Ia: 0024. As used herein, the term “compound of the inven tion' includes all compounds encompassed by formula I Such as the species embodied in formula Ia-Id, II-IV and all other (Ia) subspecies of such formulas. In addition, when the compound of the invention contain a basic or acidic group (e.g., amino or carboxyl groups), the compound can exist as a free base, free acid, or in various salt forms. All Such salt forms are included within the scope of the invention. Accordingly, those skilled in the art will recognize that reference to a compound herein, for example, reference to a “compound of the invention” or a “compound of formula I includes a compound of formula I as well as pharmaceutically acceptable salts of that com pound unless otherwise indicated. Furthermore, solvates of compounds of formula I are included within the scope of this invention. 0025. The compounds of formula I contain at least two chiral centers and therefore, these compounds may be pre In this embodiment, compounds have the (R,R) configuration pared and used in various stereoisomeric forms. Accordingly, at the * and ** carbon atoms or are enriched in a stereoiso the invention also relates to racemic mixtures, pure stereoi meric form having the (R,R) configuration at these carbon Somers (e.g., enantiomers and diastereoisomers), Stereoiso atOmS. mer-enriched mixtures, and the like unless otherwise indi 0028. In another stereoisomer, both carbon atoms identi cated. When a chemical structure is depicted herein without fied by the * and ** symbols have the (S) configuration. This any stereochemistry, it is understood that all possible stere embodiment of the invention is shown in formula Ib: oisomers are encompassed by Such structure. Thus, for example, the terms “compound of formula I.” “compounds of formula II, and so forth, are intended to include all possible (Ib) Stereoisomers of the compound. Similarly, when a particular stereoisomer is shown or named herein, it will be understood by those skilled in the art that minor amounts of other stere oisomers may be present in the compositions of the invention unless otherwise indicated, provided that the utility of the composition as a whole is not eliminated by the presence of Such other isomers. Individual enantiomers may be obtained by numerous methods that are well known in the art, includ ing chiral chromatography using a suitable chiral stationary phase or Support, or by chemically converting them into dias tereoisomers, separating the diastereoisomers by conven tional means such as chromatography or recrystallization, then regenerating the original enantiomers. Additionally, US 2011/00094.65 A1 Jan. 13, 2011

In this embodiment, compounds have the (S,S) configuration the invention, the compound of formula I is 3-1-(4-chloro at the * and ** carbon atoms or are enriched in a stereoiso phenoxy)-2-methylpropylpyrrolidine having a configura meric form having the (S,S) configuration at these carbon tion selected from: atOmS. 0029. In yet another stereoisomer, the carbon atom iden tified by the symbol * has the (S) configuration and the carbon atom identified by the symbol ** has the (R) configuration. This embodiment of the invention is shown in formula Ic:

(Ic)

In this embodiment, compounds have the (S,R) configuration C at the * and ** carbon atoms or are enriched in a stereoiso meric form having the (S,R) configuration at these carbon atOmS. 0030. In still another stereoisomer, the carbon atom iden O, tified by the symbol * has the (R) configuration and the carbon atom identified by the symbol ** has the (S) configuration. This embodiment of the invention is shown in formula Id:

(Id)

or enriched in a stereoisomeric form having Such configura tion. For example, in one embodiment of the invention, the compound of formula I is (R)-3-((R)-1-(4-chloro-phenoxy)- In this embodiment, compounds have the (R.S) configuration 2-methylpropylpyrrolidine or enriched in a stereoisomeric at the * and ** carbon atoms or are enriched in a stereoiso form having Such configuration. In another embodiment, the meric form having the (R.S) configuration at these carbon compound of formula I is (S)-3-(S)-1-(4-chlorophenoxy)-2- atOmS. methylpropylpyrrolidine or enriched in a stereoisomeric 0031 Compounds of formula Ia and Ib are enantiomers form having Such configuration. In yet another embodiment, and therefore, in separate aspects, this invention relates to the compound of formula I is (S)-3-((R)-1-(4-chlorophe each individual enantiomer (i.e., Ia or Ib), a racemic mixture noxy)-2-methylpropylpyrrolidine or enriched in a stereoiso of Ia and Ib, or an enantiomer-enriched mixture of Ia and Ib meric form having Such configuration. In still another comprising predominately Ia or predominately Ib. Similarly, embodiment, the compound of formula I is (R)-3-(S)-1-(4- compounds of formula Ic and Id are enantiomers and there chlorophenoxy)-2-methylpropylpyrrolidine or enriched in a fore, in separate aspects, this invention relates to each indi Stereoisomeric form having such configuration. vidual enantiomer (i.e., Ic or Id), a racemic mixture of Ic and 0033. In some embodiments, in order to optimize the Id, or a enantiomer-enriched mixture of Ic and Id comprising therapeutic activity of the compounds of the invention, e.g., to predominately Ic or predominately Id. treat neuropathic pain, it may be desirable that the carbon 0032. In one embodiment of the invention, the compound atoms identified by the * and * symbols have a particular of formula I is 3-1-(4-chloro-phenoxy)-2-methylpropylpyr (R,R), (S,S), (S,R), or (R.S) configuration or are enriched in a rolidine or a stereoisomer thereof. In another embodiment of Stereoisomeric form having Such configuration. For example, US 2011/00094.65 A1 Jan. 13, 2011

in one embodiment, the compounds of the invention have the ments or to limit the scope of the invention. In this regard, the (S,R) configuration of formula Ic or are enriched in a stere representation that a particular value or Substituent is pre oisomeric form having the (S,R) configuration, and in another ferred is not intended in any way to exclude other values or embodiment, the compounds of the invention have the (R.S.) Substituents from the invention unless specifically indicated. configuration of formula Id, or are enriched in a stereoiso 0039. In one aspect, this invention relates to compounds of meric form having the (R.S) configuration. In other embodi formula I: ments, the compounds of the invention are present as racemic mixtures, for example as a mixture of enantiomers of formula Ia and Ib, or as a mixture of enantiomers of formula Ic and Id. (I) 0034. This invention also includes isotopically-labeled R3 compounds of formula I, i.e., compounds of formula I where one or more atoms have been replaced or enriched with atoms R R2 having the same atomic number but an atomic mass different from the atomic mass that predominates in nature. Examples of isotopes that may be incorporated into a compound of R5 O RI formula I include, but are not limited to H, H, C, C, C, N, 1N, O, 7O, O, SS, C1, and F. Of particular R6 interest are compounds of formula I enriched in tritium or carbon-14 which can be used, for example, in tissue distribu N tion studies; compounds of formula I enriched in deuterium H especially at a site of metabolism resulting, for example, in compounds having greater metabolic stability; and com pounds of formula I enriched in a positron emitting isotope, 10040) R' is —C2-alkyl, -C-scycloalkyl optionally sub such as 'C, F, 'OandaN, which can be used, for example, stituted with 1 or 2 fluoro atoms, —Calkenyl, or —C. in Positron Emission Topography (PET) studies. 6alkynyl. In one embodiment, R' is —Coalkyl, examples of 0035. The compounds of the invention have been found to which include ethyl, propyl, isopropyl, butyl, isobutyl, and possess serotonin reuptake inhibitory activity and norepi 3-pentyl. In another embodiment, R' is —Clscycloalkyl, nephrine reuptake inhibitory activity. Among other proper examples of which include cyclopropyl, cyclopentyl, and ties, such compounds are expected to be useful as therapeutic cyclohexyl. In another embodiment, the —Clscycloalkyl is agents for treating chronic pain, Such as neuropathic pain. By substituted with 1 or 2 fluoro atoms, examples of which combining dual activity into a single compound, double include, 4.4-difluorocyclohexyl. In another embodiment, R' therapy can be achieved, i.e., serotonin reuptake inhibitory is —Calkenyl, examples of which include but-3-enyl. In activity and norepinephrine reuptake inhibitory activity, another embodiment, R' is —Cs-alkynyl, examples of which using a single active component. Since pharmaceutical com include prop-2-ynyl. positions containing one active component are typically I0041) R' through R are independently selected from easier to formulate than compositions containing two active hydrogen, halo. —Calkyl, -CF, -O-C-alkyl, —CN. components, such single-component compositions provide a —C(O)—Calkyl, -S-C alkyl, -C scycloalkyl, and significant advantage over compositions containing two - NO.; or R and R are taken together to form active components. -CH=CH-CH=CH-; or RandR are taken together to 0036 Many combined serotonin and norepinephrine form - CH CH-CH CH . reuptake inhibitors (SNRIs) are more selective for SERT than 0042. It is noted however, that when R' is ethyl, R is for NET. For example, milnacipran, dulloxetine, and ven fluoro, R is chloro, R is hydrogen, and R is hydrogen, then lafaxine and exhibit 2.5-fold, 10-fold, and 100-fold selectiv R is not fluoro or chloro. ity (measured as pK.) for SERT over NET, respectively. 10043. In one embodiment, when R' is ethyl, R is chloro, Some, however, are less selective, such as bici fadine, which Rischloro, Rishydrogen, and Rishydrogen, then R is not has a pK, at SERT of 7.0 and a pK, atNET of 6.7. Since it may hydrogen. be desirable to avoid selective compounds, in one embodi ment of the invention the compounds have a more balanced 0044. In some embodiments of the invention, one or more SERT and NET activity. positions on the aryl ring are Substituted with a non-hydrogen 0037. The nomenclature used herein to name the com moiety. For example, one such embodiment may be described pounds of the invention is illustrated in the Examples herein. by stating that that “R is a non-hydrogen moiety”. It is This nomenclature has been derived using the commercially understood that this means that R can be any of the non available AutoNom software (MDL, San Leandro, Calif.). hydrogen moieties defined in formula I, i.e., halo. —C. Compounds of formula I have a 3-phenoxymethylpyrrolidine 6alkyl, -CF, —O—Calkyl, -CN. —C(O)—Calkyl, —S—Calkyl, -CF, —Clscycloalkyl, and —NO, or it core. Thus, compounds of formula I where R' is —C2-alkyl is taken together with R to form -CH=CH-CH=CH have been named as 3-(1-phenoxyalkyl)pyrrolidines, and so or taken together with R to form - CH-CH=CH-CH-. forth. In one embodiment, at least one of the R through R groups is a non-hydrogen moiety. In another embodiment, at least Representative Embodiments two of the R through R" groups are non-hydrogen moieties. 0038. The following substituents and values are intended In still yet another embodiment, at least three of the R to provide representative examples of various aspects and through R" groups are non-hydrogen moieties. In one embodiments of the invention. These representative values embodiment, at least four of the R through R groups are are intended to further define and illustrate such aspects and non-hydrogen moieties, and in still another embodiment, all embodiments and are not intended to exclude other embodi of the R through R groups are non-hydrogen moieties. US 2011/00094.65 A1 Jan. 13, 2011

0045 Exemplary halo groups include fluoro, chloro, where R-R are as defined for formula I. In yet another bromo, and iodo. Exemplary —C-alkyl groups include embodiment, R' is —Coalkynyl, which is depicted as for —CH (“Me'), —CHCH (“Et”), and -CH(CH). Exem mula V: plary —O—Calkyl groups include —OCH (“OMe'), —O CHCH, and —OCH(CH). Exemplary —C(O)— Calkyl groups include —C(O)CH and —C(O)CHCH. (V) Exemplary —S C-alkyl groups include —SCH. Exem plary —Clscycloalkyl groups include cyclohexyl. 0046) In one embodiment, R' is C-alkyl, which is depicted as formula II:

(II)

N

where R-R are as defined for formula I. 10047. In one particular embodiment, R and Rare non N hydrogen moieties, while R. R. and Rare hydrogen, which H is depicted as formula VI: where R-R areas defined for formula I. In anotherparticular embodiment, R' is Calkyl. In anotherembodiment, R' is —C cycloalkyl optionally substituted with 1 or 2 fluoro (VI) atoms, which is depicted as formula III:

(III)

N

N H where R' is as defined for formula I. where R-R are as defined for formula I. In yet another I0048. In one particular embodiment, R and R are non embodiment, R' is —Calkenyl, which is depicted as for hydrogen moieties, while R. R. and Rare hydrogen, which mula IV: is depicted as formula VII:

(IV) (VII)

C2-6alkenyl

N N where R' is as defined for formula I. US 2011/00094.65 A1 Jan. 13, 2011

I0049. In one particular embodiment, R and R are non I0053. In one embodiment, R is hydrogen, halo, —C. hydrogen moieties, while R. R. and Rare hydrogen, which 6alkyl, -CF, —O—Calkyl, or —S-C alkyl; in is depicted as formula VIII: another aspect, this embodiment has formulas II-X. In another embodiment, R is hydrogen, fluoro, chloro, —CHs. —CF, —O—CH, or —S—CH; in another aspect, this (VIII) embodiment has formulas II-X. I0054. In one embodiment, R is hydrogen, halo. —C. 6alkyl, -CF, or —O—Calkyl; in another aspect, this embodiment has formulas II-X. In another embodiment, R is hydrogen, fluoro, chloro, —CH, —CF, or —O—CH; in another aspect, this embodiment has formulas II-X. I0055) In one embodiment, R is hydrogen, halo, —C. 6alkyl, or —O—Calkyl; in another aspect, this embodi ment has formulas II-X. In another embodiment, R is hydro gen, fluoro, chloro, —CH, or—O—CH; in another aspect, this embodiment has formulas II-X. N I0056. In one embodiment, R is hydrogen, halo, or—C. 6alkyl; in another aspect, this embodiment has formulas II-X. where R' is as defined for formula I. In another embodiment, R is hydrogen, fluoro, chloro, or 0050. In one particular embodiment, R. R. and R are —CH; in another aspect, this embodiment has formulas non-hydrogen moieties, while RandR are hydrogen, which II-X. is depicted as formula IX: 0057. In yet another embodiment, R* and R are taken together to form -CH=CH-CH=CH- or Rand Rare taken together to form —CH-CH=CH-CH , which is (IX) depicted as formula VIa and VIb, respectfully:

(XIa) S. R and N ,H where R' is as defined for formula I. (XIb) 0051. In one particular embodiment, R. R', and R are non-hydrogen moieties, while RandR are hydrogen, which is depicted as formula X:

(X) N

where R' is as defined for formula I. 0058. In addition, particular compounds of formula I that are of interest include those set forth in the Examples below, as well a pharmaceutically acceptable Salt thereof. N DEFINITIONS where R' is as defined for formula I. 0059. When describing the compounds, compositions, I0052. In one embodiment, R is hydrogen, halo, —C. methods and processes of the invention, the following terms 6alkyl, -CF —O—Calkyl, —C(O)—Calkyl, have the following meanings unless otherwise indicated. —S C-alkyl, —Clscycloalkyl, or —NO; in another Additionally, as used herein, the singular forms “a,” “an and aspect, this embodiment has formulas II-X. In another “the include the corresponding plural forms unless the con embodiment, R is hydrogen, fluoro, chloro, —CHs. text of use clearly dictates otherwise. The terms “compris —CHCH. —CF, —O—CH —O CHCH. —C(O)— ing”, “including.” and “having” are intended to be inclusive CH. —S-CH, cyclohexyl, or —NO; in another aspect, and mean that there may be additional elements other than the this embodiment has formulas II-X. listed elements. US 2011/00094.65 A1 Jan. 13, 2011

0060. The term “pharmaceutically acceptable” refers to a pound of formula I or a pharmaceutically acceptable salt material that is not biologically or otherwise unacceptable thereof, and one or more molecules of a solvent. Such sol when used in the invention. For example, the term “pharma Vates are typically crystalline solids having a substantially ceutically acceptable carrier” refers to a material that can be fixed molar ratio of solute and solvent. Representative sol incorporated into a composition and administered to a patient vents include, by way of example, water, methanol, ethanol, without causing unacceptable biological effects or interacting isopropanol, acetic acid and the like. When the solvent is in an unacceptable manner with other components of the water, the solvate formed is a hydrate. composition. Such pharmaceutically acceptable materials 0063. The term “therapeutically effective amount’ means typically have met the required standards of toxicological and an amount sufficient to effect treatment when administered to manufacturing testing, and include those materials identified a patient in need thereof, i.e., the amount of drug needed to as suitable inactive ingredients by the U.S. Food and Drug obtain the desired therapeutic effect. For example, a thera Administration. peutically effective amount for treating neuropathic pain is an 0061 The term “pharmaceutically acceptable salt' means amount of compound needed to, for example, reduce, Sup a salt prepared from a base or an acid which is acceptable for press, eliminate or prevent the symptoms of neuropathic pain administration to a patient, such as a mammal (e.g., Salts or to treat the underlying cause of neuropathic pain. On the having acceptable mammalian safety for a given dosage other hand, the term “effective amount’ means an amount regime). However, it is understood that the salts covered by Sufficient to obtain a desired result, which may not necessary the invention are not required to be pharmaceutically accept be a therapeutic result. For example, when studying a system able salts, such as salts of intermediate compounds that are comprising a norepinephrine transporter, an “effective not intended for administration to a patient. Pharmaceutically amount may be the amount needed to inhibit norepinephrine acceptable salts can be derived from pharmaceutically reuptake. acceptable inorganic or organic bases and from pharmaceu 0064. The term “treating” or “treatment” as used herein tically acceptable inorganic or organic acids. In addition, means the treating or treatment of a disease or medical con when a compound of formula I contains both a basic moiety, dition (such as neuropathic pain) in a patient, such as a mam Such as an amine, and an acidic moiety such as a carboxylic mal (particularly a human), that includes one or more of the acid, Zwitterions may be formed and are included within the following: (a) preventing the disease or medical condition term "salt as used herein. Salts derived from pharmaceuti from occurring, i.e., prophylactic treatment of a patient; (b) cally acceptable inorganic bases include ammonium, cal ameliorating the disease or medical condition, i.e., eliminat cium, copper, ferric, ferrous, lithium, magnesium, manganic, ing or causing regression of the disease or medical condition manganous, potassium, Sodium, and Zinc salts, and the like. in a patient; (c) Suppressing the disease or medical condition, Salts derived from pharmaceutically acceptable organic bases i.e., slowing or arresting the development of the disease or include Salts of primary, secondary and tertiary amines, medical condition in a patient; or (d) alleviating the Symp including Substituted amines, cyclic amines, naturally-occur toms of the disease or medical condition in a patient. For ring amines and the like, such as arginine, betaine, caffeine, example, the term “treating neuropathic pain” would include choline, N,N-dibenzylethylenediamine, diethylamine, 2-di preventing neuropathic pain from occurring, ameliorating ethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, neuropathic pain, Suppressing neuropathic pain, and alleviat ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, ing the symptoms of neuropathic pain. The term "patient' is glucamine, glucosamine, histidine, hydrabamine, isopropy intended to include those mammals, such as humans, that are lamine, lysine, methylglucamine, morpholine, piperazine, in need of treatment or disease prevention, that are presently piperadine, polyamine resins, procaine, purines, theobro being treated for disease prevention or treatment of a specific mine, triethylamine, trimethylamine, tripropylamine, disease or medical condition, as well as test Subjects in which tromethamine and the like. Salts derived from pharmaceuti compounds of the invention are being evaluated or being used cally acceptable inorganic acids include salts of boric, car in a assay, for example an animal model. bonic, hydrohalic (hydrobromic, hydrochloric, hydrofluoric 0065. The term “alkyl means a monovalent saturated or hydroiodic), nitric, phosphoric, Sulfamic and Sulfuric hydrocarbon group which may be linear or branched. Unless acids. Salts derived from pharmaceutically acceptable otherwise defined, such alkyl groups typically contain from 1 organic acids include Salts of aliphatic hydroxyl acids (e.g., to 10 carbon atoms and include, for example, —C-alkyl, citric, gluconic, glycolic, lactic, lactobionic, malic, and tar —C-alkyl, —Calkyl, -Calkyl, and —C2-alkyl. Rep taric acids), aliphatic monocarboxylic acids (e.g., acetic, resentative alkyl groups include, by way of example, methyl, butyric, formic, propionic and trifluoroacetic acids), amino ethyl, n-propyl, isopropyl. n-butyl, Sec-butyl, isobutyl, tent acids (e.g., aspartic and glutamic acids), aromatic carboxylic butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl acids (e.g., benzoic, p-chlorobenzoic, diphenylacetic, genti and the like. sic, hippuric, and triphenylacetic acids), aromatic hydroxyl 0066. The term “alkenyl' means a monovalent unsatur acids (e.g., o-hydroxybenzoic, p-hydroxybenzoic, 1-hydrox ated hydrocarbon group which may be linear or branched and ynaphthalene-2-carboxylic and 3-hydroxynaphthalene-2- which has at least one, and typically 1, 2 or 3, carbon-carbon carboxylic acids), ascorbic, dicarboxylic acids (e.g., fumaric, double bonds. Unless otherwise defined, such alkenyl groups maleic, oxalic and Succinic acids), glucoronic, mandelic, typically contain from 2 to 10 carbon atoms and include, for mucic, nicotinic, orotic, pamoic, pantothenic, Sulfonic acids example, —C2-alkenyl, -C2-galkenyl, and –C2-oalkenyl. (e.g., benzenesulfonic, camphoSulfonic, edisylic, ethane Representative alkenyl groups include, by way of example, Sulfonic, isethionic, methanesulfonic, naphthalenesulfonic, ethenyl, n-propenyl, isopropenyl. n-but-2-enyl, but-3-enyl, naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic and n-hex-3-enyl and the like. p-toluenesulfonic acids), Xinafoic acid, and the like. 0067. The term “alkynyl' means a monovalent unsatur 0062. The term “solvate” means a complex or aggregate ated hydrocarbon group which may be linear or branched and formed by one or more molecules of a solute, e.g., a com which has at least one, and typically 1, 2 or 3, carbon-carbon US 2011/00094.65 A1 Jan. 13, 2011 triple bonds. Unless otherwise defined, such alkynyl groups mean a protecting group Suitable for preventing undesired typically contain from 2 to 10 carbon atoms and include, for reactions at an amino group. Representative amino-protect example, —C2-alkynyl, -Ca-galkynyl and –Cs-oalkynyl. ing groups include, but are not limited to, t-butoxycarbonyl Representative alkynyl groups include, by way of example, (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9-fluorenyl ethynyl, prop-2-ynyl (n-propynyl), n-but-2-ynyl, n-hex-3- methoxycarbonyl (Fmoc), formyl, and the like. Standard ynyl and the like. deprotection techniques and reagents such as TFA in DCM or 0068. The term “cycloalkyl means a monovalent satu HCl in 1,4-dioxane, methanol, or ethanol, are used to remove rated carbocyclic hydrocarbon group. Unless otherwise protecting groups, when present. For example, a BOC group defined. Such cycloalkyl groups typically contain from 3 to 10 can be removed using an acidic reagent Such as hydrochloric carbon atoms and include, for example, —C-scycloalkyl, acid, trifluoroacetic acid and the like; while a Cbz group can —C-cycloalkyl and —Clscycloalkyl. Representative be removed by employing catalytic hydrogenation conditions cycloalkyl groups include, by way of example, cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl and the like. such as H. (1 atm), 10% Pd/C in an alcoholic solvent. 0075 Suitable inert diluents or solvents for use in these 0069. When a specific number of carbonatoms is intended for a particular term used herein, the number of carbonatoms schemes include, by way of illustration and not limitation, is shown preceding the term as Subscript. For example, the tetrahydrofuran (THF), acetonitrile, N,N-dimethylforma term “—C-alkyl means an alkyl group having from 1 to 6 mide (DMF), dimethylsulfoxide (DMSO), toluene, dichlo carbon atoms, and the term “—C-scycloalkyl means a romethane (DCM), chloroform (CHCl), and the like. cycloalkyl group having from 3 to 8 carbon atoms, where the 0076 All reactions are typically conducted at a tempera carbon atoms are in any acceptable configuration. ture within the range of about -78°C. to 110°C., for example 0070 The term “halo' means fluoro, chloro, bromo and at room temperature. Reactions may be monitored by use of iodo. thin layer chromatography (TLC), high performance liquid 0071 All other terms used herein are intended to have chromatography (HPLC), and/or LCMS until completion. their ordinary meaning as understood by those of ordinary Reactions may be complete in minutes, may take hours, typi skill in the art to which they pertain. cally from 1-2 hours and up to 48 hours, or days, such as up to 3-4 days. Upon completion, the resulting mixture or reaction General Synthetic Procedures product may be further treated in order to obtain the desired product. For example, the resulting mixture or reaction prod 0072 Compounds of the invention can be prepared from uct may be subjected to one or more of the following proce readily available starting materials using the following gen dures: dilution (for example with saturated NaHCO); extrac eral methods, the procedures set forth in the Examples, or by tion (for example, with ethyl acetate, CHCl, DCM, aqueous using other methods, reagents, and starting materials that are HCl); washing (for example, with DCM, saturated aqueous known to those skilled in the art. Although the following NaCl, or saturated aqueous NaHCO); drying (for example, procedures may illustrate a particular embodiment of the over MgSO4 or Na2SO, or in vacuo); filtration; being con invention, it is understood that other embodiments of the invention can be similarly prepared using the same or similar centrated (for example, in vacuo); being redissolved (for methods or by using other methods, reagents and starting example in a 1:1 acetic acid:HO Solution); and/or purifica materials known to those of ordinary skill in the art. It will tion (for example by preparative HPLC, reverse phase pre also be appreciated that where typical or preferred process parative HPLC, or crystallization). conditions (i.e., reaction temperatures, times, mole ratios of 0077. By way of illustration, compounds of formula I, as reactants, solvents, pressures, etc.) are given, other process well as their salts, can be prepared by one or more of the conditions can also be used unless otherwise stated. While following schemes, as well as the procedures set forth in the optimum reaction conditions will typically vary depending on various reaction parameters such as the particular reac examples. The * chiral center shown in the schemes is known tants, solvents and quantities used, those of ordinary skill in to be S or R, and is depicted accordingly. However, the ** the art can readily determine Suitable reaction conditions chiral centeris not known unambiguously and was designated using routine optimization procedures. R or S based upon the first elution peak by reverse phase 0073. Additionally, as will be apparent to those skilled in HPLC from the mixture of diastereomeric intermediates (the the art, conventional protecting groups may be necessary or protected alcohols). Assignment of the Stereochemistry of desired to prevent certain functional groups from undergoing Such chiral secondary alcohols can be accomplished utilizing undesired reactions. The choice of a suitable protecting group the established Mosher ester analysis (see, for example, Dale for a particular functional group as well as Suitable conditions and Mosher (1969) J. Org. Chem. 34(9):2543-2549). For and reagents for protection and deprotection of Such func compounds, where the chiral center was known to be S, then tional groups are well-known in the art. Protecting groups the first eluting peak was designated S at the ** chiral center other than those illustrated in the procedures described herein and the second eluting peak was designated Rat the ** chiral may be used, if desired. For example, numerous protecting center. For compounds, where the * chiral center was known groups, and their introduction and removal, are described in to be R, then the first eluting peak was designated R at the ** Greene and Wuts, Protecting Groups in Organic Synthesis, chiral center and the second eluting peak was designated Sat Third Edition, Wiley, New York, 1999, and references cited the ** chiral center. Furthermore, while the schemes illus therein. trates formation of one particular stereoisomer, the other Ste 0074 More particularly, in the schemes below, P repre reoisomers can be made in a similar manner by using a start sents an "amino-protecting group, a term used herein to ing material having different stereochemistry. US 2011/00094.65 A1 Jan. 13, 2011

