WO2010071575A1

WO2010071575A1 - Quaternary piperidine derivatives and uses thereof

Info

Publication number: WO2010071575A1
Application number: PCT/SE2009/051427
Authority: WO
Inventors: Peter Bernstein; Dean Brown; Bruce Thomas Dembofsky; John P Mccauley; Rebecca Urbanek
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2008-12-16
Filing date: 2009-12-15
Publication date: 2010-06-24
Anticipated expiration: 2011-06-16
Also published as: UY32333A; TW201026666A; AR074755A1

Abstract

This invention generally relates to quaternary piperidine compounds, particularly substituted 3-phenylpiperidine compounds and salts thereof. This invention also relates to pharmaceutical compositions comprising such a compound, uses of such a compound (including, for example, treatment methods and medicament preparations), and processes for making such a compound.

Description

QUATERNARY PIPERIDINE DERIVATIVES AND USES THEREOF

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[1] This patent claims the benefit of priority to U.S. Provisional Patent Application Nos. 61/229,073 (filed July 28, 2009); 61/226,389 (filed July 17, 2009); and 61/122,912 (filed December 16, 2008). The entire text of each of the above patent applications is incorporated by reference into this patent.

FIELD OF THE INVENTION [2] This invention generally relates to quaternary piperidine compounds, particularly substituted 3-phenylpiperidine compounds and salts thereof. This invention also relates to pharmaceutical compositions comprising such a compound, uses of such a compound (including, for example, treatment methods and medicament preparations), and processes for making such a compound.

BACKGROUND

[3] The brain contains neurons that communicate with each other through chemical messengers called neurotransmitters. Neurotransmitters are produced by neurons. The cellular membrane of a neuron contains receptors with which the neurotransmitters may interact. Serotonin (SERT), dopamine (DAT), and norepinephrine (NET) neurotransmitters belong to a group of neurotransmitters called the monoamine neurotransmitters .

[4] Monoamine neurotransmitters are released into the synaptic cleft between neurons and act by stimulating postsynaptic receptors. Monoamine neurotransmitters are removed (or inactivated) primarily by reuptake into presynaptic terminals. In various diseases and/or conditions where neurotransmitters are out of balance, reuptake of a particular neurotransmitter can be inhibited to improve a patient's condition and/or the disease from which the patient suffers.

[5] Selective serotonin reuptake inhibitors (SSRIs) and dual serotonin and norepinephrine reuptake inhibitors (SNRIs) are used in treating depression. Patients, however, often complain of side effects, such as, for example, weight gain and sexual dysfunction. Additionally, not all patients have a positive therapeutic response to SSRIs and/or SNRIs. In fact, SSRIs and SNRIs are generally no more efficacious than monoamine oxidase inhibitors and tricyclic antidepressants, although they do pose less serious side effect risks. Nevertheless, tricyclic antidepressants continue to be used to treat depression.

[6] Nomifensine, marketed in late 1970's by Hoescht, was an effective motivating and anxiolytic drug reported to be a selective NET:DAT reuptake inhibitor. The unique NET:DAT reuptake inhibitor profile of nomifensine was thought to confer a unique therapeutic benefit to melancholic depressive patients. Nomifensine was, however, withdrawn from the market in 1980 in the wake of nomifensine-associated immune reactions appearing in the literature, several cases of autoimmune haemolytic anaemia, and some deaths. The prevailing theory suggests a reactive metabolite of nomifensine forms a complex with proteins on red blood cells (RBC) to initiate an auto-immune complex.

[7] As the SSRIs and SNRIs are not effective in treating at least some patients suffering from depression, new treatments continue to be needed. Such treatments are particularly desirable to treat underserved subpopulations, such as, for example, patients suffering from atypical depression. As the unique NET:DAT reuptake inhibitor profile of nomifensine appeared to confer a unique therapeutic benefit to melancholic depressive patients, efforts have been undertaken to develop dual NET and DAT reuptake inhibitors that do not have the undesirable side effect profile that led to nomifensine's withdrawal.

SUMMARY OF THE INVENTION [8] This invention comprises, inter alia, piperidine compounds; methods of treatment using the piperidine compounds {e.g., uses of the piperidine compounds to treat various psychiatric disorders and as pharmacological tools); use of the piperidine compounds to make medicaments; compositions comprising the piperidine compounds {e.g., pharmaceutical compositions); methods for manufacturing the piperidine compounds; and intermediates used in such manufacturing methods.

[9] Briefly, this invention is directed, in part, to a compound of Formula (I) or a salt thereof. Formula (I) corresponds to:

Here:

[10] R¹ and R² are each independently selected halogen. [11] R³ and R⁴ are each independently selected from H, -OH, and Ci_₃alkyl. [12] Alternatively, R³ and R⁴, together with the carbon to which they are both attached, form C₃_₆Cycloalkyl.

[13] R⁵ is selected from -CN, -CF₃, -C₂-C₆alkenyl, -OR⁷, -S(=O)R⁶, -S(=O)₂R⁶, -SR⁶, -S(=O)₂NR⁷R⁸, -C(=O)NR⁷R⁸, -NR⁷C(=O)R¹², -NR⁷R⁸, -NR⁷C(=O)OR⁸, -NR⁷S(=O)₂R⁹, -NR⁷(C=O)NR⁷R⁸, and -0(C=O)NR⁷R⁸. [14] R⁶ is Ci-Cealkyl.

[15] R⁷ and R⁸ are each independently selected from H and Ci-Cβalkyl. The Ci-Cβalkyl is optionally substituted by lor 2 substituents selected from haloalkyl, Ci-C₃alkyl, -CC=O)NR¹⁰R¹ \ -OH, -CN, and -Ci-Csalkoxy.

[16] Alternatively, when R⁵ is -C(=O)NR⁷R⁸, -NR⁷R⁸, -NR⁷C(=O)OR⁸, or -S(=O)₂NR⁷R⁸, R⁷ and R⁸, together with the atom(s) to which they are both attached, may form a 3-, 4-, 5-, or 6-membered heterocycloalkyl. The 3-, 4-, 5-, or 6-membered heterocycloalkyl optionally contains at least one ring heteroatom selected from O and N in addition to: the N to which both R⁷ and R⁸ are both attached where R⁵ is -C(=O)NR⁷R⁸, -NR⁷R⁸, or -S(=O)₂NR⁷R⁸, or the N to which R⁷ is attached and the O to which R8 is attached where R⁵ is -NR⁷C(=O)OR⁸;

[17] R⁹ is selected from H, Ci-C₆alkyl, -NR⁷R⁸, and haloalkyl. [18] R¹⁰ and R¹¹ are each independently selected from H and Ci-Cβalkyl. [19] R¹² is selected from H, C_rC₆alkyl, and haloalkyl.

[20] n is selected from zero and 1. [21] p is selected from zero, 1, 2, and 3. p, however, is not zero when R⁵ is -OR⁷.

[22] The compound of Formula (I) is not 2-((R)-3-(3,4- dichlorophenyl)piperidin-3-yl)ethanol. In some embodiments, the compound of Formula (I) is not any enantiomer of 2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethanol or mixture thereof.

[23] This invention also is directed, in part, to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[24] This invention also is directed, in part, to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disorder comprising a psychiatric disorder.

[25] This invention also is directed, in part, to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disorder comprising a disorder selected from major depressive disorders, attention-deficit and disruptive behavior disorders, and cocaine-related disorders.

[26] This invention also is directed, in part, to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disorder comprising a disorder selected from atypical depression, melancholy depression, cocaine abuse, and attention deficit hyperactivity disorder. [27] This invention also is directed, in part, to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disorder comprising a disorder in which modulating norepinephrine transport receptors and/or dopamine transport receptors is beneficial.

[28] This invention also is directed, in part, to a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.

[29] In some embodiments, the medicament is for the treatment of a disorder comprising a psychiatric disorder.

[30] In some embodiments, the medicament is for the treatment of a disorder comprising a disorder selected from major depressive disorders, attention-deficit and disruptive behavior disorders, and cocaine-related disorders.

[31] In some embodiments, the medicament is for the treatment of a disorder comprising a disorder selected from atypical depression, melancholy depression, cocaine abuse, and attention deficit hyperactivity disorder. [32] In some embodiments, the medicament is for the treatment of a disorder comprising a disorder in which modulating norepinephrine transport receptors and/or dopamine transport receptors is beneficial.

[33] This invention also is directed, in part, to a pharmaceutical composition. The composition comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The composition also comprises a pharmaceutically acceptable carrier or diluent.

[34] This invention also is directed, in part, to a method for treating a disorder in a warm-blooded animal in need of such treatment. The method comprises administering to the animal a therapeutically effective amount a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[35] In some embodiments, the disorder comprises a psychiatric disorder.

[36] In some embodiments, the disorder comprises a disorder selected from major depressive disorders, attention-deficit and disruptive behavior disorders, and a cocaine-related disorders.

[37] In some embodiments, the disorder comprises a disorder selected from melancholy depression, atypical depression, cocaine abuse, and ADHD.

[38] In some embodiments, the disorder comprises a major depressive disorder.

[39] In some embodiments, the disorder comprises a disorder in which modulating norepinephrine transport receptors and/or dopamine transport receptors is beneficial.

[40] This invention also is directed, in part, to a method for modulating norepinephrine transport receptors and/or dopamine transport receptors using a compound of Formula (I) or a pharmaceutically acceptable salt thereof. [41] Further benefits of Applicants' invention will be apparent to one skilled in the art from reading this specification.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS [42] This description of illustrative embodiments is intended only to acquaint others skilled in the art with Applicants' invention, its principles, and its practical application so that others skilled in the art may readily adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples, while indicating embodiments of this invention, are intended for purposes of illustration only. This invention, therefore, is not limited to the illustrative embodiments described in this specification, and may be variously modified. In addition, it is to be appreciated that various features of the invention that are, for clarity reasons, described in the context of separate embodiments, also may be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, also may be combined to form sub-combinations thereof.

[43] As noted above, this invention is directed, in part, to a compound of Formula (I) or a salt thereof. Formula (I) corresponds to:

[44] R¹ and R² are each independently selected halogen.

[45] In some embodiments, R¹ is chlorine.

[46] In some embodiments, R¹ is fluorine.

[47] In some embodiments, R² is chlorine.

[48] In some embodiments, R² is fluorine.

[49] In some embodiments, R¹ and R² are each independently selected from chlorine and fluorine.