reaction is typically conducted using standard Mitsunobu coupling conditions, using a redox system containing an aZodicarboxylate Such as diethylazodicarboxylate or diiso 1) R3 propyl azodicarboxylate and a phosphine catalyst Such as triphenylphosphine. Deprotection then yields the desired compound of formula I.

Scheme III

R3 R3 R R2 R R2 0078 Compounds of formula I can be prepared by react

ing the appropriate alcohol starting material and the desired optionally substituted fluorobenzene using a nucleophilic R5 O R1 + R5 aromatic Substitution reaction (SAr). This reaction is typi R6 ** (S,S) R6 cally conducted using sodium hydride (NaH) in a solvent such as DMF. Deprotection then yields the desired compound of formula I. , N

Scheme II 0080 Compounds of formula I can also be prepared by 1) R3 coupling a racemic mixture of the appropriate alcohol starting R R2 material to an optionally substituted iodobenzene under Ull

mann reaction conditions to provide a racemic mixture of compounds of formula I. The Ullmann reaction is typically R5 OH conducted in the presence of a copper(I) iodide/1.10-phenan throline catalyst and a base Such as cesium carbonate, in an R6 appropriate solvent such as toluene or DMF. Chiral separa tion, followed by deprotection then yields the desired stere oisomer of formula I. Alternately, the racemic product can R3 first be deprotected, then separated by normal phase chiral HPLC. R R2 I0081. The alcohol starting materials can be prepared by the 2.2.6,6-tetramethyl-1-piperidinyloxy, free radical R5 O R1 (TEMPO) mediated oxidation of (S)-3-hydroxymethylpyrro lidine-1-carboxylic acid t-butyl ester to yield (S)-3- R6 * (S,S) formylpyrrolidine-1-carboxylic acid t-butyl ester.

N H

0079 Compounds of formula I can also be prepared using the Mitsunobu coupling reaction (Mitsunobu and Yamada (1967) M. Bull. Chem. Soc.JPN. 40:2380-2382) of the alco hol starting material and optionally substituted phenol. This US 2011/00094.65 A1 Jan. 13, 2011 11

pounds of the invention or intermediates thereofare described

-continued in the Examples set forth herein. Utility I0085 Compounds of the invention possess serotonin and norepinephrine reuptake inhibitory activity. Thus, these com pounds have therapeutic utility as combined serotonin and norepinephrine reuptake inhibitors (SNRIs). In one embodi ment, compounds of the invention possess equal or approxi mately equal serotonin reuptake inhibitory activity and nore This method is particularly useful by minimizing the amount pinephrine reuptake inhibitory activity. of racemization that can occur during oxidation. 3-Hy I0086. The inhibition constant (K) of a compound is the droxymethylpyrrolidine-1-carboxylic acid t-butyl ester, concentration of ligand in a radioligand binding inhibition where P is Boc or benzyl, is commercially available. Alter assay that would occupy 50% of the transporters if no radio nately, (S)-3-hydroxymethylpyrrolidine-1-carboxylic acid ligand were present. K. Values can be determined from radio t-butyl ester can be oxidized using any oxidizing agent Suit ligand binding studies with H-nisoxetine (for the norepi able for converting a primary alcohol into an aldehyde. Rep nephrine transporter, NET) and H-citalopram (for the resentative oxidizing agents include, for example, dimethyl serotonin transporter, SERT), as described in Assay 1. These Sulfoxide, Collin's reagent, Corey's reagent, pyridinium K, values are derived from ICso values in the binding assay dichromate and the like. The next step involves a Grignard using the Cheng-Prusoff equation and the K of the radioli reaction between the formyl compound and the Grignard gand (Cheng & Prusoff (1973) Biochem. Pharmacol. 22(23): reagent, R-Mgx, where X is chloro orbromo, for example. 3099-3108). Functional ICs values can be determined in the The step is typically conducted using standard Grignard reac functional inhibition of uptake assays described in Assay 2. tion conditions. Exemplary Grignard reagents include propy These ICso values can be converted to K values using the lmagnesium chloride (R' is propyl), cyclopropylmagnesium Cheng-Prusoff equation and the K of the transmitter for the transporter. It is noted however, that the uptake assay condi bromide (R' is cyclopropyl), ethynylmagnesium bromide (R' tions described in Assay 2 are such that the ICs values are is Calkynyl), and the like. The (R,R) and (R.S) alcohol very close to the K values, should a mathematical conversion starting materials can be prepared in a similar manner using be desired, since the neurotransmitter concentration (5-HT, (R)-Boc-3-pyrrolidinemethanol, also known as (R)-3-hy NE, or DA) used in the assay is well below its K, for the droxymethylpyrrolidine-1-carboxylic acid t-butyl ester. respective transporter. In one embodiment, compounds of the 0082 If desired, pharmaceutically acceptable salts of the invention exhibit a SERT K/NETK, in the range of 0.1 to compounds of formula I can be prepared by contacting the 100; in another embodiment, a SERT K/NETK, in the range free acid or base form of a compound of formula I with a of 0.3 to 100; and in still another embodiment, exhibit a SERT pharmaceutically acceptable base or acid. K/NETK, in the range of 0.3 to 10. I0087 Another measure of serotonin and norepinephrine 0.083 Certain of the intermediates described herein are reuptake inhibition is the plCso value. In one embodiment, believed to be novel and accordingly, Such compounds are compounds of the invention have serotonin and norepineph provided as further aspects of the invention including, for rine reuptake inhibition plCso values 27: in another embodi example, compounds of formula VII: ment, compounds of the invention have a serotonin reuptake inhibition plCs27 and a norepinephrine reuptake inhibition pICsoe8; in yet another embodiment, compounds of the (XI) invention have a serotonin reuptake inhibition plCsoe8 and a norepinephrine reuptake inhibition plCsoe7; and in another embodiment, compounds of the invention have serotonin and norepinephrine reuptake inhibition plCso values 28. In one particular embodiment, Such compounds have formula II-IV. I0088. In another embodiment, compounds of the inven tion are selective for inhibition of SERT and NET over the dopamine transporter (DAT). For example in this embodi ment, compounds of particular interest are those that exhibit a binding affinity for SERT and NET that is at least 5 times higher than the binding affinity for DAT, or that is at least 10 times higher than for DAT, or at least 20 or 30 times higher than for DAT. In another embodiment, the compounds do not exhibit significant DAT inhibition. In still another embodi or a salt thereof, where P represents an amino-protecting ment, the compounds exhibitless than 50% inhibition of DAT group, particularly t-butoxycarbonyl (BOC) where R' and activity when measured at a concentration of 794 nM. Under Rare as defined for formula I. In one embodiment of the the assay conditions used, a compound which exhibits 250% invention, compounds of the invention can be prepared by inhibition would have an estimated pK value at DAT of 26.1. deprotecting compounds of formula V to provide compounds I0089. In still another embodiment, compounds of the of formula I, or a pharmaceutically acceptable salt thereof. invention possess dopamine reuptake inhibitory activity as 0084. Further details regarding specific reaction condi well as serotonin and norepinephrine reuptake inhibitory tions and other procedures for preparing representative com activity. For example in this embodiment, compounds of par US 2011/00094.65 A1 Jan. 13, 2011

ticular interest are those that exhibit apICs at SERT and NET from a disease or medical condition (Such as neuropathic greater than or equal to 8.0, and a plCso at DAT greater than pain) can begin with a predetermined dosage or a dosage or equal to 7.0. determined by the treating physician, and will continue for a 0090. It is noted that in some cases, compounds of the period of time necessary to prevent, ameliorate, Suppress, or invention may possess either weak serotonin reuptake inhibi alleviate the symptoms of the disease or medical condition. tory activity or weak norepinephrine reuptake inhibitory Patients undergoing Such treatment will typically be moni activity. In these cases, those of ordinary skill in the art will tored on a routine basis to determine the effectiveness of recognize that such compounds still have utility as primarily therapy. For example, in treating neuropathic pain, a measure either a NET inhibitor or a SERT inhibitor, respectively, or of the effectiveness of treatment may involve assessment of will have utility as research tools. the patient’s quality of life, e.g., improvements in the patient's 0091 Exemplary assays to determine the serotonin and/or sleeping patterns, work attendance, ability to exercise and be norepinephrine reuptake inhibiting activity of compounds of ambulatory, etc. Pain scales, operating on a point basis, may the invention include by way of illustration and not limitation, also be used to help evaluate a patient's pain level. Indicators assays that measure SERT and NET binding, for example, as for the other diseases and conditions described herein, are described in Assay 1 and in Tsuruda et al. (2010) Journal of well-known to those skilled in the art, and are readily avail Pharmacological and Toxicological Methods 61(2):192-204. able to the treating physician. Continuous monitoring by the In addition, it is useful to understand the level of DAT binding physician will ensure that the optimal amount of active agent and uptake in an assay Such as that described in Assay 1. will be administered at any given time, as well as facilitating Useful secondary assays include neurotransmitter uptake the determination of the duration of treatment. This is of assays to measure inhibition of serotonin and norepinephrine particular value when secondary agents are also being admin uptake into cells expressing the respective human or rat istered, as their selection, dosage, and duration of therapy recombinant transporter (hSERT, hNET, or hDAT) as may also require adjustment. In this way, the treatment regi described in Assay 2, and ex vivo radioligand binding and men and dosing schedule can be adjusted over the course of neurotransmitter uptake assays that are used to determine the therapy so that the lowest amount of active agent that exhibits in vivo occupancy of SERT, NET and DAT in tissue as the desired effectiveness is administered and, further, that described in Assay 3. Other assays that are useful to evaluate administration is continued only so long as is necessary to pharmacological properties of test compounds include those Successfully treat the disease or medical condition. listed in Assay 4. Exemplary in vivo assays include the for malin paw test described in Assay 5, which is a reliable Pain Disorders predictor of clinical efficacy for the treatment of neuropathic 0094 SNRIs have been shown to have a beneficial effect pain, and the spinal nerve ligation model described in Assay on pain Such as painful diabetic neuropathy (duloxetine, 6. The aforementioned assays are useful in determining the Goldstein et al. (2005) Pain 116:109-118; venlafaxine, Row therapeutic utility, for example, the neuropathic pain reliev bothametal. (2004) Pain 110:697–706), fibromyalgia (dulox ing activity, of compounds of the invention. Other properties etine, Russelletal. (2008) Pain 136(3):432-444; milnacipran, and utilities of compounds of the invention can be demon Vitton et al. (2004) Human Psychopharmacology 19:S27 strated using various invitro and in vivo assays well-knownto S35), and migraine (venlafaxine, Ozyalcin et al. (2005) those skilled in the art. Headache 45(2): 144-152). Thus, one embodiment of the 0092 Compounds of the invention are expected to be use invention relates to a method for treating a pain disorder, ful for the treatment and/or prevention of medical conditions comprising administering to a patient a therapeutically effec in which the regulation of monoamine transporter function is tive amount of a compound of the invention. Typically, the implicated, in particular those conditions mediated by or therapeutically effective amount will be the amount that is responsive to the inhibition of serotonin and norepinephrine sufficient to relieve the pain. Exemplary pain disorders reuptake. Thus it is expected that patients Suffering from a include, by way of illustration, acute pain, persistent pain, disease or disorder that is treated by the inhibition of the chronic pain, inflammatory pain, and neuropathic pain. More serotonin and/or the norepinephrine transporter can be treated specifically, these include pain associated with or caused by: by administering a therapeutically effective amount of a sero arthritis; back pain including chronic low back pain; cancer, tonin and norepinephrine reuptake inhibitor of the invention. including tumor related pain (e.g., bone pain, headache, facial Such medical conditions include, by way of example, pain pain or visceral pain) and pain associated with cancer therapy disorders such as neuropathic pain, fibromyalgia, and chronic (e.g., post-chemotherapy syndrome, chronic post-Surgical pain, depressive disorders such as major depression, affective pain syndrome and post-radiation syndrome); carpal tunnel disorders such as an anxiety disorder, attention deficit hyper syndrome; fibromyalgia; headaches including chronic ten activity disorder, cognitive disorders such as dementia, and sion headaches; inflammation associated with polymyalgia, stress urinary incontinence. rheumatoid arthritis and osteoarthritis; migraine; neuropathic 0093. The amount of active agent administered perdose or pain including complex regional pain syndrome; overall pain; the total amount administered per day may be predetermined post-operative pain; shoulder pain; central pain syndromes, or it may be determined on an individual patient basis by including post-stroke pain, and pain associated with spinal taking into consideration numerous factors, including the cord injuries and multiple Sclerosis; phantom limb pain; pain nature and severity of the patient's condition, the condition associated with Parkinson's disease; and visceral pain (e.g., being treated, the age, weight, and general health of the irritable bowel syndrome). Of particular interest is the treat patient, the tolerance of the patient to the active agent, the ment of neuropathic pain, which includes diabetic peripheral route of administration, pharmacological considerations such neuropathy (DPN), HIV-related neuropathy, post-herpetic as the activity, efficacy, pharmacokinetics and toxicology neuralgia (PHN), and chemotherapy-induced peripheral neu profiles of the active agent and any secondary agents being ropathy. When used to treat pain disorders such as neuro administered, and the like. Treatment of a patient Suffering pathic pain, compounds of the invention may be administered US 2011/00094.65 A1 Jan. 13, 2011 in combination with other therapeutic agents, including anti peutically effective amount of a compound of the invention. convulsants, antidepressants, muscle relaxants, NSAIDs, When used to treat depression, compounds of the invention opioid agonists, selective serotonin reuptake inhibitors, may be administered in combination with other therapeutic Sodium channel blockers, and sympatholytics. Exemplary agents, including antidepressants. Exemplary compounds compounds within these classes are described herein. within these classes are described herein. Depressive Disorders Cognitive Disorders 0.095 Another embodiment of the invention relates to a 0098. Another embodiment of the invention relates to a method of treating a depressive disorder, comprising admin method of treating a cognitive disorder, comprising adminis istering to a patient a therapeutically effective amount of a tering to a patient a therapeutically effective amount of a compound of the invention. Typically, the therapeutically compound of the invention. Exemplary cognitive disorders effective amount will be the amount that is sufficient to alle include, by way of illustration and not limitation: dementia, viate depression and provide a sense of general well-being. which includes degenerative dementia (e.g., Alzheimer's dis Exemplary depressive disorders include, by way of illustra ease, Creutzfeldt-Jakob disease, Huntingdon's chorea, Par tion and not limitation: depression associated with Alzhe kinson's disease, Pick's disease, and senile dementia), Vascu imer's disease, bipolar disorder, cancer, child abuse, infertil lar dementia (e.g., multi-infarct dementia), and dementia ity, Parkinson's disease, postmyocardial infarction, and associated with intracranial space occupying lesions, trauma, psychosis; dysthymia, grumpy or irritable oldman syndrome; infections and related conditions (including HIV infection), induced depression; major depression; pediatric depression; metabolism, toxins, anoxia and vitamin deficiency; and mild postmenopausal depression; post partum depression; recur cognitive impairment associated with ageing. Such as age rent depression; single episode depression; and Subsyndro associated memory impairment, amnesiac disorder and age mal symptomatic depression. Of particular interest is the related cognitive decline. When used to treat cognitive disor treatment of major depression. When used to treat depressive ders, compounds of the invention may be administered in disorders, compounds of the invention may be administered combination with other therapeutic agents, including anti in combination with other therapeutic agents, including anti Alzheimer's agents and anti-Parkinson's agents. Exemplary depressants and dual serotonin-norepinephrine reuptake compounds within these classes are described herein. inhibitors. Exemplary compounds within these classes are described herein. Other Disorders

Affective Disorders 0099 SNRIs have also been shown to be effective for the treatment of stress urinary incontinence (Dmochowski 0096. Another embodiment of the invention relates to a (2003).Journal of Urology 170(4): 1259-1263). Thus, another method of treating an affective disorder, comprising admin embodiment of the invention relates to a method for treating istering to a patient a therapeutically effective amount of a stress urinary incontinence, comprising administering to a compound of the invention. Exemplary affective disorders patient a therapeutically effective amount of a compound of include, by way of illustration and not limitation: anxiety the invention. When used to treat stressurinary incontinence, disorders such as general anxiety disorder; avoidant person compounds of the invention may be administered in combi ality disorder, eating disorders such as anorexia nervosa, nation with other therapeutic agents, including anticonvul bulimia nervosa and obesity; obsessive compulsive disorder; sants. Exemplary compounds within these classes are panic disorder; personality disorders such as avoidant person described herein. ality disorder and attention deficit hyperactivity disorder 0100 Duloxetine, an SNRI, is undergoing clinical trials (ADHD); post-traumatic stress syndrome; phobias such as for evaluating its efficacy in treating chronic fatigue Syn agoraphobia, as well as simple and other specific phobias, and drome, and has recently been shown to be effective in treating Social phobia; premenstrual syndrome; psychotic disorders, fibromyalgia (Russelletal. (2008) Pain 136(3):432-444). The Such as Schizophrenia and mania; seasonal affective disorder, compounds of the invention, due to their ability to inhibit sexual dysfunction, including premature ejaculation, male SERT and NET, are also expected to have this utility, and impotence, and female sexual dysfunction Such as female another embodiment of the invention relates to a method for sexual arousal disorder, Social anxiety disorder, and Sub treating chronic fatigue syndrome, comprising administering stance abuse disorders, including chemical dependencies to a patientatherapeutically effective amount of a compound Such as addictions to alcohol, benzodiazepines, cocaine, of the invention. heroin, nicotine and phenobarbital, as well as withdrawal 0101 Sibutramine, a norepinephrine and dopamine syndromes that may arise from these dependencies. When reuptake inhibitor, has been shown to be useful in treating used to treat affective disorders, compounds of the invention obesity (Wirth et al. (2001).JAMA 286(11): 1331-1339). The may be administered in combination with other therapeutic compounds of the invention, due to their ability to inhibit agents, including antidepressants. Exemplary compounds NET, are also expected to have this utility, and another within these classes are described herein. embodiment of the invention relates to a method for treating 0097 Atomoxetine, which is 10-fold NET selective, is obesity, comprising administering to a patient a therapeuti approved for attention deficit hyperactivity disorder (ADHD) cally effective amount of a compound of the invention. therapy, and clinical studies have shown that the SNRI, ven 0102 Desvenlafaxine, an SNRI, has been shown to relieve lafaxine, can also have a beneficial effect in treating ADHD vasomotor symptoms associated with menopause (Deecheret (Mukaddes et al. (2002) Eur: Neuropsychopharm. 12(Supp al. (2007) Endocrinology 148(3):1376-1383). The com 3):421). Thus, the compounds of the invention are also pounds of the invention, due to their ability to inhibit SERT expected to be useful in methods for treating attention deficit and NET, are also expected to have this utility, and another hyperactivity disorder by administering to a patient a thera embodiment of the invention relates to a method for treating US 2011/00094.65 A1 Jan. 13, 2011 vasomotor symptoms associated with menopause, compris separate embodiments, both the generation of comparison ing administering to a patient a therapeutically effective data (using the appropriate assays) and the analysis of the test amount of a compound of the invention. data to identify test compounds of interest. Thus, a test com pound can be evaluated in a biological assay, by a method Research Tools comprising the steps of: (a) conducting a biological assay 0103 Since compounds of the invention possess both with a test compound to provide a first assay value; (b) con serotonin reuptake inhibition activity and norepinephrine ducting the biological assay with a compound of the invention reuptake inhibition activity, such compounds are also useful to provide a second assay value; wherein step (a) is conducted as research tools for investigating or studying biological sys either before, after or concurrently with step (b); and (c) tems or samples having serotonin or norepinephrine trans comparing the first assay value from Step (a) with the second porters. Any suitable biological system or sample having assay value from step (b). Exemplary biological assays serotonin and/or norepinephrine transporters may be include serotonin and norepinephrine reuptake assays. employed in Such studies which may be conducted either in vitro or in vivo. Representative biological systems or samples Pharmaceutical Compositions and Formulations suitable for such studies include, but are not limited to, cells, 0106 Compounds of the invention are typically adminis cellular extracts, plasma membranes, tissue samples, isolated tered to a patient in the form of a pharmaceutical composition organs, mammals (such as mice, rats, guinea pigs, rabbits, or formulation. Such pharmaceutical compositions may be dogs, pigs, humans, and so forth), and the like, with mammals administered to the patient by any acceptable route of admin being of particular interest. In one particular embodiment of istration including, but not limited to, oral, rectal, vaginal, the invention, serotonin reuptake in a mammal is inhibited by nasal, inhaled, topical (including transdermal) and parenteral administering a serotonin reuptake-inhibiting amount of a modes of administration. Further, the compounds of the compound of the invention. In another particular embodi invention may be administered, for example orally, in mul ment, norepinephrine reuptake in a mammal is inhibited by tiple doses per day (e.g., twice, three times or four times administering a norepinephrine reuptake-inhibiting amount daily), in a single daily dose, in a twice-daily dose, in a single of a compound of the invention. Compounds of the invention weekly dose, and so forth. It will be understood that any form can also be used as research tools by conducting biological of the compounds of the invention, (i.e., free base, pharma assays using Such compounds. ceutically acceptable salt, solvate, etc.) that is suitable for the 0104. When used as a research tool, a biological system or particular mode of administration can be used in the pharma sample comprising a serotonin transporter and/or a norepi ceutical compositions discussed herein. nephrine transporter is typically contacted with a serotonin 0107 Accordingly, in one embodiment, the invention reuptake-inhibiting or norepinephrine reuptake-inhibiting relates to a pharmaceutical composition comprising a phar amount of a compound of the invention. After the biological maceutically acceptable carrier and a compound of the inven system or sample is exposed to the compound, the effects of tion. The compositions may contain other therapeutic and/or inhibiting serotonin reuptake and/or norepinephrine reuptake formulating agents if desired. When discussing composi are determined using conventional procedures and equip tions, the “compound of the invention” may also be referred ment. Exposure encompasses contacting cells or tissue with to herein as the “active agent, to distinguish it from other the compound, administering the compound to a mammal, for components of the formulation, Such as the carrier. Thus, it is example by i.p. or i.v. administration, and so forth. This understood that the term “active agent' includes compounds determining step may comprise measuring a response, i.e., a of formula I as well as pharmaceutically acceptable salts and quantitative analysis or may comprise an observation, i.e., a Solvates of that compound. qualitative analysis. Measuring a response involves, for 0108) Pharmaceutical compositions of the invention typi example, determining the effects of the compound on the cally contain a therapeutically effective amount of a com biological system or sample using conventional procedures pound of the invention. Those skilled in the art will recognize, and equipment, Such as serotonin and norepinephrine however, that a pharmaceutical composition may contain reuptake assays. The assay results can be used to determine more than a therapeutically effective amount, i.e., bulk com the activity level as well as the amount of compound neces positions, or less than atherapeutically effective amount, i.e., sary to achieve the desired result, i.e., a serotonin reuptake individual unit doses designed for multiple administration to inhibiting and a norepinephrine reuptake-inhibiting amount. achieve a therapeutically effective amount. Typically, the 0105. Additionally, compounds of the invention can be composition will contain from about 0.01-95 wt % of active used as research tools for evaluating other chemical com agent, including, from about 0.01-30 wt %, such as from pounds, and thus are also useful in screening assays to dis about 0.01-10 wt %, with the actual amount depending upon cover, for example, new compounds having both serotonin the formulation itself, the route of administration, the fre reuptake-inhibiting activity and norepinephrine reuptake-in quency of dosing, and so forth. In one embodiment, a com hibiting activity. In this manner, a compound of the invention position Suitable for an oral dosage form, for example, may is used as a standard in an assay to allow comparison of the contain about 5-70 wt %, or from about 10-60 wt % of active results obtained with a test compound and with compounds of agent. the invention to identify those test compounds that have about 0109) Any conventional carrier or excipient may be used equal or Superior reuptake-inhibiting activity, if any. For in the pharmaceutical compositions of the invention. The example, reuptake data for a test compound or a group of test choice of a particular carrier or excipient, or combinations of compounds is compared to the reuptake data for a compound carriers or excipients, will depend on the mode of adminis of the invention to identify those test compounds that have the tration being used to treat a particular patient or type of desired properties, e.g., test compounds having reuptake-in medical condition or disease state. In this regard, the prepa hibiting activity about equal or Superior to a compound of the ration of a suitable composition for a particular mode of invention, if any. This aspect of the invention includes, as administration is well within the scope of those skilled in the US 2011/00094.65 A1 Jan. 13, 2011 pharmaceutical arts. Additionally, carriers or excipients used and antioxidants may also be present in the pharmaceutical in Such compositions are commercially available. By way of compositions. Exemplary coating agents for tablets, cap further illustration, conventional formulation techniques are Sules, pills and like, include those used for enteric coatings, described in Remington. The Science and Practice of Phar Such as cellulose acetate phthalate, polyvinyl acetate phtha macy, 20" Edition, Lippincott Williams & White, Baltimore, late, hydroxypropyl methylcellulose phthalate, methacrylic Md. (2000); and H. C. Ansel et al., Pharmaceutical Dosage acid-methacrylic acid ester copolymers, cellulose acetate tri Forms and Drug Delivery Systems, 7" Edition, Lippincott mellitate, carboxymethyl ethyl cellulose, hydroxypropyl Williams & White, Baltimore, Md. (1999). methyl cellulose acetate Succinate, and the like. Examples of 0110 Representative examples of materials which can pharmaceutically acceptable antioxidants include: water serve as pharmaceutically acceptable carriers include, but are soluble antioxidants, such as ascorbic acid, cysteine hydro not limited to, the following: Sugars, such as lactose, glucose chloride, sodium bisulfate, sodium metabisulfate, sodium and Sucrose; starches, such as corn starch and potato starch; sulfite and the like; oil-soluble antioxidants, such as ascorbyl cellulose, such as microcrystalline cellulose, and its deriva palmitate, butylated hydroxyanisole, butylated hydroxytolu tives. Such as sodium carboxymethyl cellulose, ethyl cellu ene, lecithin, propyl gallate, alpha-tocopherol, and the like; lose and cellulose acetate; powdered tragacanth; malt, gela and metal-chelating agents, such as citric acid, ethylenedi tin, talc, excipients, such as cocoa butter and Suppository amine tetraacetic acid, Sorbitol, tartaric acid, phosphoric acid, waxes; oils, such as peanut oil, cottonseed oil, safflower oil, and the like. sesame oil, olive oil, corn oil and Soybean oil; glycols, such as 0115 Compositions may also be formulated to provide propylene glycol; polyols, such as glycerin, Sorbitol, manni slow or controlled release of the active agent using, by way of tol and polyethylene glycol; esters, such as ethyl oleate and example, hydroxypropyl methyl cellulose in varying propor ethyl laurate; agar, buffering agents, such as magnesium tions or other polymer matrices, liposomes and/or micro hydroxide and aluminum hydroxide; alginic acid; pyrogen spheres. In addition, the pharmaceutical compositions of the free water, isotonic saline; Ringer's solution; ethyl alcohol; invention may contain opacifying agents and may be formu phosphate buffer Solutions; compressed propellant gases, lated so that they release the active agent only, or preferen Such as chlorofluorocarbons and hydrofluorocarbons; and tially, in a certain portion of the gastrointestinal tract, option other non-toxic compatible Substances employed in pharma ally, in a delayed manner. Examples of embedding ceutical compositions. compositions which can be used include polymeric Sub 0111 Pharmaceutical compositions are typically prepared stances and waxes. The active agent can also be in micro by thoroughly and intimately mixing or blending the active encapsulated form, if appropriate, with one or more of the agent with a pharmaceutically acceptable carrier and one or above-described excipients. more optional ingredients. The resulting uniformly blended 0116 Suitable liquid dosage forms for oral administration mixture may then be shaped or loaded into tablets, capsules, include, by way of illustration, pharmaceutically acceptable pills, canisters, cartridges, dispensers, and the like, using emulsions, microemulsions, Solutions, Suspensions, syrups conventional procedures and equipment. and elixirs. Liquid dosage forms typically comprise the active 0112. In one embodiment, the pharmaceutical composi agent and an inert diluent, Such as, for example, water or other tions are Suitable for oral administration. One exemplary Solvents, Solubilizing agents and emulsifiers, such as ethyl dosing regimen would be an oral dosage form administered alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, once or twice daily. Suitable compositions for oral adminis benzyl alcohol, benzyl benzoate, propylene glycol. 1,3-buty tration may be in the form of capsules, tablets, pills, lozenges, lene glycol, oils (e.g., cottonseed, groundnut, corn, germ, cachets, dragees, powders, granules; Solutions or Suspensions olive, castor and Sesame oils), glycerol, tetrahydrofuryl alco in an aqueous or non-aqueous liquid; oil-in-water or water hol, polyethylene glycols and fatty acid esters of sorbitan, and in-oil liquid emulsions; elixirs or syrups; and the like; each mixtures thereof. Suspensions may contain Suspending containing a predetermined amount of the active agent. agents such as, for example, ethoxylated isoStearyl alcohols, 0113. When intended for oral administration in a solid polyoxyethylene Sorbitol and Sorbitan esters, microcrystal dosage form (i.e., as capsules, tablets, pills, and the like), the line cellulose, aluminium metahydroxide, bentonite, agar composition will typically comprise the active agent and one agar and tragacanth, and mixtures thereof. or more pharmaceutically acceptable carriers, such as sodium 0117. When intended for oral administration, the pharma citrate or dicalcium phosphate. Solid dosage forms may also ceutical compositions of the invention may be packaged in a comprise: fillers or extenders. Such as Starches, microcrystal unit dosage form. The term “unit dosage form” refers to a line cellulose, lactose. Sucrose, glucose, mannitol, and/or physically discrete unit Suitable for dosing a patient, i.e., each silicic acid; binders, such as carboxymethylcellulose, algi unit containing a predetermined quantity of the active agent nates, gelatin, polyvinyl pyrrolidone. Sucrose and/or acacia: calculated to produce the desired therapeutic effect either humectants, such as glycerol, disintegrating agents. Such as alone or in combination with one or more additional units. For agar-agar, calcium carbonate, potato or tapioca Starch, alginic example, such unit dosage forms may be capsules, tablets, acid, certain silicates, and/or sodium carbonate; Solution pills, and the like. retarding agents, such as paraffin; absorption accelerators, 0118. In another embodiment, the compositions of the Such as quaternary ammonium compounds; wetting agents, invention are suitable for inhaled administration, and will Such as cetyl alcohol and/or glycerol monostearate; absor typically be in the form of an aerosol or a powder. Such bents, such as kaolin and/orbentonite clay; lubricants, such as compositions are generally administered using well-known talc, calcium Stearate, magnesium Stearate, Solid polyethyl delivery devices, such as a nebulizer, dry powder, or metered ene glycols, sodium lauryl Sulfate, and/or mixtures thereof. dose inhaler. Nebulizer devices produce a stream of high coloring agents; and buffering agents. Velocity air that causes the composition to spray as a mist that 0114 Release agents, wetting agents, coating agents, is carried into a patient's respiratory tract. An exemplary Sweetening, flavoring and perfuming agents, preservatives nebulizer formulation comprises the active agent dissolved in US 2011/00094.65 A1 Jan. 13, 2011