[50] In some embodiments, R¹ is ørt/zosubstituted, i.e., R¹ is at the ortho position of the depicted phenyl such that the compound of Formula (I) corresponds to:

In some such embodiments, for example, R¹ is chlorine. In other embodiments, R¹ is fluorine.

[51] In some embodiments, R¹ is meto-substituted, i.e., R¹ is at the meta position of the depicted phenyl such that the compound of Formula (I) corresponds to:

[52] In some embodiments, R¹ is pαra-substituted, i.e. , R¹ is at the para position of the depicted phenyl such that the compound of Formula (I) corresponds to:

[53] In some embodiments, n is zero such that no R² exists and the compound of Formula (I) corresponds to:

In some such embodiments, R¹ is chlorine. In other embodiments, R¹ is fluorine.

[54] In some embodiments, n is 1 such that the compound of Formula (I) corresponds to:

[55] In some embodiments, n is 1 , and R¹ and R² are each independently selected from chlorine and fluorine.

[56] In some embodiments, n is 1, and R¹ and R² are each chlorine.

[57] In some embodiments, n is 1, and R¹ and R² are each fluorine.

[58] In some embodiments, n is 1, one of R¹ and R² is chlorine, and the other of R¹ and R² is fluorine.

[59] In some embodiments, n is 1, R¹ is at the /?αra-position of the phenyl, and R² is at the meto-position of the phenyl such that the compound corresponds to:

In some such embodiments, for example, R¹ and R² are each chlorine. In other embodiments, R¹ and R² are each fluorine. In other embodiments R¹ is chlorine, and R² is fluorine. And in other embodiments, R¹ is fluorine, and R² is chlorine.

[60] In some embodiments, n is 1, R¹ is at the meta-position of the phenyl, and R² is at the other meto-position of the phenyl such that the compound corresponds to:

In some such embodiments, for example, R¹ and R² are each chlorine. In other embodiments, R¹ and R² are each fluorine. And in other embodiments R¹ is chlorine, and R² is fluorine.

[61] p is selected from zero, 1, 2, and 3.

[62] In some embodiments, p is zero such that the compound of Formula (I) corresponds to:

In such embodiments, R⁵ is not -OR⁷. [63] In some embodiments, p is 1 such that the compound of Formula (I) corresponds to:

[64] In some embodiments, p is 2 such that the compound of Formula (I) corresponds to:

[65] In some embodiments, p is 3 such that the compound of Formula (I) corresponds to:

[66] In the above two structures, each R can be the same or different from the other R³'s, and each R⁴ can be the same or different from the other R⁴'s.

[67] In some embodiments, R³ and R⁴ are each independently selected from H, -OH, and Chalky!. [68] In some embodiments, R³ and R⁴ are each independently selected from H, -OH, and CH₃.

[69] In some embodiments, R³ and R⁴ are each H.

[70] In some embodiments, R³ and R⁴, together with the carbon to which they are both attached, form C₃_₆Cycloalkyl.

[71] R⁵ is selected from -CN, -CF₃, -C₂-C₆alkenyl, -OR⁷, -S(=O)R⁶, -S(=O)₂R⁶, -SR⁶, -S(=O)₂NR⁷R⁸, -C(=O)NR⁷R⁸, -NR⁷C(=O)R¹², -NR⁷R⁸, -NR⁷C(=O)OR⁸, -NR⁷S(=O)₂R⁹, -NR⁷(C=O)NR⁷R⁸, and -0(C=O)NR⁷R⁸.

[72] In some embodiments, R⁵ is selected from -CN, -CF₃, -ethenyl, -OR⁷, -S(=O)R⁶, -S(=O)₂R⁶, -SR⁶, -C(=O)NR⁷R⁸, -NR⁷C(=O)R¹², -NR⁷R⁸, -NR⁷C(=O)OR⁸, -NR⁷S(=O)₂R⁹, and -0(C=O)NR⁷R⁸.

[73] In some embodiments, R⁵ is selected from -CN, -CF₃, -ethenyl, -OR⁷, -S(=O)R⁶, -S(=O)₂R⁶, -SR⁶, -NR⁷C(=O)R¹², -NR⁷R⁸, -NR⁷C(=O)OR⁸, -NR⁷S(=O)₂R⁹, and -0(C=O)NR⁷R⁸. [74] In some embodiments, R⁵ is selected from -S(=O)R⁶, -S(=O)₂R⁶, and -SR⁶.

[75] In some embodiments, R⁵ is selected from -CN, -CF₃, -ethenyl, -OH, -OCH₃, -OCH₂CH₂OH, -S(K))CH₃, -S(=O)₂CH₃, -S(=O)₂CH(CH)₂CH₃, -SCH₃,

-C(=O)N(CH₃)₂, -C(=O)NHCH₃, -NHC(=O)CF₃, -NHC(=O)CH₃

-N(CH₃)C(=O)CH₃, -NH₂, -N(CH₃)₂, -NHCH₃, -NHCH₂CH₃, -NHCH₂CH₂CF₃, -NHCH₂CH₂CN, -NHCH₂C(=O)N(CH₃)₂, -NHCH₂CH₂OH, -NHCH₂CH₂OCH₃,

-NHCH₂CF₃, -NHCH(CH₃)₂, -NHCH₂CHF₂,

, -NR⁷R⁸, -NHC(=O)OCH₃,

-N(CH₃)S(=O)₂CH₃, -NHS(=O)₂CF₃, -NHS(=O)₂N(CH₃)₂, -0(C=O)NH₂, -0(C=O)NHCH₃, and -O(C=O)N(CH₃)₂.

[76] In some embodiments, R⁵ is selected from -CN, -CF₃, -ethenyl, -OH, -OCH₃, -OCH₂CH₂OH, -S(=O)CH₃, -S(=O)₂CH₃, -S(=O)₂CH(CH)₂CH₃, -SCH₃,

-C(=O)N(CH₃)₂, -C(=O)NHCH₃, -NHC(=O)CF₃, -NHC(=O)CH₃,

-N(CH₃)C(=O)CH₃, -NR⁷R⁸, -NHC(=O)OCH₃, -N(CH₃)S(=O)₂CH₃, -NHS(=O)₂CF₃, -NHS(=O)₂N(CH₃)₂, -0(C=O)NH₂, -0(C=O)NHCH₃, and -O(C=O)N(CH₃)₂. [77] In some embodiments, R⁵ is -NR⁷R⁸.

[78] In some embodiments, R⁵ is selected from -NH₂, -N(CH₃)₂, -NHCH₃, -NHCH₂CH₃, -NHCH₂CH₂CF₃, -NHCH₂CH₂CN, -NHCH₂C(=O)N(CH₃)₂, -NHCH₂CH₂OH, -NHCH₂CH₂OCH₃, -NHCH₂CF₃, -NHCH(CH₃)₂, and -NHCH₂CHF₂.

[79] In some embodiments, R⁵ is

[80] In some embodiments, R⁵ is -NR⁷S(=O)₂R⁹. [81] R⁶ is Ci-Cealkyl. [82] In some embodiments, R⁶ is methyl. [83] In some embodiments, R⁶ is 2-methylpropan-2-yl. [84] In some embodiments, R⁷ and R⁸ are each independently selected from H and Ci-Cβalkyl. The Ci-Cβalkyl is optionally substituted by lor 2 substituents selected from haloalkyl, Ci-C₃alkyl, -CC=O)NR¹⁰R¹ \ -OH, -CN, and C_rC₃alkoxy.

[85] In some embodiments, R⁷ and R⁸ are each independently selected from H and Ci_6alkyl, wherein the Ci-Cβalkyl is substituted by 1 or 2 substituents selected from haloalkyl, -C(O)NR¹⁰R¹ \ -OH, -CN, and -Ci-C₃alkoxy.

[86] In some embodiments, R⁷ and R⁸ are each independently selected from H and Ci_6alkyl, wherein the Ci-Cβalkyl is substituted by 1 or 2 substituents selected from -CF₃, -CHF₂, -C(=O)N(CH₃)₂, -OH, -CN, and -OCH₃.

[87] In some embodiments, R⁷ is Ci_6alkyl substituted with haloalkyl. [88] In some embodiments, R⁷ is C^alkyl substituted with -OH.

[89] In some embodiments, R⁸ is hydrogen.

[90] In some embodiments, R⁷ and R⁸ are each independently selected Ci_6alkyl substituted with haloalkyl.

[91] In some embodiments, R⁷ is C^alkyl substituted with haloalkyl, and R⁸ is hydrogen.

[92] In some embodiments, R⁷ and R⁸ are each independently selected Ci_6alkyl substituted with -OH.

[93] In some embodiments, R⁷ is C^alkyl substituted with -OH, and R⁸ is hydrogen. [94] In some embodiments, R⁷ and R⁸ are each independently selected from hydrogen and Ci_₆alkyl.

[95] In some embodiments, R⁷ and R⁸ are each hydrogen. [96] In some embodiments, R⁷ and R⁸ are each independently selected Ci_6alkyl. [97] In some embodiments, any Ci_6alkyl of R⁷ and R⁸ in the above embodiments is a Ci_3alkyl. In some such embodiments, any Csalkyl is selected from n- propyl and wo-propyl. In other embodiments, any Csalkyl is w-propyl. And in other embodiments, any Csalkyl is wo-propyl.

[98] In some embodiments when R⁵ is -C(=O)NR⁷R⁸, -NR⁷R⁸, -NR⁷C(=O)OR⁸, or -S(=O)₂NR⁷R⁸, R⁷ and R⁸, together with the atom(s) to which they are both attached, may form a 3-, 4-, 5-, or 6-membered heterocycloalkyl. The 3-, 4-, 5-, or 6-membered heterocycloalkyl optionally contains at least one ring heteroatom selected from O and N in addition to: the N to which both R⁷ and R⁸ are both attached where R⁵ is -C(=O)NR⁷R⁸, -NR⁷R⁸, or -S(=O)₂NR⁷R⁸, or the N to which R⁷ is attached and the O to which R⁸ is attached where R⁵ is -NR⁷C(=O)OR⁸. [99] R⁹ is selected from H, Ci-C₆alkyl, -NR⁷R⁸, and haloalkyl.

[100] In some embodiments, R⁹ is selected from Ci-Cβalkyl, -NR⁷R⁸, and haloalkyl.

[101] In some embodiments, R⁹ is Ci-Cβalkyl. [102] In some embodiments, R⁹ is Ci-C3alkyl. [103] In some embodiments, R⁹ is -NR⁷R⁸.

[104] In some embodiments, R⁹ is haloalkyl.

[105] In some embodiments, R⁹ is selected from methyl, -N(CHs)₂, and CF3. [106] R¹⁰ and R¹¹ are each independently selected from H and Ci-Cβalkyl. [107] In some embodiments, R¹⁰ and R¹¹ are each H. [108] In some embodiments, R¹⁰ and R¹¹ are each independently selected

Ci-Cealkyl.

[109] In some embodiments, R¹⁰ and R¹¹ are each methyl. [110] R¹² is selected from H, Ci-C₆alkyl, and haloalkyl. [Ill] In some embodiments, R¹² is H. [112] In some embodiments, R¹² is selected from Ci-Cβalkyl and haloalkyl.

[113] In some embodiments, R¹² is Ci-Cβalkyl. [114] In some embodiments, R¹² is Ci-C3alkyl. [115] In some embodiments, R¹² is haloalkyl. [116] In some embodiments, R¹² is selected from CH3 and CF3. [117] In some embodiments, R¹² is CH3.

[118] In some embodiments, R¹² is CF3.

[119] Irrespective of the foregoing, the compound of Formula (I) is not 2-((R)-3- (3,4-dichlorophenyl)piperidin-3-yl)ethanol. In some embodiments, the compound of Formula (I) is not any enantiomer of 2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethanol or mixture thereof.

[120] In some embodiments, the compound corresponds in structure to Formula (IA):

[121] In some embodiments, the compound corresponds in structure to Formula

(IB):

[122] All the compounds of this invention include at least one chiral carbon, i.e., the carbon of the piperidinyl that is linked to the phenyl. To the extent a structure or chemical name in this patent does not indicate the chirality, the structure or name is intended to encompass any single chiral isomer corresponding to that structure or name, as well as any mixture of chiral isomers {e.g., the racemate). Thus, for example, Formula (I), which does not indicate the chirality, is intended to encompass any single isomer corresponding to the structure, as well as any mixture of chiral isomers. In some embodiments, a single chiral isomer is obtained by isolating it from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single chiral isomer is obtained through direct synthesis from, for example, a chiral starting material.

[123] In some embodiments, the invention is directed to a compound selected from the following (or a salt thereof, particularly a pharmaceutically acceptable salt thereof):

(S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl dimethylcarbamate; (S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl methylcarbamate; 2-(3-(3-chloro-4-fluorophenyl)piperidin-3-yl)ethanol; (S)-l-(3-(3,4-dichlorophenyl)piperidin-3-yl)-2-methylpropan-2-ol;

(S)-2-(3-(4-chlorophenyl)piperidin-3-yl)ethanol; (S)-2-(3-(3-chlorophenyl)piperidin-3-yl)ethanol; (S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethanamine; (S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)-2,2,2-trifluoroacetamide; (S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)-2,2,2-trifluoroethanamine;

(S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)acetamide; (S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)-N-methylethanamine; (S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)-N- methylmethanesulfonamide; (S)-l-(azetidin-l-yl)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethanone;

(S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)-N-methylacetamide; (S)-3-(3,4-dichlorophenyl)-3-vinylpiperidine; (3S)-3-(3,4-dichlorophenyl)-3-(2-(methylsulfinyl)ethyl)piperidine; (S)-3-(3,4-dichlorophenyl)-3-(2-(methylsulfonyl)ethyl)piperidine; (S)-3-(3,4-dichlorophenyl)-3-(2-(methylthio)ethyl)piperidine;

(S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)-N-methylacetamide; (S)-3-(3,4-dichlorophenyl)-3-(2-methoxyethyl)piperidine; (S)-3-(3-(3,4-dichlorophenyl)piperidin-3-yl)propanenitrile; (S)-(3-(3 ,4-dichlorophenyl)piperidin-3 -yl)methyl dimethylcarbamate; (S)-(3-(3,4-dichlorophenyl)piperidin-3-yl)methyl methylcarbamate;

(3 S)-tert-butyl 3 -(3 ,4-dichlorophenyl)-3 -(methylsulfϊnylmethyl)piperidine- 1 - carboxylate;

(S)-tert-butyl 3 -(3 ,4-dichlorophenyl)-3 -(methylsulfonylmethyl)piperidine- 1 - carboxylate; (S)-3-(3,4-dichlorophenyl)-3-(methoxymethyl)piperidine;

(S)-(3-(3 ,4-dichlorophenyl)piperidin-3 -yl)methanol;

(R)-3 -(3 -(3 ,4-dichlorophenyl)piperidin-3 -yl)propan- 1 -amine;

(S)-(-)-2-(3-(3,4-dichlorophenyl)-piperidine-3-yl)ethanol; 2-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethylamino)-N,N- dimethylacetamide;

(S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)- 1,1,1- trifluoromethanesulfonamide ;

N-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)-3,3,3-trifluoropropan-l- amine; methyl 3-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)propylcarbamate;

N'-{2-[(3S)-3-(3,4-dichlorophenyl)piperidin-3-yl]ethyl}-N,N-dimethylsulfamide;

N-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)-2,2-difluoroethanamine;

N-(((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)methyl)propan-2-amine; N-(((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)methyl)-2,2,2-trifluoroethanamine; methyl 2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethylcarbamate;

3-((R)-3-(3,4-dichlorophenyl)piperidin-3-yl)-N-methylpropan-l-amine;

(S)-N-(3-(3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-N- methylmethanesulfonamide; 3-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)- 1,1,1 -trifluoropropan-2-ol;

N-(3-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-N-methylacetamide;

2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl carbamate;

2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)-N-(2-methoxyethyl)ethanamine;

2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)-N-ethylethanamine; (S)-3-(2-(tert-butylsulfonyl)ethyl)-3-(3,4-dichlorophenyl)piperidine;

4-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)morpholine;

2-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethylamino)ethanol;

N-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)propan-2-amine;

2-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethoxy)ethanol; 2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)-N,N-dimethylacetamide;

2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)-N,N-dimethylethanamine;

3-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)propan-l-ol; and

(S)-3-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethylamino)propanenitrile. [124] The salts of the compounds of this invention are typically acid addition salts. In general, an acid addition salt can be prepared using various inorganic or organic acids. Such salts can typically be formed by, for example, mixing the compound with an acid (e.g., a stoichiometric amount of acid) using various methods known in the art. This mixing may occur in water, an organic solvent (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile), or an aqueous/organic mixture.

[125] A salt may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in water, oil, or other solvent. In some instances, a salt may be used to aid in the isolation or purification of the compound. In some embodiments (particularly where the salt is intended for administration to an animal, or is a reagent for use in making a compound or salt intended for administration to an animal), the salt is pharmaceutically acceptable.

[126] Examples of inorganic acids that typically may be used to form acid addition salts include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Examples of organic acids include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids. Specific examples of organic salts include cholate, sorbate, laurate, acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid (and derivatives thereof, e.g., dibenzoyltartrate), citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate (and derivatives thereof), embonate (pamoate), ethanesulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenic acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate. In some embodiments, the salt comprises a hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, methanesulphonate, or /7-toluenesulphonate salt. In other embodiments, the salt comprises a citric acid salt. In other embodiments, the salt comprises an HCl salt. And, in other embodiments, the salt comprises an acetic acid salt.

[127] Base-addition salts also are contemplated for some of the compounds of this invention. For example, it may be possible to make an alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of this invention having a suitably acidic proton with an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g., an ethoxide or methoxide) or a suitably basic organic amine (e.g., a choline or meglumine) in an aqueous medium. [128] The compounds of Formula (I) and salts thereof are intended to encompass any tautomer that may form. A "tautomer" is any other structural isomer that exists in equilibrium resulting from the migration of a hydrogen atom.

[129] It is contemplated that an amine of a compound of Formula I or a salt thereof may form an N-oxide. Such an N-oxide is intended to be encompassed by the compounds of Formula I and salts thereof. An N-oxide can generally be formed by treating an amine with an oxidizing agent, such as hydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid). See, e.g., Advanced Organic Chemistry, by Jerry March, 4^th Edition, Wiley Interscience. N-oxides also can be made by reacting the amine with m- chloroperoxybenzoic acid (m-CPBA), for example, in an inert solvent, such as dichloromethane. See L. W. Deady, Syn. Comm., 1, pp. 509-514 (1977).

[130] It is contemplated that the compounds of this invention and salts thereof could form isolatable atropisomers in certain solvents at certain temperatures. The compounds of Formula (I) and salts thereof are intended to encompass any such atropisomers. Atropisomers can generally be isolated using chiral LC. [131] The compounds of Formula (I) and salts thereof are intended to encompass any isotopically-labeled (or "radio-labeled") derivatives of a compound of Formula (I) or salt thereof. Such a derivative is a derivative of a compound of Formula (I) or salt thereof wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include ²H (also written as "D" for deuterium), ³H (also written as "T" for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³1, ¹²⁴1, ¹²⁵I, and ¹³¹L. The radionuclide that is used will depend on the specific application of that radio-labeled derivative. For example, for in vitro receptor labeling and competition assays, ³H or ¹⁴C are often useful. For radio-imaging applications, ¹¹C or ¹⁸F are often useful. In some embodiments, the radionuclide is ³H. In some embodiments, the radionuclide is ¹⁴C. In some embodiments, the radionuclide is ¹¹C. And in some embodiments, the radionuclide is ¹⁸F.

[132] The compounds of Formula (I) and salts thereof are intended to cover all solid state forms of the compounds and salts. The compounds of Formula (I) and salts thereof also are intended to encompass all solvated (e.g., hydrated) and unsolvated forms of the compounds and salts.

[133] The compounds of Formula (I) and salts thereof also are intended to encompass coupling partners in which a compound of Formula (I) or a salt thereof is linked to a coupling partner by, for example, being chemically coupled to the compound or salt or physically associated with it. Examples of coupling partners include a label or reporter molecule, a supporting substrate, a carrier or transport molecule, an effector, a drug, an antibody, or an inhibitor. Coupling partners can be covalently linked to a compound or salt via an appropriate functional group on the compound, such as a hydroxyl, carboxyl, or amino group. Other derivatives include formulating a compound or salt with liposomes.