a carrier to form a solution, or micronized and combined with art, and examples are described herein. By combining a com a carrier to form a Suspension of micronized particles of pound of the invention with a secondary agent, triple therapy respirable size. Dry powder inhalers administer the active can be achieved, i.e., serotonin reuptake inhibitory activity, agent as a free-flowing powder that is dispersed in a patient's norepinephrine reuptake inhibitory activity, and activity asso air-stream during inspiration. An exemplary dry powder for ciated with the secondary agent (e.g., antidepressant activity), mulation comprises the active agent dry-blended with an using only two active components. Since pharmaceutical excipient Such as lactose, starch, mannitol, dextrose, polylac compositions containing two active components are typically tic acid, polylactide-co-glycolide, and combinations thereof. easier to formulate than compositions containing three active Metered-dose inhalers discharge a measured amount of the components, such two-component compositions provide a active agent using compressed propellant gas. An exemplary significant advantage over compositions containing three metered-dose formulation comprises a solution or Suspension of the active agent in a liquefied propellant. Such as a chlo active components. Accordingly, in yet another aspect of the rofluorocarbon or hydrofluoroalkane. Optional components invention, a pharmaceutical composition comprises a com of Such formulations include co-solvents, such as ethanol or pound of the invention, a second active agent, and a pharma pentane, and Surfactants, such as Sorbitan trioleate, oleic acid, ceutically acceptable carrier. Third, fourth etc. active agents lecithin, and glycerin. Such compositions are typically pre may also be included in the composition. In combination pared by adding chilled or pressurized hydrofluoroalkane to a therapy, the amount of compound of the invention that is Suitable container containing the active agent, ethanol (if administered, as well as the amount of secondary agents, may present) and the Surfactant (if present). To prepare a suspen be less than the amount typically administered in mono Sion, the active agent is micronized and then combined with therapy. the propellant. Alternatively, a Suspension formulation can be I0122. A compound of the invention may be either physi prepared by spray drying a coating of Surfactant on micron cally mixed with the second active agent to form a composi ized particles of the active agent. The formulation is then tion containing both agents; or each agent may be present in loaded into an aerosol canister, which forms a portion of the separate and distinct compositions which are administered to inhaler. the patient simultaneously or sequentially. For example, a 0119 Compounds of the invention can also be adminis compound of the invention can be combined with a second tered parenterally (e.g., by Subcutaneous, intravenous, intra active agent using conventional procedures and equipment to muscular, or intraperitoneal injection). For Such administra form a combination of active agents comprising a compound tion, the active agent is provided in a sterile solution, of the invention and a second active agent. Additionally, the Suspension, or emulsion. Exemplary solvents for preparing active agents may be combined with a pharmaceutically Such formulations include water, saline, low molecular acceptable carrier to form a pharmaceutical composition weight alcohols such as propylene glycol, polyethylene gly comprising a compound of the invention, a second active col, oils, gelatin, fatty acid esters such as ethyl oleate, and the agent and a pharmaceutically acceptable carrier. In this like. A typical parenteral formulation is a sterile pH 4-7 embodiment, the components of the composition are typi aqueous Solution of the active agent. Parenteral formulations cally mixed or blended to create a physical mixture. The may also contain one or more solubilizers, stabilizers, preser physical mixture is then administered in a therapeutically Vatives, wetting agents, emulsifiers, and dispersing agents. effective amount using any of the routes described herein. These formulations may be rendered sterile by use of a sterile I0123. Alternatively, the active agents may remain separate injectable medium, a sterilizing agent, filtration, irradiation, and distinct before administration to the patient. In this or heat. embodiment, the agents are not physically mixed together 0120 Compounds of the invention can also be adminis before administration but are administered simultaneously or tered transdermally using known transdermal delivery sys at separate times as separate compositions. Such composi tems and excipients. For example, the compound can be tions can be packaged separately or may be packaged admixed with permeation enhancers, such as propylene gly together in a kit. When administered at separate times, the col, polyethylene glycol monolaurate, azacycloalkan-2-ones secondary agent will typically be administered less than 24 and the like, and incorporated into a patch or similar delivery hours after administration of the compound of the invention, system. Additional excipients including gelling agents, emul ranging anywhere from concurrent with administration of the sifiers and buffers, may be used in Such transdermal compo compound of the invention to about 24 hours post-dose. This sitions if desired. is also referred to as sequential administration. Thus, a com 0121. If desired, compounds of the invention may be pound of the invention can be orally administered simulta administered in combination with one or more other thera neously or sequentially with another active agent using two peutic agents. Thus, in one embodiment, compositions of the tablets, with one tablet for each active agent, where sequential invention may optionally contain other drugs that are co may mean being administered immediately after administra administered with a compound of the invention. For example, tion of the compound of the invention or at Some predeter the composition may further comprise one or more drugs mined time later (e.g., one hour later or three hours later). (also referred to as “secondary agents(s)) selected from the Alternatively, the combination may be administered by dif group of anti-Alzheimer's agents, anticonvulsants (antiepi ferent routes of administration, i.e., one orally and the other leptics), antidepressants, anti-Parkinson's agents, dual sero by inhalation. tonin-norepinephrine reuptake inhibitors (SNRIs), non-ste 0.124. In one embodiment, the kit comprises a first dosage roidal anti-inflammatory agents (NSAIDs), norepinephrine form comprising a compound of the invention and at least one reuptake inhibitors, opioid agonists (opioid analgesics), additional dosage form comprising one or more of the sec selective serotonin reuptake inhibitors, sodium channel ondary agents set forth herein, in quantities sufficient to carry blockers, sympatholytics, and combinations thereof. Numer out the methods of the invention. The first dosage form and ous examples of such therapeutic agents are well known in the the second (or third, etc.) dosage form together comprise a US 2011/00094.65 A1 Jan. 13, 2011 therapeutically effective amount of active agents for the treat cam, tiopinac, tiaprofenic acid, tioxaprofen, tolfenamic acid, ment or prevention of a disease or medical condition in a tolmetin, triflumidate, Zidometacin, Zomepirac, and combi patient. nations thereof. In a particular embodiment, the NSAID is 0.125 Secondary agent(s), when included, are present in a selected from etodolac, flurbiprofen, ibuprofen, indometha therapeutically effective amount. i.e., are typically adminis cin, ketoprofen, ketorolac, meloxicam, naproxen, oxaprozin, tered in an amount that produces a therapeutically beneficial piroXicam, and combinations thereof. In a particular embodi effect when co-administered with a compound of the inven ment, the NSAID is selected from ibuprofen, indomethacin, tion. The secondary agent can be in the form of a pharmaceu nabumetone, naproxen (for example, naproxen Sodium), and tically acceptable salt, Solvate, optically pure stereoisomer, combinations thereof. and so forth. Thus, secondary agents listed below are intended to include all Such forms, and are commercially available or I0132 Representative muscle relaxants include, but are not can be prepared using conventional procedures and reagents. limited to: carisoprodol, chlorZoxazone, cyclobenzaprine, 0126 Representative anti-Alzheimer's agents include, but diflunisal, metaxalone, methocarbamol, and combinations are not limited to: donepezil, galantamine, memantine, thereof. rivastigmine, selegiline, tacrine, and combinations thereof. 0.133 Representative norepinephrine reuptake inhibitors 0127 Representative anticonvulsants (antiepileptics) include, but are not limited to: atomoxetine, buproprion and include, but are not limited to: acetazolamide, albutoin, the buproprion metabolite hydroxybuproprion, maprotiline, 4-amino-3-hydroxybutyric acid, beclamide, carbamazepine, reboxetine (for example, (S,S)-reboxetine), viloxazine, and cinromide, clomethiazole, clonazepam, diazepam, combinations thereof. In a particular embodiment, the nore dimethadione, eterobarb, ethadione, ethoSuximide, ethotoin, pinephrine reuptake inhibitor is selected from atomoxetine, felbamate, fosphenyloin, gabapentin, lacosamide, lamot reboxetine, and combinations thereof. rigine, lorazepam, magnesium bromide, magnesium Sulfate, 0.134 Representative opioid agonists (opioid analgesics) mephenyloin, mephobarbital, methSuximide, midazolam, include, but are not limited to: buprenorphine, butorphanol, nitrazepam, oxazepam, oXcarbazepine, paramethadione, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromor phenacemide, pheneturide, phenobarbital, phensuximide, phone, levallorphan, levorphanol, meperidine, methadone, phenyloin, potassium bromide, pregabalin, primidone, pro morphine, nalbuphine, nalmefene, nalorphine, naloxone, nal gabide, Sodium bromide, Sodium valproate, Sulthiame, tiaga trexone, nalorphine, oxycodone, Oxymorphone, pentazocine, bine, topiramate, trimethadione, Valproic acid, valpromide, propoxyphene, tramadol, and combinations thereof. In cer vigabatrin, Zonisamide, and combinations thereof. In a par tain embodiments, the opioid agonist is selected from ticular embodiment, the anticonvulsant is selected from car codeine, dihydrocodeine, hydrocodone, hydromorphone, bamazepine, gabapentin, pregabalin, and combinations morphine, oxycodone, oxymorphone, tramadol, and combi thereof. nations thereof. 0128 Representative antidepressants include, but are not 0.135 Representative selective serotonin reuptake inhibi limited to: adinazolam, amitriptyline, clomipramine, tors (SSRIs) include, but are not limited to: citalopram and the desipramine, dothiepin (e.g., dothiepin hydrochloride), dox citalopram metabolite desmethylcitalopram, dapoxetine, epin, imipramine, lofepramine, mirtazapine, nortriptyline, escitalopram (e.g., escitalopram oxalate), fluoxetine and the protriptyline, trimipramine, Venlafaxine, Zimelidine, and fluoxetine desmethyl metabolite norfluoxetine, fluvoxamine combinations thereof. (e.g., fluvoxamine maleate), paroxetine, Sertraline and the 0129 Representative anti-Parkinson's agents include, but sertraline metabolite demethylsertraline, and combinations are not limited to: amantadine, apomorphine, benztropine, thereof. In certain embodiments, the SSRI is selected from bromocriptine, carbidopa, diphenhydramine, entacapone, citalopram, paroxetine, Sertraline, and combinations thereof. levodopa, pergolide, pramipexole, ropinirole, selegiline, tol 0.136 Representative sodium channel blockers include, capone, trihexyphenidyl, and combinations thereof. but are not limited to: carbamazepine, fosphenyloin, lamot 0130 Representative dual serotonin-norepinephrine rignine, lidocaine, mexiletine, Oxcarbazepine, phenyloin, and reuptake inhibitors (SNRIs) include, but are not limited to: combinations thereof. bicifadine, desvenlafaxine, dulloxetine, milnacipran, nefaZ 0.137 Representative sympatholytics include, but are not odone, Venlafaxine, and combinations thereof. limited to: atenolol, clonidine, doxazosin, guanethidine, 0131 Representative non-steroidal anti-inflammatory guanfacine, modafinil, phentolamine, praZosin, reserpine, agents (NSAIDs) include, but are not limited to: acemetacin, tolazoline (e.g., tolazoline hydrochloride), tamsulosin, and acetaminophen, acetyl salicylic acid, alclofenac, alminopro combinations thereof. fen, amfenac, amiprilose, amoxiprin, anirolac, apaZone, aza 0.138. The following formulations illustrate representative propaZone, benorilate, benoxaprofen, bezpiperylon, broper pharmaceutical compositions of the present invention: amole, bucloxic acid, carprofen, clidanac, diclofenac, diflunisal, diftalone, enolicam, etodolac, etoricoxib, fen bufen, fenclofenac, fenclozic acid, fenoprofen, fentiazac, Exemplary Hard Gelatin Capsules for Oral feprazone, flufenamic acid, flufenisal, fluprofen, flurbipro Administration fen, furofenac, ibufenac, ibuprofen, indomethacin, indopro fen, isoxepac, isoxicam, ketoprofen, ketorolac, lofemizole, 0.139. A compound of the invention (50 g), spray-dried lornoxicam, meclofenamate, meclofenamic acid, mefenamic lactose (440 g) and magnesium Stearate (10 g) are thoroughly acid, meloxicam, mesalamine, miroprofen, mofebutaZone, blended. The resulting composition is then loaded into hard nabumetone, naproxen, niflumic acid, nimeSulide, nitroflur gelatin capsules (500 mg of composition per capsule). biprofen, olsalazine, oxaprozin, oXpinac, oxyphenbutaZone, 0140 Alternately, a compound of the invention (20 mg) is phenylbutaZone, piroxicam, pirprofen, pranoprofen, sal thoroughly blended with starch (89 mg), microcrystalline salate, Sudoxicam, SulfaSalazine, Sulindac, Suprofen, tenoxi cellulose (89 mg) and magnesium Stearate (2 mg). The mix US 2011/00094.65 A1 Jan. 13, 2011

ture is then passed through a No. 45 mesh U.S. sieve and Exemplary Injectable Formulation for loaded into a hard gelatin capsule (200 mg of composition per Administration by Injection capsule). 0147 A compound of the invention (0.2g) is blended with Exemplary Gelatin Capsule Formulation for Oral 0.4M sodium acetate buffer solution (2.0 mL). The pH of the Administration resulting solution is adjusted to pH 4 using 0.5 N aqueous hydrochloric acid or 0.5 N aqueous sodium hydroxide, as 0141. A compound of the invention (100 mg) is thor necessary, and then Sufficient water for injection is added to oughly blended with polyoxyethylene sorbitan monooleate provide a total volume of 20 mL. The mixture is then filtered (50 mg) and starch powder (250 mg). The mixture is then through a sterile filter (0.22 micron) to provide a sterile solu loaded into a gelatin capsule (400 mg of composition per tion Suitable for administration by injection. capsule). 0142. Alternately, a compound of the invention (40 mg) is Exemplary Compositions for Administration by thoroughly blended with microcrystalline cellulose (Avicel Inhalation PH 103: 259.2 mg) and magnesium stearate (0.8 mg). The mixture is then loaded into a gelatin capsule (Size #1, White, 0.148. A compound of the invention (0.2 mg) is micronized Opaque) (300 mg of composition per capsule). and then blended with lactose (25 mg). This blended mixture is then loaded into a gelatin inhalation cartridge. The contents Exemplary Tablet Formulation for Oral of the cartridge are administered using a dry powder inhaler, Administration for example. 0149. Alternately, a micronized compound of the inven 0143 A compound of the invention (10 mg), starch (45 tion (10 g) is dispersed in a solution prepared by dissolving mg) and microcrystalline cellulose (35 mg) are passed lecithin (0.2 g) in demineralized water (200 mL). The result through a No. 20 mesh U.S. sieve and mixed thoroughly. The ing Suspension is spray dried and then micronized to form a granules so produced are dried at 50-60° C. and passed micronized composition comprising particles having a mean through a No. 16 mesh U.S. sieve. A solution of polyvinylpyr diameter less than about 1.5um. The micronized composition rolidone (4 mg as a 10% solution in sterile water) is mixed is then loaded into metered-dose inhaler cartridges containing with sodium carboxymethyl starch (4.5 mg), magnesium pressurized 1,1,1,2-tetrafluoroethane in an amount Sufficient Stearate (0.5 mg), and talc (1 mg), and this mixture is then to provide about 10 ug to about 500 ug of the compound of the passed through a No. 16 mesh U.S. sieve. The sodium car invention per dose when administered by the inhaler. boxymethyl Starch, magnesium Stearate and talc are then 0150. Alternately, a compound of the invention (25 mg) is added to the granules. After mixing, the mixture is com dissolved in citrate buffered (pH 5) isotonic saline (125 mL). pressed on a tablet machine to afford a tablet weighing 100 The mixture is stirred and Sonicated until the compound is ng. dissolved. The pH of the solution is checked and adjusted, if 0144. Alternately, a compound of the invention (250mg) necessary, to pH 5 by slowly adding aqueous 1N sodium is thoroughly blended with microcrystalline cellulose (400 hydroxide. The solution is administered using a nebulizer mg), silicon dioxide fumed (10 mg), and Stearic acid (5 mg). device that provides about 10 ug to about 500 g of the The mixture is then compressed to form tablets (665 mg of compound of the invention per dose. composition per tablet). 0145 Alternately, a compound of the invention (400 mg) EXAMPLES is thoroughly blended with cornstarch (50 mg), croscarmel lose Sodium (25 mg), lactose (120mg), and magnesium Stear 0151. The following Preparations and Examples are pro ate (5 mg). The mixture is then compressed to form a single vided to illustrate specific embodiments of the invention. scored tablet (600 mg of compositions per tablet). These specific embodiments, however, are not intended to limit the scope of the invention in any way unless specifically Exemplary Suspension Formulation for Oral indicated. Administration 0152 The following abbreviations have the following meanings unless otherwise indicated and any other abbrevia 0146 The following ingredients are mixed to form a sus tions used herein and not defined have their standard mean pension containing 100 mg of active agent per 10 mL of ing: Suspension: 0153. AcOHacetic acid 0154 BH.MeS borane dimethylsulphide complex 0.155 BSA bovine serum albumin Ingredients Amount 0156 DCM dichloromethane (i.e., methylene chloride) (O157 DIAD diisopropylazodicarboxylate Compound of the invention 1.0 g Fumaric acid 0.5 g. 0158 DMEMDulbecco's Modified Eagle's Medium Sodium chloride 2.0 g 0159. DMF N,N-dimethylformamide Methyl paraben 0.15 g (0160 DMSO dimethylsulfoxide Propyl paraben 0.05 g Granulated Sugar 25.5 g 0.161 EDTA ethylenediaminetetraacetic acid Sorbitol (70% solution) 12.85 g (0162 Et ethyl Veegum (R) K (magnesium aluminum silicate) 1.0 g (0163 EtOAc ethyl acetate Flavoring O.O35 mL. Colorings 0.5 mg (0164. EtOH ethanol Distilled water q.S. to 100 mL. 0.165 FBS fetal bovine serum 0166 hDAT human dopamine transporter 0.167 hDAT human dopamine transporter US 2011/00094.65 A1 Jan. 13, 2011 19

0168 HEPES 4-(2-hydroxyethyl)-1-piperazineethane -4°C.). A 1:1 mixture of 0.7M sodium hypochlorite in water Sulfonic acid and saturated NaHCO (56 mL total) was added dropwise. 0169 hNET human norepinephrine transporter The resulting mixture was allowed to stand in the ice bath 0170 hSERT human serotonin transporter until layers separated (-5 minutes). The layers were separated (0171 LiHMDS lithium hexamethyl disilazide and extracted with DCM (3x30 mL). The organic layer was (0172 Me methyl washed with water (30 mL) and saturated aqueous NaCl (30 (0173 MeCN acetonitrile mL), then dried over anhydrous NaSO filtered and concen 0.174 MeOH methanol trated to yield (S)-3-formylpyrrolidine-1-carboxylic acid (0175 PBS phosphate buffered saline t-butyl ester (3.0 g), which was used without further purifi (0176 PPhs triphenylphosphine cation. (0177 TEMPO 2.2,6,6-tetramethyl-1-piperidinyloxy, 0185 (S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl free radical ester (1 g, 5 mmol) and THF (10 mL, 100 mmol) were com 0.178 TFA trifluoroacetic acid bined under nitrogen, and the resulting Solution cooled to (0179 THF tetrahydrofuran -78°C. 1.0 M of Ethyl magnesium bromide in THF (7.5 mL, 0180. Any other abbreviations used herein but not defined 7.5 mmol) was added dropwise over 10 minutes. The mixture have their standard, generally accepted meaning Unless noted was allowed to warm to room temperature slowly overnight. otherwise, all materials, such as reagents, starting materials The reaction was then quenched by the dropwise addition of and solvents, were purchased from commercial Suppliers saturated aqueous NHCl (30 mL). The resulting mixture was (such as Sigma-Aldrich, Fluka Riedel-de Haen, and the like) extracted with EtOAc (2x30 mL), and the combined organic and were used without further purification. layers were washed with saturated aqueous NaHCO (1x30 0181. In all of the compounds described in the examples, mL) and saturated aqueous NaCl (1x30 mL), then dried over the two chiral centers are identified by the * and ** symbols. anhydrous MgSO4, filtered, and concentrated in vacuo to When describing the stereochemistry, the carbon atom indi yield (S)-3-(1-hydroxypropyl)pyrrolidine-1-carboxylic acid cated by the * symbol is designated first. Thus, an “SR’ t-butyl ester. designation represents a compound having the (S) configura 0186 (S)-3-(1-Hydroxypropyl)pyrrolidine-1-carboxylic tion at the carbon atom indicated by the * symbol and having acid t-butyl ester (1.5 g. 6.5 mmol) was purified by prepara the (R) configuration at the ** carbon atom. The same hold tive HPLC. The residue was dissolved in 50% AcOH/HO true for racemic mixtures. For example, an “RS/SR' desig and the diastereomers were separated using a gradient of nation represents a racemic mixture of (R.S) compounds and 10-50% AcOH/HO (0.05% TFA) over 80 minutes on a 2" (S,R) compounds, i.e., a mixture of compounds having the column at 40 mL/min. The collected fractions were lyo (R) configuration at the * carbon atom and the (S) configura philized to yield each diastereomeras an oil (565 mg, SS, 1 tion at the ** carbon atom and compounds having the (S) eluting peak, 565 mg, SR, 2" eluting peak). Each diastere configuration at the * carbon atom and the (R) configuration omer was dissolved in DCM (4 mL) and HCO resin (1 g (a) at the * carbon atom. 1.95 mmol/g) was added to recover residual TFA. The mix 0182. Note that the chiral center is known and is set forth ture was stirred for 1 hour. The product was filtered off and in the compound name and/or table. However, the ** chiral solvent was removed to yield the title compound. center specified in the compound name and/or table is not known unambiguously and is based upon the first elution Example 1 peak by reverse phase HPLC from the mixture of diastereo (S)-3-(S)-1-(2,4-Dichlorophenoxy)propylpyrroli meric intermediates (the protected alcohols). dine Preparation 1 0187. (S)-3-((S)-1-Hydroxypropyl)pyrrolidine-1-carboxy lic Acid t-Butyl Ester C 0183) O " H

HO C : :::::: H N

0188 60% NaH in mineral oil (60:40, NaH:mineral oil, 10 N mg, 260 ummol) was slowly added to a mixture of (S)-3-(S)- 1-hydroxypropyl)pyrrolidine-1-carboxylic acid t-butyl ester O (50 mg 0.2 mmol. 1 eq.) in DMF (680 uL, 8.7 mmol). The rY. resulting mixture was stirred for 15 minutes, at room tem perature. 2,4-Dichloro-1-fluorobenzene (76 LL, 3 eq.) was 0184. To a solution of (S)-3-hydroxymethyl-pyrrolidine added and the mixture was heated at 90° C. for 3 hours. The 1-carboxylic acid t-butyl ester (4.0 g. 19.9 mmol. 1.0 eq.) in reaction was quenched with MeOH (1 mL). DMF and MeOH DCM was added TEMPO (62 mg, 0.4 mmol, 0.02 eq.) and was removed under reduced pressure, leaving the BOC-pro potassium bromide (120 mg, 1.0 mmol, 0.05 eq.). The result tected intermediate, (S)-3-(S)-1-(2,4-dichlorophenoxy)pro ing mixture was cooled over ice (and a small amount of salt, pylpyrrolidine-1-carboxylic acid t-butyl ester. Deprotection US 2011/00094.65 A1 Jan. 13, 2011 20 was carried out using 1.25 M HCl in EtOH (1.7 mL, 2.2 stirring. The resulting mixture was stirred at 0°C. to room mmol). The mixture was stirred overnight at room tempera temperature overnight. then concentrated by rotary evapora ture. The product was then purified by preparative HPLC to tion. EtOAc (200 mL) was added and the solution was again yield the title compound as a mono-TFA salt (41.5 mg). MS concentrated by rotary evaporation. Additional EtOAc (200 m/z. M+H" calcd for CH,ClNO, 274.07; found 274.0. mL) was added and the Solution was concentrated by rotary evaporation. The product was dried under high vacuum to Monohydrochloride Salt yield the title salt as a thick oil/semisolid (16.7 g. D99% purity). 0189 (S)-3-(S)-1-(2,4-Dichlorophenoxy)propylpyrroli dine-1-carboxylic acid t-butyl ester (22.0 g, 58.8 mmol) was Example 2 dissolved in EtOAc (50 mL,500 mmol) and cooled to 0°C. A 0190. Following the procedures described in the examples HCl solution was prepared by the slow addition of acetyl above, and Substituting the appropriate starting materials and chloride (40.0 mL, 562 mmol) into EtOH (100 mL, 2000 reagents, compounds 2-1 to 2-75, having formula IIa, were mmol) at 0°C., then added to the EtOAc solution, while prepared as mono-TFA salts:

R3 (IIa)

R R2

R5 O R6 ::::::

:

N H

MS miz: M + H

i : :::::: R2 R3 R4 R R6 Formula calcd found

1 S S C H CHCINO 240.11 240.O 2 S S H C CHCINO 240.11 240.O 3 R. R. H C CHCINO 240.11 240.O 4 S R H C CHCINO 240.11 240.2 5 S S F C CH,CIFNO 258.10 258.2 6 S R F C CH,CIFNO 258.10 258.2 7 S S C C CH17Cl2NO 274.07 274.O 8 S R C C CH,ClNO 274.07 274.O 9 S S F H CHFNO 224.14 224.0 10 S S F H C CH,CIFNO 258.10 258.2 11 S R F H C C.H.CIFNO 258.10 258.2 12 S S H CHFNO 224.14 224.0 13 S S Me C C14H2OCINO 254.12 254.2 14 S R Me C C14H2OCINO 254.12 254.2 15 S S Me C Me CHCINO 268.14 268.2 16 S S —CF CHFNO 274.13 274.O 17 S S H —CF CHFNO 274.13 274.O 18 S S C C CH17Cl2NO 274.07 274.O 19 R. R. C C CH,ClNO 274.07 274.O 20 S S C OMe C14H2OCINO2 270.12 270.2 21 S S C CH,CIFNO 258.10 258.0 22 S S F OMe C14H1gF2NO2 272.14 272.2 23 S S C H CHCINO 240.11 240.O 24 S R C H CHCINO 240.11 240.2 25 S S C H CH,CIFNO 258.10 258.0 26 S R C H C.H.CIFNO 258.10 258.0 27 S S C H Me CHCINO 254.12 2S4O 28 S S C C CH17Cl2NO 274.07 274.O 29 R. R. C C CH,ClNO 274.07 274.O 30 R S C C CH17Cl2NO 274.07 274.O 31 S R C C CH17Cl2NO 274.07 274.O 32 S S C H C.H.CIFNO 258.10 258.0 33 R. R. C H C CH17Cl2NO 274.07 274.O S R C H C CH17Cl2NO 274.07 274.3 S S C H C F CHCl2FNO 292.06 292.0 S R C F H H CHCIFNO 276.09 276.0 3 7 S S C C H CI CHCINO 308.03 3O8.0

US 2011/00094.65 A1 Jan. 13, 2011 23

0267 (S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl Example 3 ester (2.2g, 11 mmol) and THF (20 mL, 300 mmol) were (S)-3-(S)-1-(2,3-Dichlorophenoxy)butylpyrrolidine combined under nitrogen, and the resulting solution was 0270 cooled to -78°C. 2.0M Propylmagnesium chloride in ether C (11.0 mL. 22.1 mmol) was then added dropwise over 1 hour. The mixture was allowed to warm to room temperature C O slowly overnight. Then saturated aqueous NHCl (20 mL) :::::: was added dropwise to quench the reaction. The resulting mixture was extracted with EtOAc (2x50 mL), and the com bined organic layers were washed with Saturated aqueous N NaHCO (1x100 mL) and saturated aqueous NaCl (1x100 H mL), then dried over anhydrous NaSO filtered, and con 0271 (S)-3-((S)-1-Hydroxybutyl)pyrrolidine-1-carboxy centrated in vacuo to yield a pale, yellow oil (2.6 g). The oil lic acidt-butyl ester (50 mg, 0.2 mmol) was dissolved in DMF was purified by preparative HPLC in two equal batches of 1.3 (1.0 mL, 13 mmol). NaH (5.9 mg, 246 ummol) was slowly gloading in 1:1 AcOH/HO (6 mL). The diastereomers were added and the mixture was stirred at room temperature for 15 separated by gradient (5-70% MeCN/HO; 0.05%TFA; over minutes. 1,2-Dichloro-3-fluorobenzene (67.8 mg, 411 70 minutes on a 2" BDS column). The fractions for peak 1 ummol) was added. The mixture was stirred at 70° C. for 3 were collected and lyophilized to yield an oil. The fractions hours, then concentrated. 1.2M HCl in EtOH (1.0 mL, 1.2 for peak 2 were lyophilized then repurified. Both products mmol) was added, and the mixture was stirred overnight. The were identified as clean by NMR and HPLC and identified for product was concentrated and purified by preparative HPLC mass by LCMS: to yield the title compound as a mono-TFA salt (19 mg, 100% purity). MS m/z. M+H" calcd for CHC1-NO, 288.08; 0268 (S)-3-((S)-1-Hydroxybutyl)pyrrolidine-1-carboxy found 288.0. lic acidt-butyl ester (810 mg: 1 eluting peak). H NMR (400 (0272 'H NMR (400 MHz, CDC1,) 89.89 (br. s. 1H), 9.53 MHz, CDC1) & 3.60-3.35 (m, 3H); 3.25 (dd, J=17.8, 11.4, (br. s. 1H), 7.16-7.04 (m, 2H), 6.81 (dd, J=8.1, 1.5 Hz, 1H), 1H); 2.99 (t, J=9.8, 1H); 2.38-2.25 (m, 2H); 2.25-2.13 (m, 4.36 (dd, J=11.3, 5.8 Hz, 1H), 3.50-3.36 (m, 2H), 3.36-3.22 1H); 2.04 (td, J=11.2, 6.3, 1H); 1.80-1.65 (m, 1H); 1.58-1.25 (m. 1H), 3.15-3.00 (m, 1H), 2.77 (pd, J–8.2, 5.2 Hz, 1H), (m. 11H): 0.95 (t, J=6.9, 3H). 2.34-2.06 (m, 2H), 1.77-1.66 (m, 1H), 1.60 (ddd, J=14.0, 0269 (S)-3-((R)-1-Hydroxybutyl)pyrrolidine-1-carboxy 12.0, 7.2 Hz, 1H), 1.45-132 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). lic acidt-butylester (780 mg, 2" eluting peak). "HNMR (400 Example 4 MHz, CDC1,) 83.65-3.43 (m,3H); 3.26 (dd, J=16.0, 7.6, 1H): 0273 Following the procedures described in the examples 3.13 (t, J=8.9, 1H); 2.38-2.15 (m, 3H); 1.88 (dtd, J=14.1, 6.8, above, and Substituting the appropriate starting materials and 2.4, 1H); 1.72-1.55 (m, 1H); 1.55-1.34 (m. 11H): 0.95 (t, reagents, compounds 4-1 to 4-72, having formula IIb, were J=6.7,3H). prepared as mono-TFA salts:

(IIb) R3 R R2

R5 O R6 ::::::

:

N H

MS miz: M + H

i : : : R2 R3 R4 R5 R6 Formula calcd found 1 S S H H C H H CH2CINO 254.12 2S4O 2 S R H H C H H C14H2OCINO 254.12 254.2 3 R S H H C H H C14H2OCINO 254.12 254.2 4 R. R. H H C H H C14H2OCINO 254.12 254.2 5 S S H H F H. H. C14H2OFNO 238.15 238.2 6 S S H C. H. C. H C14H9Cl2NO 288.08 288.0 7 S R H C. H. C. H C14H9Cl2NO 288.08 288.0 8 R S H C. H. C. H CHCl2NO 288.08 288.0 9 R. R. H C. H. C. H C14H9Cl2NO 288.08 288.0 10 S R H C H F H CHCIFNO 272.11 272.2 11 S S H C H F H CHCIFNO 272.11 272.2 12 S S H CI C H H C14H9Cl2NO 288.08 288.0 13 S R H CI C H H C14H9Cl2NO 288.08 288.0

US 2011/00094.65 A1 Jan. 13, 2011 27 rial that eluted second. Using this analysis, the 2" eluting (222 mg, 9.3 mmol) was slowly added in three portions, and peak material was determined to be (S,R): the mixture was stirred at room temperature for 15 minutes under nitrogen. 1-Chloro-4-fluorobenzene (984 uL. 9.3 mmol) was added. The mixture was stirred at 70° C. for 1 hour, cooled to room temperature and the reaction quenched with MeOH, then concentrated. The mixture was partitioned between EtOAc and water (25 mL each) to remove excess sodium salts. The aqueous layer was reextracted with EtOAc (3x25 mL), and the organic layers were combined and con centrated. The crude BOC-protected intermediate, (S)-3- (S)-1-(4-chlorophenoxy)-2-methylpropylpyrrolidine-1- carboxylic acid t-butyl ester, was then purified by silica gel (40 g column, 0-75% EtOAc in hexanes over 30 minutes). The desired fractions were collected and concentrated to yield the BOC-protected intermediate as a clear oil (481 mg). Deprotection was carried out using 1.25 M HCl in EtOH (11 mL, 13 mmol). The mixture was stirred overnight at room temperature under nitrogen. The solids were redissolved in 8 (S, R, S)- 1:1 AcOH/HO (10 mL) and purified by preparative HPLC Proton 8 (S, R,S) 8 (S,R,R) 8 (S,R,R) (10-70% gradient MeCN/HO). The desired fractions were Ha S.O40 S.O29 O.O11 collected to yield the title compound as a mono-TFA salt (481 Hb 2.486 2.511 -O.O25 Hc, He Overlapping non- Overlapping non- ND mg, 98% purity). MS m/z. M+H" calcd for CHCINO, equiv H's equiv H's 254.12; found 254.0. Hd, Hol' O.912 O.876 O.036 0356) "H NMR (400 MHz, CDC1) & 9.80-9.58 (m, 2H): He' Overlap with Boc Overlap with Boc ND 723-7.18 (m, 2H); 6.88-6.81 (m, 2H); 4.20 (t, J=5.5, 1H): Hf 3.209 3.212 -O.OO3 3.40-3.28 (m, 2H); 3.27-3.15 (m, 1H); 2.97-2.87 (im, 1H): Hf 2.988 3.OSO -O.O62 2.75 (qd, J=13.7, 7.8, 1H); 2.18-2.08 (m, 1H); 2.06-1.97 (m, Hg Overlap with OMe Overlap with OMe ND 1H); 1.92 (qd, J=13.5, 6.7, 1H): 0.98 (d. J=0.98,3H): 0.97 (d. Hg" 3.364 3.389 -O.O25 J=0.98, 3H). ND: not determinable Monohydrochloride Crystalline Salt 0351) Note that the first two letters correspond to the 2" 0357 (S)-3-((S)-1-Hydroxy-2-methylpropyl)pyrrolidine eluting peak material and the third letter of the diastereomer 1-carboxylic acidt-butyl ester (2.6 g. 10.7 mmol. 1.0 eq) and refers to the Mosher's ester chiral center. 1-chloro-4-fluorobenzene (3.4 mL, 32.0 mmol. 3.0 eq.) were 0352 SRS diastereomer: 1H, CDC1, 8 ppm 7.60-7.51 (m, dissolved in DMF (12 mL, 150 mmol). NaH (385 mg, 16.0 mmol. 1.5 eq.) was slowly added in three portions, and the 2H): 743-7.37 (m, 3H); 5.04 (dd, J=8.0, 4.0, 1H); 3.52 (s, mixture was stirred at room temperature for 10 minutes under 3H); 3.51-3.45 (m, 1H); 3.36 (t, J=8.4, 1H); 3.28-3.12 (m, nitrogen. The mixture was heated at 90° C. for 3 hours, then 1H); 3.07-2.90 (m. 1H); 2.59-2.39 (m. 1H); 1.97-1.80 (m, cooled to room temperature. The mixture was extracted with 2H); 1.59-145 (m, 1H); 1.43 (s.9H): 0.93 (d. J=6.8,3H): 0.90 hexanes (50 mL) and washed with water (50 mL). The aque (d. J=6.8, 3H). ous layer was reextracted with hexanes (50 mL). The organic 0353 SRR diastereomer: 1H, CDC1.8 ppm 7.62-7.52 (m, layers were combined, dried under NaSO, filtered, and con 2H); 7.44-7.36 (m, 3H); 5.06-4.98 (m, 1H); 3.52 (s, 3H): centrated. The crude BOC-protected intermediate was then 3.52-3.45 (m, 1H); 3.39 (t, J=8.8, 1H); 3.30-3.14 (m, 1H): purified by column chromatography (eluting with hexanes 3.10-2.96 (m. 1H); 2.60-240 (m, 1H); 1.96-1.80 (m, 2H): and ether, 0-100%, combiflash). Deprotection was carried out 1.58-1.45 (m, 1H); 1.43 (s, 9H): 0.96 (m, 6H). using 1.20 MHCl in EtOH (150 mL, 180 mmol). The mixture was stirred at room temperature for 48 hours. The solution Example 5 was concentrated until dry to yield the crude product as a (S)-3-(S)-1-(4-Chlorophenoxy)-2-methylpropyl mono-HCl salt. The crude mono-HCl salt was dissolved in pyrrolidine isopropanol (5 mL) to produce an oil, which was heated to at 55° C. Diisopropyl ether (25 mL) was slowly added under 0354) constant stirring to form a homogeneous Solution, which was cooled to room temperature. The reaction vessel was scarred and seed crystals (from heating and slowly cooling 100 mg of C crude HCl salt using similar conditions) were added during the cooling process. Solids formed and the solution was allowed to sit at room temperature for 1 hour. The solids were filtered and washed with diisopropyl ether (10 mL) to yield a O white solid (1.4 g). The filtrate was concentrated and crystal :::::: H lization was repeated twice to yield a total of 2.4 g (from 3 precipitations). The precipitate was dissolved in water and lyophilized to give the title compound as an off-white crys N talline solid (2.4g, 99% purity). H Example 6 0358. Following the procedures described in the examples 0355 (S)-3-((S)-1-Hydroxy-2-methylpropyl)pyrrolidine above, and Substituting the appropriate starting materials and 1-carboxylic acid t-butyl ester (750 mg, 3.1 mmol) was dis reagents, compounds 6-1 to 6-77, having formula IIc, were solved in DMF (11 mL, 140 mmol). Washed and dried NaH prepared as mono-TFA salts: US 2011/00094.65 A1 Jan. 13, 2011 28

(IIc)

::::::

N

MS miz: M + H

i : : : R2 R 3 Formula calcd found

S R 238. 238.2 RRFS C14H2OFNO 238. 238.2 CHCIFNO 272. 272.1 CHCIFNO 272. 272.1 CHCIFNO 29O. 29O.O CHCIFNO 29O. 29O.O CH3Cl2FNO 306. 306.0 CH3Cl2FNO 306. 306.0 CH3Cl2FNO 306. 306.0 1 CHCIFNO 29O. 290.2 254. 2S4O 288. 288.0 288. 288.0 288. 288.2 288. 288.2 288. 288.0 272. 272.O 272. 272.O 272. 272.2 272. 272.2 288. 288.2 288. 288.2 288. 288.0 24 268. 268.2 322. 322.2 288. 288.0 288. 288.0 288. 288.0 SS 288. 288.0 306. 306.0 306. 306.0 306. 306.0 3O2. 302.0 306. 306.0 322. 322.0 29O. 29O.O O e C15H2CIFNO2 3O2. 3.02.2 CH,Cl2FNO 324. O 324.0 CHCINO 268. 268.2 CHCINO 268. 268.2 CHCINO 268. 268.2 CHCINO 268. 268.2 e CH23NO 248. 248.2 e CHCINO 268. 268.2 CHCINO 268. 268.2 e CHCINO 268. 268.2 C15H2CINO2 284. 284.4 C15H2CINO2 284. 284.2 C15H3CIFNO 322. 322.2 S CHCIFNO 322. 322.0 C15H3CIFNO 322. 322.2 C15H3CIFNO 322. 322.2 i.O 2 C14H2ON2O3 26S. 265.2 CHFNO 238. 238.2 S C14H2OFNO 238. 238.2 CHCIFNO 272. 272.2

US 2011/00094.65 A1 Jan. 13, 2011

using a gradient of (10-70% MeCN/HO and 0.05% TFA) 0439 (S)-3-((R)-1-Hydroxypentyl)pyrrolidine-1-car over 80 minutes on a 2" column at 40 mL/min. The collected boxylic acid t-butyl ester (40.0 mg, 155 ummol) was dis fractions were lyophilized to yield the following as oils: (S)- solved in DMF (100 mL, 12.9 mmol). While stirring, 60% 3-((S)-1-hydroxypentyl)pyrrolidine-1-carboxylic acid t-bu tylester (100 mg; 1 eluting peak) and (S)-3-((R)-1-hydroxy sodium hydride in oil (0.4:0.6, sodium hydride:mineral oil, pentyl)pyrrolidine-1-carboxylic acid t-butyl ester (789 mg: 18.6 mg, 311 Limmol) was slowly added, and the mixture was 2" eluting peak). stirred for 15 minutes. 1,2,4,5-Tetrafluorobenzene (52.1 uL. 466 ummol) was added. The mixture was then heated at 90° Example 7 C. for 3 hours. The reaction was quenched with MeOH (1 mL), and the solvent was removed under reduced pressure. (S)-3-((R)-1-(2,4,5-Trifluorophenoxy)pentylpyrroli 1.25M HCl in EtOH (2.0 mL, 2.5 mmol) was added, and the dine mixture was stirred overnight. The product was concentrated 0438 and purified by preparative HPLC to yield the title compound as a mono-TFA salt (19.2 mg, 97% purity). MS m/z. M+H" F calcd for CHFNO, 288.15; found 288.2.

Example 8

F 0440 Following the procedures described in the examples above, and Substituting the appropriate starting materials and F reagents, compounds 8-1 to 8-13, having formula IId, were prepared as mono-TFA salts:

(IId)

::::::

N

R3 R4 R R6 Formula calcd found

H CHCINO 268.14 268.2 H CH2FNO 3O2.17 3.02.2 F CHFNO 252.17 252.2 C CHCINO 268.14 268.4 —CF CH2FNO 3O2.17 3.02.2 C H C15H2Cl2NO 3O2.10 302.0 Me C H CH2CINO 282.15 282.2 C C15H2Cl2NO 3O2.10 302.0 Me CH2CINO 282.15 282.4 C CH2CINO 282.15 282.2 C CH2 CIFNO 336.13 336.O 1 2 H C C15H2Cl2NO 3O2.10 302.0 1 3 C H C CH2Cl2NO 3O2.10 302.0 US 2011/00094.65 A1 Jan. 13, 2011 32

0441 1. (S)-3-((R)-1-(2-Chlorophenoxy)pentylpyrroli NaHCO (1x100 mL) and saturated aqueous NaCl (1x100 dine mL), then dried over anhydrous MgSO, filtered, and concen 0442. 2. (S)-3-((R)-1-(2-Trifluoromethylphenoxy)pentyl) trated in vacuo. The crude product was purified by column pyrrolidine chromatography (80 g SiO, ethyl ether) to yield (S)-3-((S)- 0443 3. (S)-3-((R)-1-(4-Fluorophenoxy)pentylpyrroli 1-hydroxy-3-methylbutyl)pyrrolidine-1-carboxylic acid dine t-butyl ester (1.6 g) and (S)-3-((R)-1-hydroxy-3-methylbutyl) 0444 4. (S)-3-((R)-1-(4-Chlorophenoxy)pentylpyrroli pyrrolidine-1-carboxylic acid t-butyl ester (2.2 g) as oils. dine 0445. 5. (S)-3-((R)-1-(4-Trifluoromethylphenoxy)pentyl) 0456. This experiment was repeated under similar condi pyrrolidine tions and the product had the following NMR. 0446 6. (S)-3-((R)-1-(2,3-Dichlorophenoxy)pentylpyr 0457 'HNMR (400 MHz, CDC1) 83.59 (ddd, J=9.8, 7.0, rolidine 2.8 Hz, 1H), 3.46 (d. J–21.5 Hz, 2H), 3.24 (td, J=10.2, 7.2 Hz, 0447 7. (S)-3-((R)-1-(3-Chloro-2-methylphenoxy)pen 1H), 2.97 (dd, J=22.4, 12.3 Hz, 2H), 2.25-2.09 (m, 1H), tylpyrrolidine 2.08-1.97 (m. 1H), 1.90-1.65 (m, 2H), 1.46 (s.9H), 1.43-1.36 0448 8. (S)-3-((R)-1-(2,4-Dichlorophenoxy)pentylpyr (m. 1H), 1.17 (ddd, J=13.8, 9.8, 2.8 Hz, 1H), 0.92 (dd, J=13.7, rolidine 6.6 Hz, 6H). 0449. 9. (S)-3-((R)-1-(2-Chloro-4-methylphenoxy)pen tylpyrrolidine 0450 10. (S)-3-((R)-1-(4-Chloro-2-methylphenoxy)pen Example 9 tylpyrrolidine 0451 11. (S)-3-((R)-1-(4-Chloro-2-trifluoromethylphe (S)-3-(S)-1-(2,3-Dichlorophenoxy)-3-methylbutyl noxy)pentylpyrrolidine pyrrolidine 0452 12. (S)-3-((R)-1-(2,6-Dichlorophenoxy)pentylpyr 0458 rolidine 0453 13. (S)-3-((R)-1-(3,5-Dichlorophenoxy)pentylpyr rolidine Preparation 5 C (S)-3-((S)-1-Hydroxy-3-methylbutyl)pyrrolidine-1- C carboxylic Acid t-Butyl Ester

O

0454) :::::: H

N H

HO

:::::: H

N 0459 (S)-3-((S)-1-Hydroxy-3-methylbutyl)pyrrolidine 1-carboxylic acid t-butyl ester (50 mg, 0.2 mmol) was dis solved in DMF (940 uL. 12 mmol). Sodium hydride (5.6 mg, OX-0 233 Lummol) was then slowly added, and the mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3- fluoro-benzene (64.1 mg, 388 ummol) was added. The mix ture was stirred at 70° C. for 3 hours, then concentrated under vacuum. 1.2M HCl in EtOH (1.1 mL, 1.3 mmol) was added, and the mixture was stirred overnight. The product was con 0455 (S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl centrated and purified by preparative HPLC to yield the title ester (6.0 g, 30.1 mmol) and THF (60 mL, 700 mmol) were compound as a mono-TFA salt (37.4 mg, 100% purity). MS combined under nitrogen, and the resulting solution was m/z. M+H" calcd for CHC1NO, 302.10; found 302.2. cooled to -78°C. 2.0M Isobutylmagnesium chloride in ether (18.1 mL, 36.1 mmol) was then added dropwise over 10 Example 10 minutes. The mixture was allowed to warm to room tempera ture slowly overnight. Then aqueous saturated NHCl (100 0460. Following the procedures described in the examples mL) was added dropwise to quench the reaction. The result above, and Substituting the appropriate starting materials and ing mixture was extracted with EtOAc (2x100 mL), and the reagents, compounds 10' to 10-86, having formula IIe, were combined organic layers were washed with Saturated aqueous prepared as mono-TFA salts:

US 2011/00094.65 A1 Jan. 13, 2011 36

0546 86. (S)-3-(S)-1-(2-Chloro-3,5,6-trifluorophe 0552 (S)-3-(R)-2-Ethyl-1-hydroxybutyl)pyrrolidine-1- noxy)-3-methylbutylpyrrolidine carboxylic acidt-butyl ester (28 mg, 0.1 mmol) was dissolved Preparation 6 in DMF (380 uL, 4.9 mmol). 60% Sodium hydride in oil (S)-3-((R)-2-Ethyl-1-hydroxybutyl)pyrrolidine-1- (0.4:0.6, sodium hydride:mineral oil, 18.6 mg, 310 ummol) carboxylic Acid t-Butyl Ester was slowly added, and the resulting mixture was stirred at 0547 room temperature for 15 minutes. 1,2-Dichloro-3-fluoroben Zene (23.8 uL. 206 ummol) was added and the mixture was

stirred at 70° C. for 3 hours. The mixture was concentrated, treated with 1.25M HCl in EtOH (578 uL, 722 ummol), then stirred overnight at room temperature. The product was con centrated under vacuum, redissolved in 1:1 AcOH:HO, fil HO tered, and purified by preparative HPLC to yield the title compound as a mono-TFA salt (5.3 mg, 97% purity). MS m/z: M+H" calcd for CHCINO, 316.12; found 316.3. N Example 12 y–o 0553 Following the procedures described in the examples O above, and Substituting the appropriate starting materials and reagents, compound 12-1, having formula IIf was also pre 0548 (S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl pared as a mono-TFA salt: ester (0.8 g., 3.8 mmol:) and THF (8 mL. 90 mmol) were combined under nitrogen, and the resulting solution was cooled to -78°C. 2M 3-Pentylmagnesium bromide in ether (4.70 mL, 9.4 mmol) was then added dropwise over 1 hour. (IIf) The mixture was allowed to warm to room temperature R3 slowly overnight. Then aqueous saturated NHCl (5 mL) was R R2 added dropwise to quench the reaction. The resulting mixture was extracted with EtOAc (2x25 mL), and the combined organic layers were washed with Saturated aqueous NaHCO (25 mL) and saturated aqueous NaCl (25 mL), then dried over R5 O MgSO filtered, and concentrated in vacuo. The crude prod R6 :::::: uct was purified by flash chromatography (5-25% EtOAc in Hexanes) to yield the following as clear oils: 0549 (S)-3-(R)-2-ethyl-1-hydroxybutyl)pyrrolidine-1- N carboxylic acid t-butyl ester (48 mg, 2" eluting peak). "H H NMR (400 MHz, CDOD) & 3.59-3.55 (m, 1H), 3.49-3.44 (m. 2H), 3.26-3.23 (m, 1H), 3.14-3.08 (m, 1H), 2.46-2.38 (m, MS m/z: M + H' 1H), 1.89-1.82 (m, 1H), 1.62-1.53 (m, 2H), 1.46 (s, 9H), 1.44-1.39 (m, 2H), 1.26-1.15 (m, 2H), 0.95-0.90 (m, 6H). # * * * R2 R3 R?4 R Ré Formula calcd found 0550 (S)-3-((S)-2-ethyl-1-hydroxybutyl)pyrrolidine-1- carboxylic acid t-butyl ester (28 mg, 1 eluting peak). H 1 S S Cl C H H H CHCINO 316.12 316.2 NMR (400 MHz, CDOD) & 3.51-3.43 (m, 2H), 3.39-3.34 (m. 1H), 3.27-3.20 (m, 1H), 2.97-2.89 (m, 1H), 2.42-2.34 (m, 0554. 1. (S)-3-(S)-1-(2,3-Dichlorophenoxy)-2-ethylbu 1H), 2.09-2.03 (m. 1H), 1.76-1.68 (m. 1H), 1.61-1.54 (m, tylpyrrolidine 1H), 1.46 (s, 9H) 1.45-140 (2H, m), 1.29-1.23 (m, 1H), 1.1.0-1.04 (m, 1H), 0.95-0.90 (m, 6H). Example 13 Example 11 (S)-3-((R)-1-(2,3-Dichlorophenoxy)-2-ethylbutyl (S)-3-(s)-1-(Naphthalen-1-yloxy)propylpyrrolidine pyrrolidine 0551 0555

C O

::::::

O : H

N H US 2011/00094.65 A1 Jan. 13, 2011 37

0556 (S)-3-((S)-1-Hydroxypropyl)pyrrolidine-1-car 0563) 5. (S)-3-(S)-2-Methyl-1-(naphthalen-1-yloxy)pro boxylic acid t-butyl ester (500 mg, 2.2 mmol) was dissolved pylpyrrolidine in DMF (8.0 mL, 100 mmol). 60:40 NaH:Mineral Oil (262 0564 6. (S)-3-((R)-2-Methyl-1-(naphthalen-1-yloxy)pro mg, 6.5 mmol) was added carefully in three separate portions pylpyrrolidine and then stirred for 15 minutes. The mixture was then treated 0565 7. (R)-3-((R)-2-Methyl-1-(naphthalen-1-yloxy) with 2-fluoronaphthalene (562 uL, 4.4 mmol) and stirred at propylpyrrolidine 70° C. for 3 hours. The mixture was cooled to room tempera ture. An additional 200 mg of 60% NaH:mineral oil was 0566 8. (S)-3-(S)-3-Methyl-1-(naphthalen-1-yloxy)bu added and the mixture was stirred at 70° C. for 14 hours. The tylpyrrolidine reaction was quenched with MeOH until bubbling ceased. 0567 9. (S)-3-((R)-3-Methyl-1-(naphthalen-1-yloxy)bu The mixture was concentrated and the BOC-intermediate was tylpyrrolidine purified by silica gel chromatography (0-30% EtOAc in Hex anes). The purified material was then treated with 1.25 M of Preparation 7 HCl in EtOH (12.2 mL, 15.3 mmol) and stirred overnight at room temperature. The mixture was concentrated and placed (S)-3-((R)-Cyclopropylhydroxymethyl)pyrrolidine on high vacuum to yield the title compound as an oily com 1-carboxylic Acid t-Butyl Ester and (S)-3-((S)-cyclo pound (mono-HCl salt; 242 mg). MS m/z. M+H calcd for propylhydroxymethyl)pyrrolidine-1-carboxylic Acid CH, NO, 256.16; found 256.2. t-Butyl Ester 0557 H NMR (400 MHz, DMSO) & 8.94 (s. 2H), 8.22 8.14 (m, 1H), 7.90-7.83 (m. 1H), 7.56-7.36 (m, 4H), 7.06 (d. 0568 J=7.1 Hz, 1H), 4.70 (d. J=5.6 Hz, 1H), 3.39-3.33 (m, 1H), 3.20-31.5 (m, 2H), 2.99-2.84 (m, 1H), 2.76-2.71 (m, 1H), 2.12-2.08 (m. 1H), 1.98-1.88 (m, 1H), 1.80-1.69 (m, 2H), 0.91 (t, J=74 Hz, 3H). HO Example 14 0558 Following the procedures described in the examples above, and substituting the appropriate starting materials and reagents, compounds 14-1 to 14-9, having formula VIa, were N also prepared as mono-TFA salts: Y- -k O

(XIa) 0569 (S)-3-Formyl-pyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 5 mmol) and THF (10 mL, 100 mmol) were combined under nitrogen, and the resulting solution was cooled to -78°C. 0.5M Cyclopropylmagnesium bromide in THF (15 mL, 7.5 mmol) was then added dropwise over 10 O :::::: minutes. The mixture was allowed to warm to room tempera ture slowly overnight. Then aqueous saturated NHCl (30 mL) was added dropwise to quench the reaction. The result N ing mixture was extracted with EtOAc (2x30 mL), and the H combined organic layers were washed with Saturated aqueous MS m/z. M+H" NaHCOs (1x30 mL) and saturated aqueous NaCl (1x30 mL), then dried over anhydrous MgSO filtered, and concentrated # * :::::: RI Formula calcd found in vacuo. The crude product was purified by preparative 1 S R ethyl C17H2NO 2S6.16 256.2 HPLC (15-55% MeCN:HO+0.05% TFA over 80 minutes) 2 S R propyl C18H23NO 270.18 270.2 on a 2" column to yield (S)-3-((R)-cyclopropylhydroxym 3 S S propyl C18H23NO 270.18 270.2 ethyl)pyrrolidine-1-carboxylic acidt-butyl ester (520 mg. 2" 4 R. S isopropyl C18H23NO 270.18 270.2 eluting peak) and (S)-3-((S)-cyclopropylhydroxymethyl)pyr 5 S S isopropyl C18H23NO 270.18 270.2 6 S R isopropyl C18H23NO 270.18 270.2 rolidine-1-carboxylic acid t-butyl ester (418 mg, 1 eluting 7 R R isopropyl C18H23NO 270.18 270.2 peak). The lyophilized solids were dissolved in EtOAc and 8 S S isobutyl CoH23NO 284.19 284.2 washed with saturated aqueous NHCO, the organics were 9 S R isobutyl CoH23NO 284.19 284.2 separated, dried over NaSO and the solvent was removed under reduced pressure. (0559) 1. (S)-3-((R)-1-(Naphthalen-1-yloxy)propylpyrro (0570 For the (S,S) compound (1 eluting peak): 'H NMR (400 MHz, CDC1) & 3.69-3.48 (m, 3H), 3.48- 2.98 (m, 6H), logo 2. (S)-3-((R)-1-(Naphthalen-1-yloxy)butylpyrroli 2.87- 2.65 (m, 2H), 2.63- 2.16 (m, 2H), 2.16-1.88 (m, 2H), 1.80-1.64 (m, 5H), 1.47 (s, 20H), 1.01-0.86 (m, 2H), 0.68-0. of 3. (S)-3-(S)-1-(Naphthalen-1-yloxy)butylpyrroli 35 (m, 4H), 0.35–0.20 (m, 4H). (0571 For the (S,R) compound (2" eluting peak): "H o 4. (R)-3-(S)-2-Methyl-1-(naphthalen-1-yloxy)pro NMR (400 MHz, CDC1) & 3.71-3.39 (m, 1H), 3.35-3.12 (m, pylpyrrolidine 1H), 2.88-2.70 (m. 1H), 2.39 (dd, J=15.3, 8.9 Hz, 1H), 2.05 US 2011/00094.65 A1 Jan. 13, 2011 38

1.91 (m, 1H), 1.84-1.64 (m, 1H), 1.46 (s, 4H), 1.01-0.87(m, (749 uL, 6.2 mmol) was added, and the mixture was stirred 1H), 0.67-0.46 (m, 1H), 0.27 (d. J=19.2 Hz, 1H). overnight at 70° C. The mixture was concentrated and the BOC-protected intermediate was purified by silica gel chro Example 15 matography (0-10% EtOAc in hexanes for 10 minutes, 10-50% in 10 minutes) and the desired fractions were isolated (S)-3-((R)-(3-Chloro-2-methylphenoxy)cyclopropyl and concentrated. The crude material was then treated with methylpyrrolidine 1.25M HCl in EtOH (23.2 mL, 29.0 mmol) and stirred over 0572 night at room temperature. The product was concentrated under vacuum and purified by preparative HPLC to yield the title compound as a mono-TFA salt (240 mg. 99.4% purity). MS m/z. M+H" calcd for CHCINO,266.12; found 266. O. C 0574 H NMR (400 MHz, DMSO) & 9.14 (s. 2H), 7.15 (t, J=8.1 Hz, 1H), 7.08-7.01 (m, 2H), 4.04 (t, J=7.3 Hz, 1H), 3.42-3.32 (m. 1H), 3.29-3.20 (m, 1H), 3.19-3.09 (m, 1H), 3.08-2.98 (m. 1H), 2.74-2.63 (m. 1H), 2.24 (s.3H), 2.13-2.01 (m. 1H), 1.86-1.73 (m, 1H), 1.11-1.01 (m, 1H), 0.52-0.44 (m, 1H), 0.43-0.35 (m. 1H), 0.27-0.20 (m. 1H), 0.19-0.11 (m, 1H). 0573 (S)-3-((R)-Cyclopropylhydroxymethyl)pyrroli dine-1-carboxylic acid t-butyl ester (1.0 g, 4.1 mmol) was Example 16 dissolved in DMF (15 mL, 200 mmol). Washed and dried 0575 Following the procedures described in the examples sodium hydride (298 mg, 12.4 mmol) was added carefully in above, and Substituting the appropriate starting materials and three separate portions and the resulting mixture was stirred at reagents, compounds 16-1 to 16-104, having formula IIIa, room temperature for 15 minutes. 2-Chloro-6-fluorotoluene were also prepared as mono-TFA salts:

(IIIa) R3 R R2

R5 O R6 ::::::

:

N H

MS miz: M + HT

: : : R2 R3 R4 R5 R6 Formula calcd found C H CHCINO 252.11 252.2 C H CHCINO 252.11 252.2 Me H C15H2NO 232.16 232.2 SMe H CHNOS 264.13 264.O SMe H CHNOS 264.13 264.O C C H CH17ClNO 286.07 286.0 C C H CH17ClNO 286.07 286.0 C C H CH17ClNO 286.07 286.0 C F H CH,CIFNO 270.10 270.O C F H CH,CIFNO 270.10 270.O F C H CH,CIFNO 270.10 270.O Me Me CH23NO 246.18 246.2 Me C C15H2OCINO 266.12 266.0 Me C C15H2OCINO 266.12 266.0 Me C H CHCINO 266.12 266.0 —CF C H C15H17CIFNO 320.10 320.2 —CF C H C15H17CIFNO 320.10 320.2 OMe C H CH2CINO2 282.12 282.2 C H C H CH17ClNO 286.07 286.0 C H C H CH17ClNO 286.07 286.0 2 1 C H C H CH,ClNO 286.07 286.0 2 2 C H H CH,CIFNO 270.10 270.O 2 3 C H Me C15H2OCINO 266.12 266.0

US 2011/00094.65 A1 Jan. 13, 2011 42

0666 91. (S)-3-((R)-(4-Chloro-3-fluorophenoxy)cyclo minutes, then stirred at room temperature overnight. The propylmethylpyrrolidine reaction was quenched with saturated aqueous NHCl (50 0667 92. (R)-3-((R)-(4-Chloro-3-fluorophenoxy)cyclo mL) and the mixture stirred at room temperature for 30 min propylmethylpyrrolidine utes. The mixture was extracted with EtOAc (200 mL). The 0668 93. (S)-3-(S)-(4-Chloro-3-fluorophenoxy)cyclo propylmethylpyrrolidine organic layer was washed with Saturated aqueous NaHCO 0669 94. (S)-3-(S)-(4-Chloro-3-methylphenoxy)cyclo (2x75 mL), then saturated aqueous NaCl. The aqueous layers propylmethylpyrrolidine were combined and re-extracted with EtOAc (75 mL). The 0670 95. (S)-3-((R)-(4-Chloro-3-methylphenoxy)cyclo organic layers were combined, dried over NaSO, filtered, propylmethylpyrrolidine and concentrated under reduced pressure. The material was 0671 96. (S)-3-(S)cyclopropyl-(3,5-dichlorophenoxy) then placed on high vacuum for 10 minutes to yield a crude methylpyrrolidine oil. The oil was dissolved in 50% AcOH/HO and purified by 0672 97. (S)-3-((R)cyclopropyl-(3,5-dichlorophenoxy) preparative HPLC (10-70% MeCN/HO; 0.05% TFA; over methylpyrrolidine 80 minutes on a 2" column at 40 mL/min). The fractions were 0673 98. (S)-3-(S)-(3-Chloro-5-fluorophenoxy)cyclo collected and lyophilized to yield 3-cyclopentanecarbonyl-2- propylmethylpyrrolidine oXopyrrolidine-1-carboxylic acid t-butyl ester (6 g) as a yel 0674) 99. (S)-3-((R)-(3-Chloro-5-fluorophenoxy)cyclo low solid. MS m/z. M+H" calcd for CHNO 281.3: propylmethylpyrrolidine found 282.2. 0675 100. (S)-3-(S)-(3-Chloro-5-methoxyphenoxy)cy clopropylmethylpyrrolidine 0682 3-Cyclopentanecarbonyl-2-oxopyrrolidine-1-car 0676) 101. (S)-3-(S)-(4-Chloro-3,5-dimethylphenoxy) boxylic acid t-butyl ester (1.2g, 4.4 mmol) was dissolved in cyclopropylmethylpyrrolidine THF (3.5 mL, 43.7 mmol) under nitrogen. 2MBH.MeS in 0677 102. (S)-3-((R)-(4-Chlorophenoxy)cyclopropylm THF (6.6 mL, 13.1 mmol) was added via syringe over 15 ethylpyrrolidine minutes. The mixture was stirred at room temperature for 1 0678 103. (S)-3-(S)-(4-Chlorophenoxy)cyclopropylm hour, then heated at 65°C. for 24 hours. After an additional 48 ethylpyrrolidine hours, the mixture was placed on an ice bath and the reaction 0679 104. (S)-3-(S)cyclopropyl-(4-trifluoromethylphe slowly quenched with cold MeOH (100 mL). The mixture noxy)methylpyrrolidine was stirred for 15 minutes, then diluted with EtOAc (30 mL), and washed with saturated aqueous NaHCO (2x50 mL). The Preparation 8 organic layer was dried over NaSO, filtered, and concen trated by rotary evaporation to yield a yellow oil (300 mg). 3-(Cyclopentylhydroxymethyl)pyrrolidine-1-car The oil was purified by preparative HPLC (2" column:5-50% boxylic Acid t-Butyl Ester MeCN/HO: 0.1% TFA buffer; at 40 mL/min over 80 min utes). The desired fractions were collected, frozen and lyo 0680 philized to yield the title compound (939 mg). MS m/z: M+H" calcd for CHNO. 269.3; found 270.4. 0683 H NMR (400 MHz, CDC1) & 3.60-3.50 (m, 4H), 3.40 (t, 1H), 2.00- 1.59 (m. 1H), 1.58-1.56 (m. 11H), 1.50 (s, 9H). Example 17 3-(2-Chloro-4-methylphenoxy)cyclopentylmethyl pyrrolidine 0684

C

O 0681 2-Oxopyrrolidine-1-carboxylic acid t-butyl ester (9.3 g, 50.4 mmol) was dissolved in THF (60 mL. 800 mmol) under nitrogen and was then cooled at -78°C. 2M Lithium diisopropylamide in heptane/THF/ethylbenzene (34 mL) was added over 40 minutes, and the resulting mixture was stirred N for 1.5 hours at -78°C. Cyclopentanecarbonyl chloride (6.1 H mL, 50 mmol) was dissolved in THF (4.0 mL, 49 mmol) and slowly added dropwise via syringe to the mixture over 30 US 2011/00094.65 A1 Jan. 13, 2011 43

0685 3-(Cyclopentylhydroxymethyl)pyrrolidine-1-car 0688 Some products were obtained as “mixtures” of all boxylic acid t-butyl ester (94 mg. 35umol) was dissolved in 196 stereoisomers: R.R. R.S., S.S, and S.R. Some products DMF (1.1 mL, 14 mmol). 60% sodium hydride in oil (60:40, werepeak beingseparated designated purified the by SS/RR SE mixture HPLC, of enantiomers. with the 2" Sodium hydride: mineral oil, 17 mg, 420 umol) was added, 0689) 1... 3-Cyclopentyl-(2,3-dichlorophenoxy)methyl and the mixture stirred for 15 minutes, at room temperature. pyrrolidine 0690 2. 3-(3-Chloro-2-trifluoromethylphenoxy)cyclo 3-chloro-4-fluorotoluene (130 uL. 1.0 mmol) was added, and pentylmethylpyrrolidine the mixture was heated at 90° C. for 24 hours. The reaction 0691 3. 3-(3-Chloro-2-trifluoromethylphenoxy)cyclo was quenched with MeOH (1 mL) and DMF/MeOH was pentylmethylpyrrolidine removed under vacuum. The solids were filtered off and then 06924, 3-Cyclopentyl-(2,4-dichlorophenoxy)methyl deprotected using 1.25M HCl in EtOH (1.0 mL, 1.3 mmol). (0.683rrolidine 5. 3-Cyclopentyl-(2,4-dichlorophenoxy)methyl The mixture was stirred overnight at room temperature. pyrrolidine 0686. The crude product was dissolved in 1:1 AcOH:HO 0694 6. 3-(2-Chloro-4-methylphenoxy)cyclopentylm (1.4 mL), filtered, and purified by preparative HPLC to yield ethylpyrrolidine the title compound as a mixture of all 4 stereoisomers (R.R. 0695 7. 3-(4-Chloro-2-methylphenoxy)cyclopentylm R.S., S.S, and S.R) as mono-TFA salts (4.2 mg, 100% purity). eth lyrrollins MS m/z. M+H" calcd for CHCINO, 294.15; found 294. 069 3-Cyclopentyl-(2,6-dichlorophenoxy)methyl 2. pyrrolidine 0697 9. 3-Cyclopentyl-(3,5-dichlorophenoxy)methyl pyrrolidine Example 18 0698. 10. 3-Cyclopentyl-(3,5-dichlorophenoxy)methyl pyrrolidine 0687. Following the procedures described in the examples 0699 11. 3-(4-Chlorophenoxy)cyclopentylmethylpyr above, and Substituting the appropriate starting materials and rolidine reagents, compounds 18-1 to 18-12, having formula Mb. 0700 12. 3.-Cyclopentyl-(4-fluorophenoxy)methylpyr were also prepared as mono-TFA salts: rolidine

(IIIb) R3 R R2

R5 O R6 ::::::

:

N H

# * :::::: R2 R3 R4 R5 R6 Formula calcd found

1 mixture C C H CH2Cl2NO 3.14.10 3.14.O 2 SRRS - CF Cl H H C7H2CIFNO 348.13 348.2 3 SS/RR CF, CI H H C7H2CIFNO 348.13 348.2 4 SRRS C H Cl CH2Cl2NO 3.14.10 3.14.O S SSRR C H Cl CH2Cl2NO 3.14.10 3.14.O 6 SRRS C H Me H C.H.CINO 294.15 294.2 7 mixture Me H Cl C.H.CINO 294.15 294.2 8 mixture C H. H. Cl CH2Cl2NO 3.14.10 3.14.O 9 SRARS H C H Cl CH2Cl2NO 3.14.10 3.14.O 10 SSRR H C H Cl CH2Cl2NO 3.14.10 3.14.O 11 mixture H H Cl CH2CINO 28O14 28O2 12 mixture H H F CH2FNO 264.17 264.2 US 2011/00094.65 A1 Jan. 13, 2011 44