[134] This invention provides, in part, for methods to treat various disorders in animals, particularly mammals. Mammals include, for example, humans. Mammals also include, for example, companion animals (e.g., dogs, cats, and horses), livestock animals (e.g., cattle and swine); lab animals (e.g., mice and rats); and wild, zoo, and circus animals (e.g., bears, lions, tigers, apes, and monkeys). It is contemplated that the compounds and salts of this invention may generally be used to treat a range of disorders in which modulating the norepinephrine transport receptor and/or dopamine transport receptor is beneficial. Accordingly, this invention is directed, in part, to a method of using a compound of Formula (I) or salt thereof for treating a norepinephrine transport receptor and/or dopamine transport receptor associated condition therewith.

[135] In some embodiments, a compound or salt of this invention is used to modulate at least one norepinephrine transport receptor and/or dopamine transport receptor. The terms "modulate", "modulates", "modulating", or "modulation", as used in this patent, mean the activation (i.e., act as an agonist) or inhibition (i.e., act as antagonist) of the norepinephrine transport receptor and/or dopamine transport receptor. In some embodiments, the terms "modulate", "modulates", "modulating", or "modulation" mean the inhibition of at least one norepinephrine transport receptor and/or dopamine transport receptor. [136] In some embodiments, the compound or salt thereof exhibits a Ki value of less than about 1.5 μM toward NET and/or DAT using an assay described below in the Example 118. In some embodiments, the compound or salt thereof exhibits a Ki value of from about 0.1 nM to about 1.5 μM toward NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of from about 0.1 nM to about 700 nM toward NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of from about 0.1 nM and 200 nM toward NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of from about 0.1 nM and 100 nM toward NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of less than about 1200 nM toward NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of less than about 100 nM toward NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of less than about 50 nM toward NET and/or DAT. And in some embodiments, the compound or salt exhibits a Ki value of less than about 10 nM toward NET and/or DAT. [137] In some embodiments, a compound or salt of this invention is administered to an animal in which the modulation of at least one norepinephrine transport receptor and/or dopamine transport receptor in the animal is beneficial to the animal for treating a disorder. The compound or salt is normally administered to the animal in the form of a pharmaceutical composition that also comprises at least one carrier, diluent, or excipient. [138] In some embodiments, a compound or salt of this invention is administered to an animal to treat a psychiatric disorder in the animal. Psychiatric disorders include, for example: (1) mood disorder(s), such as, for example:

(a) depressive disorder(s), such as major depressive disorder(s) (e.g., melancholy depression and atypical depression) and dysthymic disorder(s),

(b) bipolar depression and/or bipolar mania, such as, for example, bipolar I (bipolar disorders with manic, depressive or mixed episodes) and bipolar II,

(c) cyclothymiac's disorder(s), and

(d) mood disorder(s) due to a general medical condition; (2) attention-deficit and disruptive behavior disorder(s), such as, for example, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), and affective disorders; and (3) substance-related disorder(s), such as, for example, substance dependence; substance abuse; substance intoxication; substance withdrawal; alcohol-related disorder(s); amphetamine (or amphetamine-like)-related disorder(s); caffeine-related disorder(s); cannabis-related disorder(s); cocaine-related disorder(s) (e.g.; cocaine abuse); hallucinogen-related disorder(s); inhalant-related disorder(s); nicotine-related disorder(s)s; opioid-related disorder(s)s; phencyclidine (or phencyclidine-like)-related disorder(s); and sedative-, hypnotic- or anxiolytic-related disorder(s).

Further discussion relating to psychiatric disorders may be found in, for example, the American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, Washington, DC, American Psychiatric Association, 2000.

[139] In some embodiments of this invention, a compound or salt of this invention (generally a therapeutically effective amount) is used for therapy.

[140] In some embodiments of this invention, a compound or salt of this invention is used to treat a major depressive disorder. In some such embodiments, the compound or salt is administered (generally a therapeutically effective amount) to an animal to treat a major depressive disorder in the animal. In some embodiments, the disorder comprises melancholy depression. In other embodiments, the disorder comprises atypical depression.

[141] In some embodiments of this invention, a compound or salt of this invention is used to treat an attention-deficit or disruptive behavior disorder. In some such embodiments, the compound or salt is administered (generally a therapeutically effective amount) to an animal to treat an attention-deficit or disruptive behavior disorder in the animal. In some embodiments, the disorder comprises ADHD.

[142] In some embodiments of this invention, a compound or salt of this invention is used to treat a cocaine-related disorder. In some such embodiments, the compound or salt is administered (generally a therapeutically effective amount) to an animal to treat a cocaine-related disorder in the animal. In some such embodiments, the disorder comprises cocaine abuse.

[143] In some embodiments, a compound or salt of this invention is used to make a medicament (i.e., a pharmaceutical composition). In general, the pharmaceutical composition comprises a therapeutically effective amount of the compound or salt. Pharmaceutical compositions comprising a compound or salt of this invention can vary widely. Although it is contemplated that a compound or salt of this invention could be administered by itself (i.e., without any other active or inactive ingredient), the pharmaceutical composition normally will instead comprise one or more additional active ingredients and/or inert ingredients. The inert ingredients present in the pharmaceutical compositions of this invention are sometimes collectively referred to as "carriers, diluents, and excipients." Methods for making pharmaceutical compositions and the use of carriers, diluents, and excipients are well known in the art. See, e.g., for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 15th Edition, 1975.

[144] In some embodiments of this invention, a compound or salt of this invention (generally a therapeutically effective amount) is used to make a medicament for treating a major depressive disorder. In some such embodiments, the disorder comprises melancholy depression. In other embodiments, the disorder comprises atypical depression.

[145] In some embodiments of this invention, a compound or salt of this invention (generally a therapeutically effective amount) is used to make a medicament for treating a cocaine-related disorder. In some such embodiments, the disorder comprises cocaine abuse.

[146] In some embodiments of this invention, a compound or salt of this invention (generally a therapeutically effective amount) is used to make a medicament for treating an attention-deficit or disruptive behavior disorder. In some such embodiments, the disorder comprises ADHD.

[147] It is contemplated that compositions comprising a compound or salt of this invention may be formulated for a variety of suitable routes and means of administration, including oral, rectal, nasal, topical, buccal, sublingual, vaginal, inhalation, insufflation, or parenteral administration. In some embodiments, the compound or salt is administered orally. In some embodiments, the compound or salt is administered intravenously. In some embodiments, the compound or salt is administered intramuscularly. In some embodiments, the compound or salt is administered subcutaneously. And, in some embodiments, the compound or salt is administered intraperitoneally, intrathoracially, epidurally, intrathecally, intracerebroventricularly, and injection into the joints. [148] It is contemplated that pharmaceutical compositions of this invention may, for example, be in the form of solids, aqueous or oily solutions, suspensions, emulsions, creams, ointments, mists, gels, nasal sprays, suppositories, finely divided powders, and aerosols or nebulisers for inhalation. In some embodiments, the composition comprises a solid or liquid dosage form that may be administered orally. [149] Solid form compositions may include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier may comprise one or more substances. Such substances are generally inert. A carrier also may act as, for example, a diluent, flavoring agent, solubilizer, lubricant, preservative, stabilizer, suspending agent, binder, or disintegrating agent. It also may act as, for example, an encapsulating material. Examples of often suitable carriers include pharmaceutical grade mannitol, lactose, magnesium carbonate, magnesium stearate, talc, lactose, sugar (e.g., glucose and sucrose), pectin, dextrin, starch, tragacanth, cellulose, cellulose derivatives (e.g., methyl cellulose and sodium carboxymethyl cellulose), sodium saccharin, low-melting wax, and cocoa butter.

[150] In powders, the carrier is typically a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is typically mixed with the carrier having the desirable binding properties in suitable proportions and compacted into the desired shape and size. [151] For preparing suppository compositions, a low-melting wax (e.g., a mixture of fatty acid glycerides and cocoa butter) is typically first melted, followed by dispersing the active ingredient therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient-sized molds and allowed to cool and solidify. Examples of non-irritating excipients that may be present in suppository compositions include, for example, cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

[152] Liquid compositions can be prepared by, for example, dissolving or dispersing the compound or a salt of this invention in a carrier, such as, for example, water, water/propylene glycol solutions, saline aqueous dextrose, glycerol, or ethanol. In some embodiments, aqueous solutions for oral administration can be prepared by dissolving a compound or salt of this invention in water with a solubilizer (e.g., a polyethylene glycol). Colorants, flavoring agents, stabilizers, and thickening agents, for example, also may be added. In some embodiments, aqueous suspensions for oral use can be made by dispersing the compound or salt of this invention in a finely divided form in water, together with a viscous material, such as, for example, one or more natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, or other suspending agents. If desired, the liquid composition also may contain other non-toxic auxiliary inert ingredients, such as, for example, wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. Such compositions also may contain other ingredients, such as, for example, one or more pharmaceutical adjuvants. [153] In some embodiments, the pharmaceutical composition comprises from about 0.05% to about 99% (by weight) of a compound or salt of this invention. In some such embodiments, for example, the pharmaceutical composition comprises from about 0.10% to about 50% (by weight) of a compound or salt of this invention. [154] When a compound or salt of this invention is administered as a sole therapy for treating a disorder, a "therapeutically effective amount" is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; reduce the risk of the disorder getting worse; or delay or reduce the risk of onset of the disorder. [155] The optimum dosage and frequency of administration will depend on the particular condition being treated and its severity; the species of the patient; the age, sex, size and weight, diet, and general physical condition of the particular patient; brain/body weight ratio; other medication the patient may be taking; the route of administration; the formulation; and various other factors known to physicians (in the context of human patients), veterinarians (in the context of non-human patients), and others skilled in the art.

[156] It is contemplated that, in some embodiments, the optimum amount of a compound or salt of this invention is from about 0.05 to about 300 mg/kg body weight per day. In other embodiments, the optimum amount is less than about 200 mg/kg body weight per day. In other embodiments, the optimum amount is from about 1 to about 1000 mg/kg body weight per day, or from about 1 to about 100 mg/kg body weight per day (e.g., about 15 mg/kg body weight per day).

[157] It is contemplated that the pharmaceutical compositions can be in one or more unit dosage forms. Accordingly, the composition may be divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be, for example, a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these in packaged forms. The unit dosage form alternatively can be a packaged preparation in which the package contains discrete quantities of the composition, such as, for example, packeted tablets, capsules, or powders in vials or ampoules. Unit dosage forms may be prepared by, for example, various methods well known in the art of pharmacy.

[158] It is contemplated that a dosage can be given once daily or in divided doses, such as, for example, from 2 to 4 times per day. In some embodiments, the dose is conventionally formulated in an oral dosage form by compounding from about 5 to about 250 mg per unit of dosage with, for example, one or more inert or active ingredients using accepted pharmaceutical practices.

[159] In some embodiments, a compound or salt of this invention is administered concurrently, simultaneously, sequentially, or separately with one or more other pharmaceutically active compounds. In some such embodiments, the other pharmaceutically active compound(s) is/are selected from the following:

(i) Antidepressants, which are contemplated to include, for example, one or more of agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, mirtazeprine, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, ramelteon, reboxetine, robalzotan, selegiline, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(ii) Antipsychotics, which are contemplated to include, for example, one or more of quetiapine and pharmaceutically active isomer(s) and metabolite(s) thereof; and amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, dibenzapine, divalproex, droperidol, duloxetine, eszopiclone, fluphenazine, haloperidol, iloperidone, lamotrigine, lithium, loxapine, mesoridazine, molindone, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, thiothixene, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone, and equivalents thereof.

(iii) Anxiolytics, which are contemplated to include, for example, one or more of alnespirone, azapirones, benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, suriclone, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof, (iv) Anticonvulsants, which are contemplated to include, for example, one or more of carbamazepine, oxcarbazepine, valproate, lamotrogine, gabapentin, topiramate, phenytoin, ethoxuximide, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof, (v) Alzheimer's therapies, which are contemplated to include, for example, donepezil, galantamine, memantine, rivastigmine, tacrine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (vi) Parkinson's therapies and agents for the treatment of extrapyramidal symtpoms, which are contemplated to include, for example, one or more of levodopa, carbidopa, amantadine, pramipexole, ropinirole, pergolide, cabergoline, apomorphine, bromocriptine, MAOB inhibitors (e.g., selegine and rasagiline), COMT inhibitors (e.g., entacapone and tolcapone), alpha-2 inhibitors, anticholinergics (e.g., benztropine, biperiden, orphenadrine, procyclidine, and trihexyphenidyl), dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists, and inhibitors of neuronal nitric oxide synthase, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (vii) Migraine therapies, which are contemplated to include, for example, one or more of almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, and equivalents, and pharmaceutically active isomer(s) and metabolite(s) thereof.

(viii) Stroke therapies, which are contemplated to include, for example, one or more of abciximab, activase, disufenton sodium, citicoline, crobenetine, desmoteplase,repinotan, traxoprodil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (ix) Urinary incontinence therapies, which are contemplated to include, for example, one or more of darafenacin, dicyclomine, falvoxate, imipramine, desipramine, oxybutynin, propiverine, propanthedine, robalzotan, solifenacin, alfazosin, doxazosin, terazosin, tolterodine, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (x) Neuropathic pain therapies, which are contemplated to include, for example, one or more of gabapentin, lidoderm, pregablin, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(xi) Nociceptive pain therapies, which are contemplated to include, for example, one or more of celecoxib, cideine, etoricoxib, fentanyl, hydrocodone, hydromorphone, levo-alpha-acetylmethadol, lumiracoxib, meperidine, methadone, morphine, oxycodone, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol, propoxyphene, sufentanyl, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(xii) Insomnia therapies, which are contemplated to include, for example, one or more of allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, estazolam, eszopicline, ethchlorvynol, etomidate, flurazepam, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, midazolam, nisobamate, pagoclone, pentobarbital, perlapine, phenobarbital, propofol, quazepam, ramelteon, roletamide, suproclone, temazepam, triazolam, triclofos,secobarbital, zaleplon, Zolpidem, zopiclone, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(xiii) Mood stabilizers, which are contemplated to include, for example, one or more of carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof. (^χi^γ) Medications for treating obesity, such as, for example, orlistat, sibutramine, rimonabant, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(xv) Agents for treating ADHD, which are contemplated to include, for example, one or more of amphetamine, methamphetamine, dextroamphetamine, atomoxetine, methylphenidate, dexmethylphenidate, modafmil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

(xvi) Agents used to treat substance abuse disorders, dependence, and withdrawal, which are contemplated to include, for example, one or more of nicotine replacement therapies (e.g., gum, patches, and nasal spray); nicotinergic receptor agonists, partial agonists, and antagonists, (e.g., varenicline); acomprosate; bupropion; clonidine; disulfϊram; methadone; naloxone; naltrexone; and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

[160] In some embodiments, the other pharmaceutically active ingredient(s) comprises a cognitive enhancing agent.

[161] In some embodiments, the other pharmaceutically active ingredient(s) comprises a memory enhancing agent. [162] In some embodiments, the other pharmaceutically active ingredient(s) comprises a choline esterase inhibitor.

[163] In some embodiments, the other pharmaceutically active ingredient(s) comprises anti-inflammatory agent.

[164] In some embodiments, the antipsychotic comprises an atypical antipsychotic agent. Atypical antipsychotic agents include, for example, olanzapine (marketed as Zyprexa), aripiprazole (marketed as Ability), risperidone (marketed as Risperdal), quetiapine (marketed as Seroquel), clozapine (marketed as Clozaril), ziprasidone (marketed as Geodon), and olanzapine/fluoxetine (marketed as Symbyax).

[165] In some embodiments, the other pharmaceutically active ingredient(s) comprises a selective serotonin reuptake inhibitor (or "serotonin-specific reuptake inhibitor" or SSRI"). Such agents include, for example, fluoxetine (marketed as, for example, Prozac), paroxetine (marketed as, for example, Paxil), citalopram (marketed as, for example, Celexa), dapoxetine, mesembrine, excitalopram (marketed as, for example, Lexapro), fluvoxamine (marketed as, for examle, Luvox), zimelidine (marketed as, for example, Zelmid), and sertraline (marketed as, for example, Zoloft).

[166] In some embodiments, a compound or salt of this invention is administered as part of a combination therapy with chemotherapy.

[167] In some embodiments in which a combination therapy is used, the amount of the compound or salt of this invention and the amount of the other pharmaceutically active agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the animal patient. In this context, the combined amounts are "therapeutically effective amount" if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; reduce the risk of the disorder getting worse; or delay or reduce the risk of onset of the disorder. Typically, such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this patent for the compound or salt of this invention and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).

[168] When used in a combination therapy, it is contemplated that the compound or salt of this invention and the other active ingredients may be administered in a single composition, completely separate compositions, or a combination thereof. It also is contemplated that the active ingredients may be administered concurrently, simultaneously, sequentially, or separately. The particular composition(s) and dosing frequency(ies) of the combination therapy will depend on a variety of factors, including, for example, the route of administration, the condition being treated, the species of the patient, any potential interactions between the active ingredients when combined into a single composition, any interactions between the active ingredients when they are administered to the animal patient, and various other factors known to physicians (in the context of human patients), veterinarians (in the context of non-human patients), and others skilled in the art.

[169] In general, compounds of Formula (I) can be prepared in accordance with the following Schemes and the general knowledge of one skilled in the art and/or in accordance with the methods set forth in the Examples that follow. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one skilled in the art. Combinatorial techniques can be employed in the preparation of compounds, for example, where the intermediates possess groups suitable for these techniques.

Scheme 1

Here, R , R , R , and R are as defined above. Step l

[170] A compound in accordance with Formula (III) can be obtained by treating an appropriate amine compound in accordance with Formula (II) with an appropriate acylating agent, such as, for example, di-tert-butyl dicarbonate in an appropriate solvent, such as, for example, THF.

Step 2

[171] A compound in accordance with Formula (IV) can be obtained by treating a compound in accordance with Formula (III) with an appropriate acylating agent, such as, for example, dimethylcarbamoyl chloride in an appropriate solvent, such as, for example, pyridine.

Step 3

[172] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (IV) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Scheme 2

Here, R¹, R², and R⁷ are as defined above; and R¹³ is methyl or ethyl.

Step l

[173] A compound in accordance with Formula (VI) can be obtained by treating an appropriate benzylic halide compound in accordance with Formula (V) with an appropriate alkylating agent, such as, for example, sodium cyanide and an appropriate phase-transfer catalyst, such as, for example, N-benzyl-N,N-diethylethanaminium chloride in an appropriate solvent, such as, for example, chloroform and water. Step 2

[174] A compound in accordance with Formula (VII) can be obtained by treating a compound in accordance with Formula (VI) with an appropriate base, such as, for example, sodium hydride and an appropriate halide, such as, for example, 2-(2-bromoethoxy)tetrahydro-2H-pyran in an appropriate solvent, such as, for example, THF.

Step 3

[175] A compound in accordance with Formula (VIII) can be obtained by treating a compound in accordance with Formula (VII) with an appropriate base, such as, for example, lithium diisopropylamide and an appropriate halide, such as, for example, ethyl 3-bromopropanoate, in an appropriate solvent, such as, for example, THF.

Step 4

[176] A compound in accordance with Formula (IX) can be obtained by treating a compound in accordance with Formula (VIII) with an appropriate hydrogenation catalyst, such as, for example, Raney Nickel 2800 under H₂ at a pressure of, for example, 50 psig in an appropriate solvent, such as, for example, methanol and ammonium hydroxide at elevated temperature of, for example, 55⁰C.

Step 5

[177] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (IX) with an appropriate reducing agent, such as, for example, BH₃ THF in an appropriate solvent, such as, for example, THF. This intermediate was cooled and an appropriate solvent, such as, for example, methanol, was added. Then, an appropriate acid, such as, for example, hydrochloric acid, was added. The reaction may then be heated at an elevated temperature of, for example, 6O⁰C.

Scheme 3

Here, R¹ and R² are as defined above.

Step l [178] A compound in accordance with Formula (X) can be obtained by treating an appropriate alcohol compound in accordance with Formula (III) with an appropriate oxidizing agent, such as, for example, pyridinium dichromate, in an appropriate solvent, such as, for example, DMF.

Step 2 [179] A compound in accordance with Formula (XI) can be obtained by treating a compound in accordance with Formula (X) with an appropriate methylating agent, such as, for example, trimethylsilylchloride, in an appropriate solvent, such as, for example, methanol.