Preparation 9 g; 1 eluting peak) and (S)-3-((R)-cyclohexylhydroxym ethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.7 g. 2" (S)-3-((R)-Cyclohexylhydroxymethyl)pyrrolidine-1- eluting peak). carboxylic Acid t-Butyl Ester Example 19 (S)-3-(S)-Cyclohexyl-(2,6-dichlorophenoxy)methyl 0701 pyrrolidine 0703 C HOn

O C :::::: H N” rik N H 0702 (S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl 0704 (S)-3-((R)-Cyclohexylhydroxymethyl)pyrrolidine ester (2.8 g. 13.8 mmol) was dissolved in THF (50 mL) under 1-carboxylic acid t-butyl ester (190 mg. 670 ummol), was nitrogen and cooled at -78°C. Cyclohexylmagnesium chlo combined with PPhs (79 mg 0.3 mmol), THF (0.2 mL), and ride (2.0M in ether; 10.0 mL. 20.0 mmol. 1.4 eq) was added 2,6-dichlorophenol (73 mg, 0.5 mmol). DIAD (59 uL, 0.3 via Syringe over approximately 10 minutes. The resulting mmol) was added and the mixture was allowed to stand at mixture was stirred at -78°C. for 20 minutes, then placed in room temperature for 2 hours. EtOH (1.0 mL) and 4.0 NHCl an ice bath for 30 minutes. The reaction was quenched with in dioxane (0.5 mL, 2.0 mmol) were added, and the mixture saturated aqueous NHCl (15 mL). THF was removed under was allowed to stand at room temperature overnight. The reduced pressure, and the remaining material was extracted Solvent was removed under reduced pressure, and the remain with EtOAc (3x30 mL). The organics were washed with ing material was dissolved in 50% AcOH (6 mL) and purified water (25 mL) and saturated aqueous NaCl (25 mL), dried by preparative HPLC (1" C18 column; 10-50% MeCN over 1 over NaSO, and concentrated to yield the crude product. hour). The clean fractions were pooled and lyophilized to This material was dissolved in MeCN (10 mL), water (8 mL), yield the title compound as a mono-TFA salt (37 mg, 95% and MeOH (11 mL). The material was purified by preparative purity). MS m/z. M+H" calcd for CHC1-NO, 328.12: HPLC in 3 portions (2" C18 column; 20-50% MeCN over 1 found 328.4. hour; the desired compound was recovered at ~46%). The fractions were collected from the first eluting and second Example 20 eluting, separately, and the Mecn was removed. Each frac 0705 Following the procedures described in the examples tion was extracted with DCM (3x125 mL), dried over above, and Substituting the appropriate starting materials and NaSO, and concentrated to yield (S)-3-((S)-cyclohexylhy reagents, compounds 20-1 to 20-7. having formula IIIc, were droxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.1 also prepared as mono-TFA salts:

(IIIc) R3 R R2

R5 O R6 ::::::

:

N H MS m/z. M+H" i : :::::: R2 R3 R? Rs R6 Formula calcd found

1 S R F H H H H C7H2FNO 278.18 278.2 2 RRSS OMe H H H H C18H27NO2 290.2O 290.2 3 S R —NO2 H H H H C17H2N2O3 3.05.18 3OS.2 4 S R - C(O)CH H H H H C19H27NO2 3.02.20 3.02.2 S S R C1 F H H H C7HCIFNO 312.15 321.2 6 RSFSR H C H C H CHCINO 328.12 328.0 7 S R H F H H H C7H2FNO 278.18 278.2 US 2011/00094.65 A1 Jan. 13, 2011

0706 The (S,R) compounds were prepared using the (S,R) 2H), 1.84-1.68 (m, 4H), 1.60- 1.55 (m, 2H), 1.52-1.44 (m, alcohol. The RR/SS and RS/SR compounds were prepared 1H), 1.39 (s.9H), 1.33-1.29 (m, 2H). using the (R,R) alcohol and the (R.S) alcohol, respectively. 0707 1. (S)-3-((R)-Cyclohexyl-(2-fluorophenoxy)me Example 21 thylpyrrolidine 3-(3,5-Dichloro-phenoxy)-(4,4-difluorocyclohexyl) 0708 2. 3.-Cyclohexyl-(2-methoxyphenoxy)methylpyr methylpyrrolidine rolidine 0709. 3. (S)-3-((R)-Cyclohexyl-(2-nitrophenoxy)methyl 0718 pyrrolidine 0710 4. 1-2-((R)-Cyclohexyl-(S)-pyrrolidin-3-yl-meth C F oxy)phenylethanone 0711 5. (S)-3-((R)-(2-Chloro-3-fluorophenoxy)cyclo hexylmethylpyrrolidine 0712) 6. 3-Cyclohexyl-(3,5-dichlorophenoxy)methyl pyrrolidine C 0713 7. (S)-3-((R)-Cyclohexyl-(3-fluorophenoxy)me N thylpyrrolidine H Preparation 10 0719 (R)-3-(S)-(4,4-Difluorocyclohexyl)hydroxym ethylpyrrolidine-1-carboxylic acid t-butyl ester (44.0 mg. 3-(4,4-Difluorocyclohexyl)hydroxymethylpyrroli 138 ummol), copper(I) iodide (7.9 mg, 41 Lummol), o-phenan dine-1-carboxylic Acid t-Butyl Ester throline (15 mg, 83 lummol) and cesium carbonate (89.8 mg, 276 ummol) were combined. 1,3-Dichloro-5-iodobenzene (75.2 mg, 276 ummol) was added, followed by the addition of 0714) toluene (220 LL, 2.1 mmol). Air was bubbled through the mixture, the vessel was sealed, and the mixture was heated at F 105° C. for 48 hours. The mixture was filtered, rinsed with DCM, and concentrated. The crude material was treated with F 1.25M HCl in EtOH (5.8 mL, 7.2 mmol) and stirred over HO night. The mixture was concentrated, redissolved in 1:1 AcOH:HO and purified by preparative HPLC to yield the title compound as a mono-TFA salt (1.5 mg.96% purity). MS m/z. M+H" calcd for CHC1F, NO, 364.10; found 364. O. "Sg Example 22 O (S)-3-(S)-Cyclopropyl(naphthalen-1-yloxy)methyl pyrrolidine 0715. The title compound was prepared in a manner simi 0720 lar to that described in Preparation 9 for the synthesis of (S)-3-((R)-cyclohexylhydroxymethyl)pyrrolidine-1-car boxylic acid t-butyl ester. (S)-3-Formylpyrrolidine-1-car boxylic acid t-butyl ester and LiHMDS were dissolved in THF under nitrogen and cooled at -78° C. 4,4-Difluoro Clu cyclohexanecarbonyl chloride (prepared by treatment of 4.4- difluorocyclohexane carboxylic acid with thionyl chloride in O :::::: H THF at 50° C. for 2 hours), was then added and the resulting mixture was stirred at -78° C. then allowed to reach room N temperature overnight. BH.MeS in THF was added and the H resulting mixture stirred at room temperature for 1 hour, then refluxed for 1 hour. The solids (1.03 g) were separated and 0721 (S)-3-((S)-Cyclopropylhydroxymethyl)pyrroli dissolved in 1:1 AcOH:HO (20 mL) and purified by prepara dine-1-carboxylic acid t-butyl ester (35 mg, 140 ummol), tive HPLC (BDS, 40-60%). This was repeated twice to yield: copper(I) iodide (8.3 mg, 43.5 ummol), o-phenanthroline 0716 SS/RR stereoisomers (220 mg: 1 eluting peak). "H (15.7 mg, 87 ummol), and 1-iodonaphthalene (73.7 mg, 290 NMR (400MHz, DMSO) & 3.37-3.26 (m, 2H), 3.20-3.15 (m, ummol) were combined. Toluene (463 uL, 4.4 mmol) was 1H), 3.13- 3.06 (m. 1H), 2.94-2.85 (m. 1H), 2.30-2.16 (m, added, followed by the addition of cesium carbonate (94.5 1H), 2.04-1.94 (m, 2H), 1.90-1.56 (m, 6H), 1.42-1.40 (m, mg, 290 ummol). Air was bubbled through the mixture, the 1H), 1.39 (s.9H), 1.34-1.26 (m, 2H). vessel was sealed, and the mixture was heated at 105° C. for 0717 SR/RS stereoisomers (360 mg: 2" eluting peak). "H 72 hours. The mixture was filtered, rinsed with DCM, and NMR (400 MHz, DMSO) & 3.40-3.32 (m, 2H), 3.20-3.08 (m, concentrated. The crude material was treated with 1.25MHCl 2H), 3.03-2.94 (m, 1H), 2.29-2.18 (m, 1H), 2.04-1.94 (m, in EtOH (1.2 mL, 1.5 mmol) and stirred overnight. The mix US 2011/00094.65 A1 Jan. 13, 2011 46 ture was concentrated, redissolved in 1:1 AcOH:HO and 11.3 mmol) dropwise. The resulting mixture was allowed to purified by preparative HPLC to yield the title compound as a warm to room temperature slowly overnight. The reaction mono-TFA salt (3.5 mg, 99% purity). MS m/z. M+H calcd was quenched with saturated aqueous NHCl (30 mL), added for CH, NO, 268.16; found 268.2. dropwise. The resulting mixture was extracted with EtOAc (2x30 mL), then the combined organic layers were washed Example 23 with saturated aqueous NaHCO (1x30 mL) and saturated 0722 Following the procedures described in the examples aqueous NaCl (1x30 mL), then dried over anhydrous MgSO, above, and Substituting the appropriate starting materials and filtered, and concentrated in vacuo to yield the crude product, reagents, compounds 23-1 and 23-2, having formula VIa, which was then purified by preparative HPLC (10-50% were also prepared as mono-TFA salts: MeCN:HO; 0.05% TFA; over 80 minutes). Each diastere omer dissolved in EtOAc and free based by adding saturated aqueous NH CO. The organics were separated, dried over NaSO and the solvent removed to yield (S)-3-((S)-1-hy (VIa) droxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl ester (105 mg: 1 eluting peak) and (S)-3-((R)-1-hydroxy-but-3- enyl)pyrrolidine-1-carboxylic acid t-butyl ester (90 mg. 2" eluting peak). O :::::: Example 24 (S)-3-(S)-1-(3-Chloro-2-methylphenoxy)but-3- N H enyl-pyrrolidine MS m/z. M+H" 0727 # * :::::: RI R4 Formula calcd found

1 S R cyclopropyl H C18H2NO 268.16 268.2 C 2 S S cyclopropyl CI C18H2CINO 3O2.12 3.02.2 0723 1. (S)-3-((R)-Cyclopropyl-(2-methyl-3-vinylphe noxy)methylpyrrolidine 0724 2. (S)-3-(S)-(4-Chloronaphthalen-1-yloxy)cyclo propylmethylpyrrolidine :::::: Preparation 11 (S)-3-((S)-1-Hydroxy-but-3-enyl)pyrrolidine-1-car N boxylic Acid t-Butyl Ester 0725

0728 (S)-3-((S)-1-Hydroxy-but-3-enyl)pyrrolidine-1- carboxylic acid t-butyl ester (31 mg, 130 ummol) was dis solved in DMF (470 uL, 6.1 mmol). 60% Sodium hydride in oil (0.4:0.6, sodium hydride: mineral oil, 10.1 mg, 169 ummol) was carefully added, and the mixture allowed to stand for 15 minutes. 2-Chloro-6-fluorotoluene (47.0LL,390 ummol) was added. The mixture was stirred at 70° C. for 3 hours. The reaction was quenched with MeOH, and the sol vent was removed. 1.2M HCl in EtOH (630 ul, 760 pummol) was added, and the mixture was stirred overnight. The prod uct was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (1 mg, 100% purity). MS m/z. M+H" calcd for CHCINO, 266.12: found 266.0.

Example 25 0726 (S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl 0729. Following the procedures described in the examples ester (1.5 g, 7.5 mmol) was dissolved in THF (15.0 mL, 186 above, and Substituting the appropriate starting materials and mmol). The reaction mixture and cooled at -78°C., before reagents, compounds 25-1 and 25-2, having formula IVa, adding allylmagnesium bromide (1.0M in ether; 11.3 mL, were also prepared as mono-TFA salts: US 2011/00094.65 A1 Jan. 13, 2011 47

Example 26 0735 (S)-3-1 (2,3,6-Trichlorophenoxy)prop-2-ynylpyr (IVa) rolidine R3

R R2 C

R5 O 21 C R6 :::::: C O A

:::::: H N H

MS m/z. M+H" N H # * * * R2 R3 R4 R5 R6 Formula calcd found 1 S S H H C H H CHCINO 252.11 252.0 0736. A mixture of (S)-3-(1-hydroxyprop-2-ynyl)pyrroli 2 S R Me H C H H CHCINO 266.12 266.0 dine-1-carboxylic acid t-butyl ester (21.0 mg. 93.2 mmol) and DIAD (22.0LL, 112 ummol) was dissolved intoluene (65 0730) 1. (S)-3-(S)-1-(4-Chlorophenoxy)but-3-enylpyr uL. 610 Lummol) at room temperature. PPhs (29.3 mg, 112 rolidine ummol) and 2.3.6-trichlorophenol (20.2 mg, 102 Lummol) 0731 2. (S)-3-((R)-1-(4-Chloro-2-methylphenoxy)but-3- were dissolved in toluene (0.1 mL, 1 mmol) and heated at enylpyrrolidine 100° C. The t-butyl ester mixture was slowly added into the phenol mixture at 100°C., and stirred for 1 hour. The mixture Preparation 12 was then removed from the heat and stirred at room tempera ture overnight. The mixture was then concentrated and the (S)-3-(1-Hydroxyprop-2-ynyl)pyrrolidine-1-car resulting residue was treated with 1.25M HCl in EtOH (0.6 boxylic Acid t-Butyl Ester mL, 0.8 mmol) at room temperature overnight. The mixture was concentrated and the residue was redissolved in a mixture 0732 of 50% AcOH/HO (1.4 mL) and MeCN (0.2 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound as a mono-TFA salt (21.2 mg, 99% purity). MS m/z. M+H" calcd for CHCINO, 304.00; found HO A 3O4.O. :::::: H Example 27 0737. Following the procedures described in the examples above, and Substituting the appropriate starting materials and N reagents, compounds 27-1 and 27-2, having formula Va, were yrys also prepared, typically as a mono-TFA salt: (Va) (0733 0.5 M Ethynylmagnesium bromide in THF (6.3 mL, R3 3140 umol) was added dropwise over 5 minutes to a stirred R R2 solution of (S)-3-formylpyrrolidine-1-carboxylic acidt-butyl ester (0.5g, 2 mmol) in THF (5 mL, 60 mmol) at 0°C. The mixture was allowed to warm to room temperature. After 4 R5 O A hours, the reaction was quenched with the addition of Satu rated aqueous NHCl (10 mL) and extracted with EtOAc R6 :::::: (2x10 mL). The organic layers were combined, dried over MgSO filtered, and concentrated in vacuo. : 0734. This material was then dissolved in a mixture of N MeCN (2.0 mL), water (3.0 mL) and AcOH (3.0 mL), filtered H and purified by reverse phase preparative HPLC. The mixed MS m/z. M+H" fractions were combined and frozen dried. After lyophiliza tion, the solids were partitioned between EtOAc (40.0 mL) # * * * R2 R3 R4 R5 R6 Formula calcd found and saturated NaHCO (20.0 mL). The organic layer was 1 SSFSR C C H H H CHCl2NO 270.04 27O.O washed with saturated aqueous NaCl (20.0 mL), dried over 2 SS/SR Me H C H H CHCINO 250.09 250.2 NaSO, filtered and concentrated to give the title compound as a yellowish oil (168.2 mg). US 2011/00094.65 A1 Jan. 13, 2011 48

0738 1. (S)-3-1-(2,3-Dichlorophenoxy)prop-2-ynyl Elmer) added and bound radioactivity quantitated via liquid pyrrolidine Scintilation spectroscopy. Inhibition curves and Saturation 0739 2. (S)-3-1-(4-Chloro-2-methylphenoxy)prop-2- isotherms were analyzed using GraphPad Prism Software ynylpyrrolidine package (GraphPad Software, Inc., San Diego, Calif.). ICso values were generated from concentration response curves Assay 1 using the Sigmoidal Dose Response (variable slope) algo rithm in Prism GraphPad. K and B values for the radio hSERT, hNET, and hDAT Binding Assays ligand were generated from Saturation isotherms using the Saturation Binding Global Fit algorithm in Prism GraphPad. 0740 Membrane radioligand binding assays were used to pK, (negative decadic logarithm of K) values for test com measure inhibition of labeled ligand (H-citalopram or pounds were calculated from the best-fit ICso values, and the H-nisoxetine or H-WIN35428) binding to membranes pre K. Value of the radioligand, using the Cheng-Prusoff equation pared from cells expressing the respective human recombi (Cheng & Prusoff (1973) Biochem. Pharmacol. 22(23):3099 nant transporter (hSERT orhNET or hiDAT) in order to deter 3.108): KICs/(1+L/K), where L-concentration radio mine the pK values of test compounds at the transporters. ligand. 0745 Compounds of the invention that were tested in this Membrane Preparation From Cells Expressing assay were found to exhibit pK values as set forth below: hSERT, hNET, or hDAT 0741. Recombinant human embryonic kidney (HEK-293) derived cell lines stably transfected with hSERT or hNET, SERT NET respectively, were grown in DMEM medium supplemented Ex. pK, pK, with 10% dialyzed FBS (for hSERT) or FBS (for hNET), 100 1 e8.0 e8.0 ug/mL penicillin, 100 g/mL Streptomycin, 2 mM 2-1 e7.O e8.0 L-glutamine and 250 ug/mL of the aminoglycoside antibiotic 2-2 e8.0 e8.0 2-3 e8.0 e7.0 G418, in a 5% CO, humidified incubator at 37° C. When 2-4 n.d. n.d. cultures reached 80% confluence, the cells were washed thor 2-5 e8.0 e8.0 oughly in PBS (without Ca" and Mg) and lifted with 5 mM 2-6 n.d. n.d. EDTA in PBS. Cells were pelleted by centrifugation, resus 2-7 e8.0 e8.0 2-8 n.d. n.d. pended in lysis buffer (10 mM Tris-HCl, pH7.5 containing 1 2-9 e7.O e8.0 mM EDTA), homogenized, pelleted by centrifugation, then 2-10 n.d. n.d. resuspended in 50 mM Tris-HCl, pH 7.5 and 10% sucrose at 2-11 n.d. n.d. 4°C. Protein concentration of the membrane suspension was 2-12 e7.O e7.0 2-13 e8.0 e8.0 determined using a Bio-Rad Bradford Protein Assay kit. 2-14 n.d. n.d. Membranes were snap frozen and stored at -80° C. Chinese 2-15 n.d. n.d. hamster ovary membranes expressing hDAT (CHO-DAT) 2-16 e8.0 e7.0 were purchased from PerkinElmer and stored at -80° C. 2-17 e8.0 e7.0 2-18 e8.0 e7.0 2-19 e8.0 e8.0 Binding Assays 2-2O n.d. n.d. 2-21 e8.0 e8.0 0742 Binding assays were performed in a 96-well assay 2-22 e8.0 e8.0 plate in a total volume of 200 ul assay buffer (50 mM Tris 2-23 e8.0 e8.0 HCl, 120 mM. NaCl, 5 mMKC1, pH 7.4) with 0.5, 1, and 3 ug 2-24 n.d. n.d. membrane protein, for SERT, NET and DAT respectively. 2-2S e8.0 e8.0 2-26 e7.O e8.0 Saturation binding studies, to determine radioligand K val 2-27 e8.0 e8.0 ues for H-citalopram, H-nisoxetine, or H-WIN35428, 2-28 e8.0 e8.0 respectively were conducted using 12 different radioligand 2-29 e8.0 e8.0 concentrations ranging from 0.005-10 nM (3H-citalopram); 2-30 e8.0 e7.0 2-31 n.d. n.d. 0.01-20 nM (3H-nisoxetine) and 0.2-50 nM (H-WIN35428). 2-32 e8.0 e8.0 Inhibition assays for determination of pK values of test com 2-33 e8.0 e7.0 pounds were conducted with 1.0 nM H-citalopram, 1.0 nM 2-34 n.d. n.d. H-nisoxetine or 3.0 nMH-WIN35428, at 11 different con 2-3S n.d. n.d. 2-36 e7.O e7.0 centrations oftest compound ranging from 10 uM to 100 uM. 2-37 e8.0 e8.0 0743 Stock solutions (10 mM in DMSO) of test com 2-38 e8.0 e8.0 pound were prepared and serial dilutions made using Dilution 2-39 e8.0 e8.0 Buffer (50 mM Tris-HCl, 120 mM. NaCl, 5 mM KC1, pH 7.4, 2-40 e8.0 e8.0 2-41 e8.0 e8.0 0.1% BSA, 400 uMascorbic acid). Non-specific radioligand 2-42 e8.0 e8.0 binding was determined in the presence of 1 uM dulloxetine, 2-43 e8.0 e8.0 1 uM desipramine or 10 uM GBR12909 (each in Dilution 2-44 e8.0 e8.0 Buffer) for the hSERT, hNET or hDAT assays, respectively. 2-45 n.d. n.d. 2-46 e7.O e8.0 0744. Following a 60 minute incubation at 22°C. (or a 2-47 e8.0 e8.0 period sufficient to reach equilibrium), the membranes were 2-48 e8.0 e8.0 harvested by rapid filtration over a 96-well UniFilter GF/B 2-49 e7.O e8.0 plate, pretreated with 0.3% polyethyleneimine, and washed 6 2-SO e8.0 e7.0 2-51 n.d. n.d. times with 300 ul wash buffer (50 mM Tris-HCl, 0.9% NaCl, 2-52 e8.0 e8.0 pH 7.5 at 4°C.). Plates were dried overnight at room tem 2-53 a 7.O a8.0 perature, approximately 45 ul of MicroScintTM-20 (Perkin