Step 3 [180] A compound in accordance with Formula Formula Formula Formula

FormulaXII can be obtained by treating a compound in accordance with Formula FormulaXI with an appropriate acylating agent, such as, for example, di-tert-butyl dicarbonate, in an appropriate solvent, such as, for example, THF. Step 4

[181] A compound in accordance with Formula (XIII) can be obtained by treating a compound in accordance with Formula (XII) with an appropriate reagent, such as, for example, methyl magnesium bromide in an appropriate solvent, such as, for example, THF.

Step 5

[182] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XIII) with an appropriate acid, such as, for example TFA or HCL in an appropriate solvent, such as, for example, methylene chloride. Scheme 4

Here, R¹ and R² are as defined above.

Step l

[183] A compound in accordance with Formula (Ib) and (Ic) can be obtained by treating an appropriate aromatic halide compound in accordance with Formula (I) with an appropriate reducing agent, such as, for example, lithium aluminum hydride, in an appropriate solvent, such as, for example, THF.

Scheme 5

Here, R¹ and R² are as defined above.

Step l [184] A compound in accordance with Formula (XIV) can be obtained by treating an appropriate alcohol compound in accordance with Formula (III) with an appropriate alkylating agent, such as, for example, methanesulfonyl chloride in the presence of an appropriate base, such as, for example, triethylamine in an appropriate solvent, such as, for example, methylene chloride. Step 2

[185] A compound in accordance with Formula (XV) can be obtained by treating an appropriate mesylate compound in accordance with Formula (XIV) with an appropriate azide, such as, for example, sodium azide in an appropriate solvent, such as, for example, DMSO. Step 3

[186] A compound in accordance with Formula (XVI) can be obtained by treating an appropriate azide compound in accordance with Formula (XV) with an appropriate reducing agent, such as, for example, triphenylphosphine in an appropriate solvent, such as, for example, THF and water. Step 4

[187] A compound in accordance with Formula (XVII) can be obtained by treating a compound in accordance with Formula (XVI) with an appropriate acylating agent, such as, for example, di-tert-butyl dicarbonate in an appropriate solvent, such as, for example, THF.

Step 5

[188] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XVII) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Scheme 6

Here, R¹, R², R⁷ and R⁸ are as defined above.

Step l

[189] A compound in accordance with Formula (XVIII) can be obtained by treating an appropriate mesylate of a compound in accordance with Formula (XIV) with an appropriate alkyl amine, such as, for example, methylamine in an appropriate solvent, such as, for example, THF.

Step 2

[190] A compound in accordance with Formula (XIX) can be obtained by treating an appropriate amine of a compound in accordance with Formula (XVIII) with an appropriate aldehyde, such as, for example, 1,5 -dimethyl- lH-pyrazole-3-carbaldehyde in the presence of a suitable dehydrating agent, such as, for example, sodium triacetoxyborohydride in a suitable solvent such as, for example, 1,2-dichloroethane.

Step 3

[191] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XIX) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride. Scheme 7

Here, R¹, R², R⁷ and R¹² are as defined above.

Step l

[192] A compound in accordance with Formula (XX) can be obtained by treating an appropriate amine of a compound in accordance with Formula (XVII) with an appropriate acylating agent, such as, for example, acetic anhydride in an appropriate solvent, such as, for example, pyridine.

Step 2

[193] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XX) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Scheme 8

Here, R¹, R², R⁷ and R⁹ are as defined above.

Step l

[194] A compound in accordance with Formula (XXI) can be obtained by treating an appropriate amine compound in accordance with Formula (XVII) with an appropriate acylating agent, such as, for example, methanesulfonyl chloride with an appropriate base, such as, for example, triethylamine in an appropriate solvent, such as, for example, 1 ,2-dichloroethane. Step 2

[195] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXI) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Scheme 9

Here, R¹, R² and R⁷ are as defined above.

Step l

[196] A compound in accordance with Formula (XXIII) can be obtained by treating an appropriate acid compound in accordance with Formula (XXII) with an appropriate amine, such as, for example, azetidine in the presence of a suitable dehydrating agent, such as, for example, EDC and a suitable base, such as, for example, diisopropylethylamine in an appropriate solvent, such as, for example, DCM.

Step 2

[197] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXIII) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Scheme 10

Here, R¹ and R² are as defined above.

Step l

[198] A compound in accordance with Formula (XXV) can be obtained by treating an appropriate mesylate compound in accordance with Formula (XXIV) with an appropriate base, such as, for example, sodium t-butoxide, in an appropriate solvent, such as, for example, DMSO.

Step 2

[199] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXV) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Scheme 11

Here, R¹, R² and R⁶ are as defined above.

Step l

[200] A compound in accordance with Formula (XXVI) can be obtained by treating an appropriate mesylate compound in accordance with Formula (XXIV) with an appropriate thiolate, such as, for example, sodium methanethiolate in an appropriate solvent, such as, for example, THF.

Step 2

[201] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXVI) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride. Step 3

[202] A compound in accordance with Formula (XXVII) can be obtained by treating an appropriate thiol compound in accordance with Formula (XXVI) with an appropriate oxidizing agent, such as, for example, m-CPBA in an appropriate solvent, such as, for example, 1,2-dichloroethane.

Step 4

[203] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXVII) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Step 5

[204] A compound in accordance with Formula (XXVIII) can be obtained by treating an appropriate thiol compound in accordance with Formula (XXVI) with an excess of an appropriate oxidizing agent, such as, for example, m-CPBA in an appropriate solvent, such as, for example, 1,2-dichloroethane.

Step 6

[205] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXVIII) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Scheme 12

Here, R¹, R² and R⁷ are as defined above.

Step l

[206] A compound in accordance with Formula (XXIX) can be obtained by treating an appropriate alcohol compound in accordance with Formula (III) with an appropriate alkylating agent, such as, for example, methyl iodide with a suitable base, such as, for example, sodium hydride in an appropriate solvent, such as, for example, THF. Step 2

[207] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXIX) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Scheme 13

Here, R*and R² are as defined above.

Step l

[208] A compound in accordance with Formula (XXX) can be obtained by treating an appropriate mesylate compound in accordance with Formula (XXIV) with an appropriate metal cyanide agent, such as, for example, sodium cyanide, in an appropriate solvent, such as, for example, DMSO.

Step 2

[209] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXX) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Step 3

[210] A compound in accordance with Formula (XXXI) can be obtained by treating an appropriate cyano compound in accordance with Formula (XXX) with an appropriate hydrogenation catalyst, such as, for example, Raney Nickel 2800 under H₂ at a pressure of, for example, 50 psig, in an appropriate solvent, such as, for example, methanol and ammonia in methanol.

Step 4

[211] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXXI) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Scheme 14

Here, R , 1 , r R_> 2 , _π R7 and R are as defined above. Step 1

[212] A compound in accordance with Formula (XXXII) can be obtained by treating an appropriate alkene compound in accordance with Formula (XXV) with an appropriate oxidizing agent, such as, for example, ozone, in an appropriate solvent, such as, for example, DCM. Step 2

[213] A compound in accordance with Formula (XXXIII) can be obtained by treating a compound in accordance with Formula (XXXII) with an appropriate reducing agent, such as, for example, sodium borohydride in an appropriate solvent, such as, for example, ethanol.

Step 3

[214] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXXIII) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Step 4

[215] A compound in accordance with Formula (XXXIV) can be obtained by treating a compound in accordance with Formula (XXXIII) with an appropriate acylating agent, such as, for example, dimethylcarbamoyl chloride in an appropriate solvent, such as, for example, pyridine.

Step 5

[216] A compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXXIV) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.

Scheme 15

Here, R¹² is as defined above.

Step l

[217] A compound in accordance with Formula (XXXVI) can be obtained by treating an appropriate amine compound in accordance with Formula (XXXV) with an appropriate acylating agent, such as, for example, trifluoracetic anhydride, in the presence of an appropriate base, such as, for example, diisopropylethylamine, in an appropriate solvent, such as, for example, DCM.

Step 2

[218] A compound in accordance with Formula (Id) can be obtained by treating an appropriate BOC protected amine compound with Formula (XXXVI) with an appropriate acid, such as, for example, trifluoroacetic acid or hydrochloric acid, in an appropriate solvent, such as, for example, DCM or diethyl ether.

Step 3

[219] A compound in accordance with Formula (Ie) can be obtained by treating an appropriate amide compound in accordance with Formula (Id) with an appropriate reducing agent, such as, for example borane THF complex in an appropriate solvent, such as, for example, THF followed after reaction by an appropriate acidic quench, such as, for example, methanol and aqueous hydrochloric acid.

Scheme 16

Step l

[220] A compound in accordance with Formula (XXXVIII) can be obtained by treating an appropriate alcohol compound in accordance with Formula (XXXVII) with an appropriate oxidizing agent, such as, for example, pyridinium chlorochromate, in an appropriate solvent, such as, for example, DCM.

Step 2

[221] A compound in accordance with Formula (XXXIX) can be obtained by treating an appropriate aldehyde compound in accordance with Formula (XXXVIII) with any of a set of appropriate primary or secondary amines and an appropriate reducing agent, such as, for example, sodium triacetoxyborohydride in an appropriate solvent, such as, for example, 1,2 dichloroethane.

Step 3

[222] A compound in accordance with Formula (I) can be obtained by treating an appropriate BOC protected amine compound in accordance with Formula (XXXIX) with an appropriate acid, such as, for example, trifluoroacetic acid or hydrochloric acid, in an appropriate solvent, such as, for example, DCM or diethyl ether. EXAMPLES

[223] The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples below, but rather defined by the claims appended hereto.

Examples 1-117. Compound Preparation

[224] The compound preparation examples below illustrate the preparation of a variety of different compounds of this invention and intermediates for making such compounds. It is expected that one skilled in the art of organic synthesis, after reading the above compound synthesis discussion and these examples alone or in combination with the general knowledge in the art, can adapt and apply the methods to make any compound encompassed by this invention. The general knowledge in the art includes, for example:

A) Conventional procedures for using protective groups and examples of suitable protective groups, which are described in, for example, Protective Groups in Organic Synthesis, T. W. Green, P. G. M. Wuts, Wiley-Interscience, New York

(1999).

B) References discussing various organic synthesis reactions, include textbooks of organic chemistry, such as, for example, Advanced Organic Chemistry, March 4th ed, McGraw Hill (1992); and Organic Synthesis, Smith, McGraw Hill, (1994). They also include, for example, R.C. Larock, Comprehensive Organic

Transformations, 2nd ed., Wiley- VCH: New York (1999); F.A. Carey; R.J. Sundberg, Advanced Organic Chemistry, 2nd ed., Plenum Press: New York (1984); L. S. Hegedus, Transition Metals in the Synthesis of Complex Organic Molecules, 2nd ed., University Science Books: Mill Valley, CA (1994); L. A. Paquette, Ed., The Encyclopedia of Reagents for Organic Synthesis, John Wiley:

New York (1994); A.R. Katritzky, O. Meth-Cohn, CW. Rees, Eds., Comprehensive Organic Functional Group Transformations, Pergamon Press: Oxford, UK (1995); G. Wilkinson; F. G A. Stone; E. W. Abel, Eds., Comprehensive Organometallic Chemistry, Pergamon Press: Oxford, UK (1982); B.M. Trost; I. Fleming, Comprehensive Organic Synthesis, Pergamon Press: Oxford, UK (1991); A.R. Katritzky, CW. Rees Eds., Comprehensive Heterocyclic Chemistry, Pergamon Press: Oxford, UK (1984); A.R. Katritzky; CW. Rees, E.F.V. Scriven, Eds., Comprehensive Heterocyclic Chemistry II, Pergamon Press: Oxford, UK (1996); C. Hansen; P. G. Sammes; J.B. Taylor, Eds., Comprehensive Medicinal Chemistry:

Pergamon Press: Oxford, UK (1990). In addition, recurring reviews of synthetic methodology and related topics include: Organic Reactions, John Wiley: New York; Organic Syntheses; John Wiley: New York; The Total Synthesis of Natural Products, John Wiley: New York; The Organic Chemistry of Drug Synthesis, John Wiley: New York; Annual Reports in Organic Synthesis, Academic Press: San

Diego CA; and Methoden der Organischen Chemie (Houben-Weyl), Thieme: Stuttgart, Germany.

C) References discussing heterocyclic chemistry include, for example, example, Heterocyclic Chemistry, J.A. Joule, K. Mills, G. F. Smith, 3rd ed., Cheapman and Hall, p. 189-225 (1995); and Heterocyclic Chemistry, TX. Gilchrist, 2^nd ed.

Longman Scientific and Technical, p. 248-282 (1992).

D) Databases of synthetic transformations, including Chemical Abstracts, which may be searched using either CAS Online or SciFinder; and Handbuch der Organischen Chemie (Beilstein), which may be searched using SpotFire. [225] All temperatures are in degrees Celsius (⁰C). Unless otherwise stated, operations were carried out at room or ambient temperature (18-25°C). Unless otherwise stated reaction progress is monitored by HPLC, LC-MS or TLC. Oven-dried standard laboratory glassware is used and routine manipulations were done at ambient temperature under a blanket of nitrogen unless otherwise indicated. Commercially available reagents and anhydrous solvents were typically used as received. Evaporations were typically performed under reduced pressure using a rotary evaporator. Preparative chromatography is performed using ICN silica gel 60, 32-63 μ or a suitable equivalent. Products were dried under reduced pressure at 40⁰C or a suitable temperature.

[226] The names of the compounds exemplified in this patent were generated using AutoNom 2000 within ISIS/Draw. AutoNom (Automatic Nomenclature) is a chemical-name-generating program that assigns systematic IUPAC (International Union of Pure and Applied Chemistry) chemical names to drawn structures at the press of a button. [227] Mass Spectrometer Conditions.

[228] The spectrometer used for a particular LCMS analysis is referred to in the text. All final compounds were analyzed using Methods MSl 'high resolution' mode as described below. Unless otherwise indicated, all m/z ratios are reported as the M+l ion. [229] Mass Spectrometer Method 1 (referred to as "MSl ")

Instrumentation: Agilent TOF 6210 fronted by an Agilent 1200 LC Ionization mode: Electrospray Column: Zorbax SB-C8 2.1x30mm x 1.8um

Mobile phase A: Water:Acetonitrile:Formic acid (98:2:0.1 v/v) Mobile Phase B: Water:Acetonitrile:Formic acid (2:98:0.05 v/v) Gradient: Time in min (%B): 0(5); 1.5(95); 1.9(95); 2(5).

[230] This instrument can be run in both a 'standard' and 'high resolution mode.' The only difference between the 'standard' and 'high resolution' method is the infusion of reference lock mass ions for the 'high resolution' calibration adjustment. All data reported to 5 decimal places was recorded in 'high resolution' mode.

[231] Mass Spectrometer Method IA (referred to as "MSlA ") Instrumentation: Agilent TOF 6210 fronted by an Agilent 1200 LC Ionization mode: Electrospray Column: Zorbax SB-C8 2. lx30mm x 1.8um Mobile phase A: Water:Methanol:Formic acid (98:2:0.1 v/v) Mobile Phase B: Water:Methanol:Formic acid (2:98:0.05 v/v) Gradient: Time in min (%B): 0(5); 1.5(95); 1.9(95); 2(5).

[232] This instrument can be run in both a 'standard' and 'high resolution mode.' The only difference between the 'standard' and 'high resolution' method is the infusion of reference lock mass ions for the 'high resolution' calibration adjustment. All data reported to 5 decimal places was recorded in 'high resolution' mode.

[233] Mass Spectrometer Method 2 (referred to as "MS2 ") Instrumentation: Waters Acquity SQD

Ionization mode: Electrospray Column: Acquity UPLC BEH C 18 2. lx50mm x 1.7um

Mobile phase A: Water:Acetonitrile:Formic acid (98:2:0.1 v/v) Mobile Phase B: Water:Acetonitrile:Formic acid (2:98:0.05 v/v) Gradient: Time in min (%B): 0(5); 0.9(95); 1.2(95); 1.3(5); 1.4(5). [234] Mass Spectrometer Method 3 (referred to as "MS3 ") Instrumentation: Waters ZMD fronted with an Agilent 1100 LC

Ionization mode: APCI

Column: Zorbax SB-C8 2.1x50mm x 5um Mobile phase A: Water:Acetonitrile:Formic acid (98:2:0.1 v/v) Mobile Phase B: Water:Acetonitrile:Formic acid (2:98:0.05 v/v) Gradient: Time in min (%B): 0(5); 3(90); 4(90); 4.5(5); 5(5).

[235] NMR Conditions. [236] At least one of the following two methods was used to determine nuclear magnetic resonance spectrometry: a Varian Unity Inova 400 spectrometer operating at 400 MHz for ¹H equipped with a 5 mm inverse detection triple resonance probe for detection of ¹H, ¹³C, ³¹P with the magnetic field provided by a 9.4 Tesla Oxford instruments super-conducting magnet and Sun Microsystems SunBlade 1000 workstation as host, or, alternatively, a Bruker Avance DPvX 400 or DPX 300 spectrometer operating at 300 mHz, 400 or 500 mHz equipped with a 5 mm inverse detection triple resonance TXI probe for detection of ¹H, ¹³C, ¹⁵N with the magnetic field provided by a 9.4 Tesla Oxford instruments super-conducting magnet and an HP workstation wx5000 operating under Windows XP with the WIN-NMR software as host computer. [237] Chemical shifts are reported in parts-per-million (δ) from a tetramethylsilane internal standard. Chemical shifts are reported using the automatic processing features within ACDLABS V 10.0.

[238] The multiplicities of the NMR spectra absorptions may be abbreviated by: s, singlet; br, broad peak; bs, broad singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet.

[239] General chromatographic methods used for purification.

[240] Method A: Separation using reverse-phase HPLC with gradient elution on a Phenomenex Gemini Cl 8 column (250 x 21.2 mm, 5 micron) as stationary phase and ACN in H₂O (+ 0.1% formic acid) as the mobile phase.

[241] Method B: Elution on silica gel using an isocratic run with either pure organic solvent (such as: CH₂CL₂, EtOAc, ether, etc.) or mixtures of solvents (such as 25% CH₂Cl₂ in Hexane, 10% MeOH in CH₂Cl₂, etc.). [242] Method C: Elution on silica gel using an increasing gradient of polar solvent (such as: MeOH (0-10%) in EtOAc, CH₂Cl₂ (0-50%) in hexane, EtOAc (0-40%) in hexane, etc.).

[243] Method D: Separation using reverse-phase HPLC with gradient elution on a Phenomenex Gemini NX C18 column (15O x 30mm, 5 μm) as stationary phase and ACN gradient in Buffer (pH=9, NH4CO3 in water) as the mobile phase.

[244] Method E: Preparative separation using a Berger SFC equipped with a Chiral Tech IC column (21 x 250 mm) with dual wavelength detector (220 & 254 nm) and 25% MeOH with 0.5% dimethyl ethylamine in CO₂ as eluant. Flow rate was 50-70 ml/min. Purity of collected fractions were determined using an analytical SFC system equipped with diode array and mass spec detector.

[245] Example 1. (S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl dimethylcarbamate.

[246] Further benefits of Applicants' invention will be apparent to one skilled in the art from reading this specification.

[247] Product IA: (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2- hydroxyethyl)piperidine-l-carboxylate.

(S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethanol (2.00 g, 7.29 mmol) was dissolved in THF (50 mL). To this was added di-tert-butyl dicarbonate (7.66 mL, 7.66 mmol) at 25°C. The reaction was stirred under nitrogen for 18 hr. The reaction was concentrated, and then extracted with DCM and NaHCCb solution. It was dried over Na₂SO₄, filtered, concentrated then purified using flash silica gel chromatography with 25% EtOAc/DCM as eluent. (development with UV (weak) and Iodine stain). The pure product IA (2.88 g, 105%) was obtained as a clear gum. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.55 (d, /=2.44 Hz, IH) 7.50 (d, /=8.55 Hz, IH) 7.33 (d, /=8.55 Hz, IH) 4.07 (d, /= 14.04 Hz, IH) 3.89 (d, /=4.27 Hz, IH) 3.53 (dt, /=12.82, 4.88 Hz, IH) 3.12-3.20 (m, 3H) 3.02-3.10 (m, IH) 2.10 (d, /=13.43 Hz, IH) 1.64-1.77 (m, 3H) 1.51 (td, /=9.46, 6.10 Hz, IH) 1.40 (s, 9H) 1.26 (dd, /=9.46, 3.97 Hz, IH). m/z (ES+) (M-tBu)+ = 318.06522; HPLC r, = 1.33 min (MSl).