US 2011/00094.65 A1 Jan. 13, 2011 52

Assay 2 ruda et al. (2010) Journal of Pharmacological and Toxico logical Methods 61(2):192-204 (data indicated by an asterisk hSERT, hNET and hDAT Neurotransmitter Uptake in the table), and were found to have serotonin and norepi Assays nephrine reuptake inhibition plCso values as follows: 0746 Neurotransmitter uptake assays were used to mea sure inhibition of H-serotonin (H-5-HT), H-norepineph rine (H-NE), and H-dopamine (H-DA) uptake into cells expressing the respective transporter (hSERT. hNET or SERT NET hDAT) in order to determine the plCs values of test com Ex. pICso pICso pounds at the transporters. 1 e8.0 e8.0 2-1 e7.0 e8.0 2-2 e8.0 e8.0 H-5-HT, H-NE, and H-DAUptake Assays 2-3 n.d. n.d. 2-4 e8.0: is 7.0% 0747 HEK-293 derived cell lines stably-transfected with 2-5 e8.0 e8.0 hSERT, hNET, or hDAT, respectively, were grown in DMEM 2-6 e8.0: is 7.0% medium supplemented with 10% dialyzed FBS (for hSERT) 2-7 e8.0 e8.0 or FBS (for hNET and hDAT), 100 g/mL penicillin, 100 2-8 e8.0: is 7.0% 2-9 n.d. n.d. ug/mL Streptomycin, 2 mM L-glutamine and 250 g/mL of 2-10 is 7.0% e8.0: the aminoglycoside antibiotic G418 (for hSERT and hNET) 2-11 is 7.0% e8.0: or 800 ug/mL (for hDAT), in a 5% CO humidified incubator 2-12 n.d. n.d. at 37° C. When cultures reached 80% confluence, the cells 2-13 e8.0 e8.0 2-14 e8.0: is 7.0% were washed thoroughly in PBS (without Ca" and Mg")and 2-15 e8.0: is 7.0% lifted with 5 mM EDTA in PBS. Cells were harvested by 2-16 n.d. n.d. centrifugation at 1100 rpm for 5 minutes, washed once by 2-17 n.d. n.d. resuspension in PBS, then centrifuged. The supernatant was 2-18 e7.0 e7.O 2-19 e7.0 e7.O discarded and the cell pellet resuspended, by gentle tritura 2-2O is 7.0% is 7.0% tion, in room temperature Krebs-Ringer bicarbonate buffer 2-21 e7.0 e8.0 containing HEPES (10 mM), CaCl (2.2 mM), ascorbic acid 2-22 e7.0 e8.0 (200 uM) and pargyline (200 uM), pH 7.4. The final concen 2-23 e7.0 e8.0 2-24 is 7.0% is 7.0% tration of cells in the cell suspension was 7.5x10" cells/mL, 2-2S e7.0 e8.0 1.25x10 cells/mL, and 5.0x10 cells/mL for SERT, NET, and 2-26 n.d. n.d. DAT cell lines, respectively. 2-27 e7.0 e8.0 0748 Neurotransmitter uptake assays were performed in a 2-28 e8.0 e8.0 2-29 e8.0 e8.0 96-well assay plate in a total volume of 400 ul assay buffer 2-30 n.d. n.d. (Krebs-Ringer bicarbonate buffer containing HEPES (10 2-31 e8.0: e8.0: mM), CaCl (2.2 mM), ascorbic acid (200LM) and pargyline 2-32 e8.0 e8.0 (200uM), pH 7.4) with 1.5x10" and 2.5x10 cells, for SERT, 2-33 n.d. n.d. 2-34 e8.0: is 7.0% NET, and DAT respectively. Inhibition assays for determina 2-3S e8.0: e8.0: tion of plCso values of test compounds were conducted with 2-36 n.d. n.d. 11 different concentrations, ranging from 10LM to 100 uM. 2-37 e7.0 e8.0 Stock solutions (10 mM in DMSO) of test compound were 2-38 e7.0 e8.0 2-39 e7.0 e8.0 prepared and serial dilutions prepared using 50 mM Tris-HCl, 2-40 e7.0 e8.0 120 mM NaCl, 5 mM KC1, pH 7.4, 0.1% BSA, 400 uM 2-41 e7.0 e8.0 ascorbic acid. Test compounds were incubated for 30 minutes 2-42 e8.0 e8.0 at 37°C. with the respective cells, prior to addition of radio 2-43 e7.0 e8.0 2-44 e8.0 e8.0 labeled neurotransmitter, H-5-HT (20 nM final concentra 2-45 e8.0: e8.0: tion), H-NE (50 nM final concentration) or H-DA (100 nM 2-46 il.C. il.C. final concentration). Non-specific neurotransmitter uptake 2-47 e7.0 e8.0 was determined in the presence of 2.5uM dulloxetine, 2.5uM 2-48 e8.0 e8.0 2-49 il.C. il.C. desipramine, or 10 uMGBR-12909 (each in Dilution Buffer) 2-SO il.C. il.C. for the hSERT, hNET, or hDAT assays, respectively. 2-51 e8.0: e8.0: 0749. Following a 10 minute incubation, at 37° C., with 2-52 e7.0 e8.0 radioligand, the cells were harvested by rapid filtration over a 2-53 il.C. il.C. 2-54 il.C. il.C. 96-well UniFilter GF/B plate, pretreated with 1% BSA, and 2-55 e7.0 e8.0 washed 6 times with 650 LA wash buffer (ice cold PBS). 2-56 il.C. il.C. Plates were dried overnight at 37° C. ~45 uL of MicroS 2-57 e7.0 e7.O cintTM-20 (PerkinElmer) added and incorporated radioactiv 2-58 e8.0 e8.0 2-59 il.C. il.C. ity quantitated via liquid Scintillation spectroscopy Inhibition 2-60 e7.0 e7.O curves were analyzed using GraphPad Prism Software pack 2-61 il.C. il.C. age (GraphPad Software, Inc., San Diego, Calif.). ICso values 2-62 e7.0 e8.0 were generated from concentration response curves using the 2-63 il.C. il.C. 2-64 e8.0: e8.0: Sigmoidal Dose Response (variable slope) algorithm in 2-6S e8.0: e8.0: Prism GraphPad. 2-66 e8.0 e8.0 0750 Compounds of the invention were tested in this 2-67 il.C. il.C. assay or in a fluorescence-based assay as described in Tsu

US 2011/00094.65 A1 Jan. 13, 2011

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SERT NET Ex. pI C5 O Ex. pICso pICso 6-2O 6-93 e8.0 e8.0 6-21 6-94 e8.0: e8.0: 6-22 6-95 e8.0: is 7.0% 6-23 6-96 e8.0 e8.0 6-24 6-97 e8.0 e8.0 6-2S oo 6-98 e7.0 e8.0 6-26 6-99 e7.0 e8.0 6-27 6-100 is 7.0% e8.0: 6-28 o 6-101 e8.0: is 7.0% 6-29 s 6-102 n.d. n.d. 6-30 6-103 e8.0 e8.0 6-31 6-104 n.d. n.d. 6-32 17 e8.0: e8.0: 6-33 o o 8-1 e8.0: e8.0: 6-34 s 8-2 e8.0: is 7.0% 6-35 8-3 is 7.0% e8.0: 6-36 8-4 e8.0: is 7.0% 6-37 o 8-5 e8.0: e8.0: 6-38 s s g 8-6 e8.0: is 7.0% 6-39 8-7 e8.0: is 7.0% 6-40 8-8 is 7.0% e8.0: 6-41 8-9 e8.0: e8.0: 6-42 s 8-10 is 7.0% e8.0: 6-43 8-11 e8.0: is 7.0% 6-44 6. s 8. o 8-12 is 7.0% is 7.0% 6-45 19 e7.0 e8.0 6-46 e 8. o : 8. o : 20-1 l. l. 6-47 20-2 l. l. 6-48 20-3 l. l. 6-49 20-4 il.C. il.C. 6-SO 20-5 e8.0 e8.0 6-51 20-6 l. l. 6-52 20-7 l. l. 6-53 21 il.C. il.C. 6-54 22 e8.0: e8.0: 6-55 23-1 e8.0: e8.0: 6-56 23-2 il.C. il.C. 6-57 24 e8.0 e8.0 6-58 25-1 e8.0 e8.0 6-59 2S-2 il.C. il.C. 6-60 26 e7.0 e8.0 6-61 27-1 e7.0 e8.0 6-62 27-2 l. l. 6-63 6-64 n.d. = not determined 6-65 6-66 6-67 Ex Vivo SERT and NET Transporter Occupancy 6-68 Studies 6-69 6-70 0751 Ex vivo radioligand binding and neurotransmitter 6-71 6-72 uptake assays are used to determine the in vivo occupancy of 6-73 SERT and NET, in selected brain regions, following in vivo 6-74 administration (acute or chronic) of test compounds. Follow 6-75 ing administration of test compound (by intravenous, intrap 6-76 6-77 eritoneal, oral, Subcutaneous or other route) at the appropriate 6-78 dose (0.0001 to 100 mg/kg), rats (2n=4 per group) are eutha 6-79 nized at specific time points (10 minutes to 48 hours) by 6-8O 6-81 decapitation and the brain dissected on ice. Relevant brain 6-82 regions are dissected, frozen and stored at -80° C. until use. 6-83 6-84 Ex Vivo SERT and NET Radioligand Binding 6-85 Assays 6-86 6-87 0752 For ex vivo radioligand binding assays, the initial 6-88 6-89 rates of association of SERT (3H-citalopram), and NET (H- 6-90 nisoxetine) selective radioligands with rat brain crude homo 6-91 genates, prepared from vehicle and test compound-treated 6-92 animals, are monitored (see Hess et al. (2004).J. Pharmacol. Exp. Ther. 310(2): 488-497). Crude brain tissue homogenates US 2011/00094.65 A1 Jan. 13, 2011 56 are prepared by homogenizing frozen tissue pieces in 0.15 limited to, cold ligand binding kinetics assays (Motulsky and mL (per mg wet weight) of 50 mM Tris-HCl, 120 mM. NaCl, Mahan (1984) Molecular Pharmacol. 25(1): 1-9) with mem 5 mMKC1, pH 7.4 buffer. Radioligand association assays are branes prepared from cells expressing hSERT or hNET con performed in a 96-well assay plate in a total volume of 200 ul ventional membrane radioligand binding assays using radio assay buffer (50 mM Tris-HCl, 120 mM. NaCl, 5 mM KC1, 0.025% BSA, pH 7.4) with 650 ug wet weight tissue (equiva labeled, for example, tritiated, test compound; radioligand lent to 25 ug protein). Homogenates are incubated for up to 5 binding assays using native tissue from, for example rodent or minutes with H-citalopram (3 nM) and H-nisoxetine (5 human brain; neurotransmitter uptake assays using human or nM), respectively, prior to termination of the assay by rapid rodent platelets; neurotransmitter uptake assays using crude, filtration over a 96-well UniFilter GF/B plate, pretreated with or pure, synaptosome preparations from rodent brain. 0.3% polyethyleneimine. Filters then are washed 6 times with 300 ulwashbuffer (50 mM Tris-HCl, 0.9% NaCl, pH 7.4 at 4° Assay 5 C.). Non-specific radioligand binding is determined in the presence of 1 uMduloxetine, or 1 uM despiramine, for H-cit alopram or H-nisoxetine, respectively. The plates are dried Formalin Paw Test overnight at room temperature. ~45 ul of MicroScintTM-20 (PerkinElmer) is added and bound radioactivity quantitated 0755 Compounds are assessed for their ability to inhibit via liquid Scintillation spectroscopy. The initial rates of asso the behavioral response evoked by a 50 ul injection of forma ciation of H-citalopram and H-nisoxetine are determined lin (5%). A metal band is affixed to the left hind paw of male by linear regression using GraphPad Prism Software package Sprague-Dawley rats (200-250 g) and each rat is conditioned (GraphPad Software, Inc., San Diego, Calif.). The average to the band for 60 minutes within a plastic cylinder (15 cm rate of radioligand association to brain tissue homogenates diameter). Compounds are prepared in pharmaceutically from vehicle-treated animals us determined. The % occu acceptable vehicles and administered systemically (i.p. p.o.) pancy of test compounds then us determined using the fol at pre-designated times before formalin challenge. Spontane lowing equation: ous nociceptive behaviors consisting of flinching of the % occupancy=100x (1-(initial rate association for test injected (banded) hind paw are counted continuously for 60 compound-treated tissue? mean rate association for minutes using an automated nociception analyzer (UCSD vehicle-treated tissue)) Anesthesiology Research, San Diego, Calif.). Antinocicep EDso values are determined by plotting the log 10 of the dose tive properties of test articles are determined by comparing of the test compound against the '% occupancy. EDso values the number offlinches in the vehicle and compound-treated are generated from concentration response curves using the rats (Yaksh TL et al., “An automated flinch detecting system Sigmoidal Dose Response (variable slope) algorithm in for use in the formalin nociceptive bioassay” (2001).J. Appl. GraphPad Prism. Physiol. 90(6):2386-2402). Ex Vivo SERT and NET Uptake Assays 0753 Ex vivo neurotransmitter uptake assays, in which Assay 6 the uptake of H-5-HT or H-NE into rat brain crude homo genates, prepared from vehicle and test compound-treated Spinal Nerve Ligation Model animals, are used to measure in vivo SERT and NET trans porter occupancy (see Wong et al. (1993) Neuropsychophar 0756 Compounds are assessed for their ability to reverse macology 8(1):23-33). Crude brain tissue homogenates are tactile allodynia (increased sensitivity to an innocuous prepared by homogenizing frozen tissue pieces in 0.5 mL (per mechanical stimulus) induced by nerve injury. Male Sprague mg wet weight) of 10 mM HEPES buffer pH 7.4, containing Dawley rats are Surgically prepared as described in Kim and 0.32 M sucrose, 200 uMascorbic acid and 200 uM pargyline, Chung "An experimental model for peripheral neuropathy at 22°C. Neurotransmitter uptake assays are performed in a produced by segmental spinal nerve ligation in the rat' (1992) 96-well Axygen plate in a total volume of 350 ul assay buffer Pain 50(3):355-363. Mechanical sensitivity is determined as (Krebs-Ringer bicarbonate buffer with 10 mM HEPES, 2.2 the 50% withdrawal response to innocuous mechanical mM CaCl2, 200 uMascorbic acid and 200 uM pargyline, pH stimuli (Chaplan et al., “Quantitative assessment of tactile 7.4) with 50 ug protein. Homogenates are incubated for 5 allodynia in the rat paw” (1994).J. Neurosci. Methods 53(1): minutes at 37°C. with H-5-HT (20 nM) and H-NE (50 nM), 55-63) before and after nerve injury. One to four weeks post respectively, prior to termination of the assay by rapid filtra Surgery, compounds are prepared in pharmaceutically accept tion over a 96-well UniFilter GF/B plate, pretreated with 1% able vehicles and administered systemically (i.p. p.o.). The BSA. Plates are washed 6 times with 650 ul wash buffer (ice degree of nerve injury-induced mechanical sensitivity before cold PBS) and dried overnight at 37°C., prior to addition of and after treatment serves as an index of the compounds ~45 ul of MicroScintTM-20 (Perkin Elmer). Incorporated antinociceptive properties. radioactivity is quantitated via liquid Scintillation spectros (0757. While the present invention has been described with copy. Non-specific neurotransmitter uptake is determined in reference to specific aspects or embodiments thereof, it will parallel assays in which tissue homogenates are incubated be understood by those of ordinary skilled in the art that with H-5-HT (20 nM) or H-NE (50 nM) for 5 minutes at 4° various changes can be made or equivalents can be substituted C. without departing from the true spirit and scope of the inven tion. Additionally, to the extent permitted by applicable Assay 4 patent statues and regulations, all publications, patents and Other Assays patent applications cited herein are hereby incorporated by 0754) Other assays that are used to evaluate the pharma reference in their entirety to the same extent as if each docu cological properties of test compounds include, but are not ment had been individually incorporated by reference herein. US 2011/00094.65 A1 Jan. 13, 2011 57

What is claimed is: 16. The compound of claim 1, where Rand Rare taken 1. A compound of formula I: together to form -CH=CH-CH=CH . 17. The compound of claim 1, where R and Rare non hydrogen moieties, and R. R. and Rare hydrogen. 18.The compound of claim 1, where R and Rare non (I) hydrogen moieties, and R. R. and Rare hydrogen. 19. The compound of claim 1, where R and Rare non hydrogen moieties, and R. R. and Rare hydrogen. 20. The compound of claim 1, where R. R. and R are non-hydrogen moieties, and RandR are hydrogen. 21. The compound of claim 1, where R. R', and Rare non-hydrogen moieties, and RandR are hydrogen. 22. The compound of claim 1, which is 3-1-(4-chloro phenoxy)-2-methylpropylpyrrolidine. 23. The compound of claim 1, which has a configuration selected from: N R3 R3 where: R" is selected from —C2-alkyl, -Cascycloalkyl option R R2 R R2

ally substituted with 1 or 2 fluoro atoms, —Calkenyl, and —Calkynyl; R through Rare independently selected from hydrogen, R5 halo. —Calkyl, -CF, —O—Calkyl, —CN, R6 —C(O)—Calkyl, - S-Clalkyl, -C-scycloalkyl, and NO; or R and R are taken together to form -CH=CH-CH=CH-; or R and R are taken together to form —CH-CH=CH-CH : with the proviso that when R is ethyl, R is fluoro, R is R3 chloro, R is hydrogen, and R is hydrogen, then R is not fluoro or chloro; R or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, where R is —C2-alkyl selected from ethyl, propyl, isopropyl, butyl, isobutyl, and R5 3-pentyl. 3. The compound of claim 1, where R' is —Clscycloalkyl R6 optionally substituted with 1 or 2 fluoro atoms, selected from cyclopropyl, cyclopentyl, cyclohexyl, and 4.4-difluorocyclo hexyl. 4. The compound of claim 1, where R' is but-3-enyl. 5. The compound of claim 1, where R' is prop-2-ynyl. or enriched in a stereoisomeric form having Such configura 6. The compound of claim 1, where R is hydrogen, halo, tion. —Calkyl, -CF, —O—C-alkyl, -C(O)—Calkyl, 24. The compound of claim 23, which is selected from —S C-alkyl, —Clscycloalkyl, or —NO. (R)-3-((R)-1-(4-chloro-phenoxy)-2-methylpropylpyrroli dine, (S)-3-(S)-1-(4-chlorophenoxy)-2-methylpropylpyr 7. The compound of claim 6, where R is hydrogen, fluoro, rolidine, (S)-3-((R)-1-(4-chlorophenoxy)-2-methylpropyl chloro, —CH, —CHCH. —CF —O—CH, pyrrolidine, and (R)-3-(S)-1-(4-chlorophenoxy)-2- —O CHCH. —C(O)—CH, S CH, cyclohexyl, or methylpropylpyrrolidine. NO. 25. A method of preparing the compound of claim 1, the 8. The compound of claim 1, where R is hydrogen, halo, process comprising deprotecting a compound of the formula: —Calkyl, -CF, —O—C-alkyl, or —S Calkyl. 9. The compound of claim8, where R is hydrogen, fluoro, chloro, —CH —CF, —O—CH, or —S-CH. 10. The compound of claim 1, where R is hydrogen, halo, —Calkyl, -CF, or —O—Calkyl. 11. The compound of claim 10, where R is hydrogen, fluoro, chloro, —CH —CF, or —O—CH. 12. The compound of claim 1, where R is hydrogen, halo, —Calkyl, or —O—Calkyl. 13. The compound of claim 12, where R is hydrogen, fluoro, chloro, —CH, or —O—CH. 14. The compound of claim 1, where R is hydrogen, halo, or —Calkyl. 15. The compound of claim 14, where R is hydrogen, fluoro, chloro, or —CH. US 2011/00094.65 A1 Jan. 13, 2011

where P represents an amino-protecting group, to provide 28. A pharmaceutical composition of claim 27, further a compound of formula I, or a salt thereof. comprising a second therapeutic agent selected from anti 26. An intermediate useful in the synthesis of the com Alzheimer's agents, anticonvulsants, antidepressants, anti pound of claim 1, having the formula: Parkinson's agents, dual serotonin-norepinephrine reuptake inhibitors, non-steroidal anti-inflammatory agents, norepi nephrine reuptake inhibitors, opioid agonists, selective sero R3 tonin reuptake inhibitors, sodium channel blockers, sym patholytics, and combinations thereof. 29. A method of treating a patient that is suffering from a disease or disorder that is treated by the inhibition of the serotonin and/or the norepinephrine transporter, comprising administering a therapeutically effective amount of the com pound of claim 1. 30. The method of claim 29, wherein the disorder or dis ease is selected from pain disorders, depressive disorders, affective disorders, attention deficit hyperactivity disorders, cognitive disorders, stress urinary incontinence, chronic fatigue syndrome, obesity, and vasomotor symptoms associ ated with menopause. 31. The method of claim 30, wherein the pain disorder is where P represents an amino-protecting group. neuropathic pain, fibromyalgia, or chronic pain. 27. A pharmaceutical composition comprising a com pound of claim 1, and a pharmaceutically acceptable carrier. c c c c c