[248] Product IB: (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2- (dimethylcarbamoyloxy)ethyl)piperidine-l-carboxylate.

To a solution of IA (0.135 g, 0.36 mmol) in pyridine (1 mL) was added dimethylcarbamic chloride (0.332 mL, 3.61 mmol). The resulting mixture was heated to 88 ⁰C overnight. Solvent was evaporated and saturated NaHCO₃ was added. The mixture was extracted with EtOAc (3x). Combined organic layers were dried over Na₂SO₄, filtered, and cone. Purified by flash silica gel ISCO column (12g, 230nm), eluting with 0-20% EtOAc/DCM to give IB (0.115 g, 71.6%) as a colorless oil. m/z (ES+)(M+Na)+ =467, (M-IOO, base) 345; HPLC r, = 1.02min (MS2).

[249] Title compound: (S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl dimethylcarbamate.

To a solution of IB (0.115 g, 0.26 mmol) in EtOAc (1.937 ml) was added HCl (0.646 ml, 2.58 mmol). The solution was stirred at room temperature overnight. Saturated NaHCCb was added and the mixture was extracted with EtOAC (2x). Combined organic layers were dried over Na₂SO₄, filtered, and cone. Purified by flash silica gel ISCO column (4g, 230nm), eluting with 0-10% MeOH/DCM to give title compound (0.069 g, 77%) as a colorless oil. m/z (ES+) (M+ 1)+ =345.11316; HPLC r, = 0.86min (MSl). ¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.4-1.71 (m, 2H) 1.82 (ddd, /=13.33, 9.33, 3.69 Hz, IH) 1.88-2.13 (m, 3H) 2.33 (br. s., IH) 2.63-2.90 (m, 8H) 2.95 (d, /=12.65 Hz, 150H) 3.22 (d, /= 12.65 Hz, IH) 3.76-3.95 (m, 2H) 7.19 (dd, /=8.43, 2.32 Hz, IH) 7.36-7.46 (m, 2H).

[250] Example 2. (S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl methylcarbamate.

[251] Product 2A: (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2- (methylcarbamoyloxy)ethyl)piperidine-l-carboxylate.

To a solution of IA (0.174 g, 0.46 mmol) in dry DCM (2.298 ml) was added Et₃N (0.026 ml, 0.19 mmol) at 0⁰C. The solution was stirred at 0⁰C for 5 min, methyl isocyanate (0.045 g, 0.79 mmol) was added. The solution was stirred at room temperature overnight. Water was added and the mixture was extracted with DCM (2x). Combined organic layers were dried over Na₂SO₄, filtered and cone. Purified by flash silica gel ISCO column (12g, 230nm), eluting with 0-30% EtOAc/DCM to give 2A (0.182 g, 91%) as a white solid. ¹H NMR (300 MHz, CHLOROFORM-J) δ ppm 1.47 (br. s., 9H) 1.59 (d, /=4.64 Hz, IH) 1.68-1.82 (m, IH) 1.89 (t, /=6.22 Hz, 2H) 2.06 (dd, /=3.58, 1.90 Hz, IH) 2.71 (d, /=3.79 Hz, 3H) 3.11-3.36 (m, 2H) 3.55 (ddd, /=2.48, 1.48, 1.32 Hz, IH) 3.66-3.96 (m, 2H) 4.03 (d, /=13.49 Hz, IH) 7.19 (d, /= 8.43 Hz, IH) 7.38 (d, /=8.64 Hz, IH) 7.46 (d, /=1.90 Hz, IH). m/z (ES+) (M+l)+=431; HPLC r, = 0.95 min (MS2).

[252] Title compound: (S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl methylcarbamate.

To the solution of 2A (0.165 g, 0.38 mmol) in EtOAc (3.35 ml) was added HCl (0.478 ml, 1.91 mmol). The solution was then stirred at room temperature overnight. Saturated NaHCO₃ was added and the mixture was extracted with EtOAc (2x). Combined organic layers were dried over Na₂SO₄, filtered, and cone. Purified by flash silica gel ISCO column (4g, 230nm), eluting with 0-10% MeOH/DCM with 1% NH₄OH to give title compound (0.069 g, 54.5%) as a colorless oil. ¹H NMR (300 MHz, CHLOROFORM-J) δ ppm 1.40-1.70 (m, 2H) 1.80 (ddd, /=13.44, 9.33, 3.58 Hz, IH) 1.88-2.11 (m, 4H) 2.71 (d, /=2.74 Hz, 3H) 2.82 (t, = 5.16 Hz, H) 2.93 (d, /=12.65 Hz, IH) 3.22 (d, /=12.86 Hz, IH) 3.71-3.93 (m, 2H) 4.39 (d, /=2.11 Hz, IH) 7.18 (dd, /=8.54, 2.21 Hz, IH) 7.37-7.46 (m, 2H). m/z (ES+) (M+l)+ = 331.09778; HPLC r, = 0.77 min (MSl).

[253] Example 3. 2-(3-(3-chloro-4-fluorophenyl)piperidin-3-yl)ethanol (Racemic).

[254] Product 3A: 2-(3-chloro-4-fluorophenyl)acetonitrile.

Into a 3 neck flask equipped with a magnetic stirrer, a condenser, and an addition funnel was placed water (75 mL) then sodium cyanide(13.16 g, 268.49 mmol), then chloroform (100 mL) and the phase transfer catalyst N-benzyl-N,N-diethylethanaminium chloride (3.06 g, 13.42 mmol). The mixture was stirred vigorously as 4-(bromomethyl)-2-chloro-l- fluorobenzene (30 g, 134.25 mmol) was added dropwise as a chloroform solution over 30 min at 25°C. The mixture was stirred for an additional 3 hr at 25°C, and then the reaction was heated to 45°C for an additional 2 hr. The reaction was cooled, separated into layers and the organic layer washed with 0.5 N NaOH then brine. The chloroform layer was dried over Na₂SO₄, filtered, and concentrated. The aqueous layers were combined and treated with IN NaOH solution and bleach (caution exothermic) before disposal of the cyanide containing waste. The pure 3A (22.05 g, 97%) was obtained as an oil. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.39 (dd, /=6.56, 2.29 Hz, IH) 7.21 (dd, /=4.43, 2.29 Hz, IH) 7.17 (d, /=8.55 Hz, IH) 3.71 (s, 2H). [255] Product 3B: 2-(3-chloro-4-fluorophenyl)-4-(tetrahydro-2H-pyran-2- yloxy)butanenitrile.

Into a IL three-neck flask equipped with condenser, dropping funnel and thermocouple adaptor was placed sodium hydride 60% dispersion in oil (2.476 g, 61.92 mmol). The reaction flask was placed in a water bath to control temperature. Ice was added to maintain temperature under 25°C. To the flask was added THF (200 mL). 3A (10 g, 58.97 mmol) was then added dropwise over 30 min. The mixture was stirred for an additional 2 hr the 2-(2-bromoethoxy)tetrahydro-2H-pyran (13.56 g, 64.86 mmol) was added dropwise over 30 min with similar temperature control. After 18 hr at room temperature, the reaction was quenched with saturated NaHCCb solution and ether was added. The ether layer was washed 2x with NaHCCb solution, then it was dried over K₂CO₃, filtered and concentrated. The crude product was purified by silica gel chromatography using 1 :1 DCM/Hexanes to give 3B (12.88 g, 73.4%) as a liquid. This product is -85% pure. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.43 (ddd,

/=13.89, 6.71, 2.29 Hz, IH) 7.19-7.31 (m, IH) 7.16 (t, /=8.55 Hz, IH) 4.52-4.70 (m, IH) 3.97-4.10 (m, IH) 3.73-3.96 (m, 2H) 3.33-3.63 (m, 2H) 2.02-2.28 (m, 2H) 1.84 (td, /= 7.93, 4.27 Hz, IH) 1.68-1.78 (m, IH) 1.46-1.66 (m, 4H); mix of diastereomers. m/z (ES+) (M+H)+ = 298.10046; HPLC r, = 1.29 min (MSl). [256] Product 3C: Ethyl 4-(3-chloro-4-fluorophenyl)-4-cyano-6-(tetrahydro-

2H-pyran-2-yloxy)hexanoate.

Into a 3 -neck flask equipped with a magnetic stirrer, condenser, addition funnel, and thermocouple adapter was placed 3B (12.88 g, 43.26 mmol). The material was dissolved in THF (300 mL) and the flask was placed in a water bath. LDA mono THF 1.5 M solution in cyclohexane (30.3 mL, 45.42 mmol) was added dropwise over 15 min while maintaining the temperature by addition of ice to the water bath, (mild exotherm observed). After stirring at room temperature for 30 min, the ethyl 3-bromopropanoate (8.22 g, 45.42 mmol) was added dropwise as a THF solution. Again temperature was maintained at 23°C by the addition of ice to the water bath. After addition was complete, the reaction was warmed to 50⁰C with an oil bath. The reaction was cooled then quenched with NaHCO₃ solution. This was poured into EtOAC and the layers were separated. The organic layer was washed with NaHCO₃ and then with brine, then dried over Na₂SO₄, filtered, and concentrated. The crude residue was then purified by silica gel chromatography using 5% EtOAc in DCM as eluent to give 3C (8.14 g, 47.3%) as a liquid. ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.49 (dt, /=6.41, 2.44 Hz, IH) 7.32 (ddd, /=8.55, 4.27, 2.44 Hz, IH) 7.17 (td, /=8.55, 1.83 Hz, IH) 4.46 (ddd, /=9.84, 3.81, 3.43 Hz, IH) 4.08 (dd, /=7.02, 5.19 Hz, 2H) 3.81 (dt, /=10.38, 6.71 Hz, IH) 3.66- 3.75 (m, 2H) 3.43 (ddd, /=10.38, 6.87, 4.12 Hz, 2H) 2.50 (qd, /=7.99, 5.65 Hz, OH) 2.35 (dddd, /=14.19, 7.02, 6.87, 2.14 Hz, 2H) 2.17-2.28 (m, 2H) 2.12 (ddd, /=15.95, 10.91, 4.88 Hz, IH) 1.40-1.79 (m, 6H) 1.22 (t, /=7.17 Hz, 3H); mix of diastereomers. m/z (ES+) (M+H)+ =398.15244; HPLC r, = 1.39 min (MSl).

[257] Product 3D: 5-(3-chloro-4-fluorophenyl)-5-(2-(tetrahydro-2H-pyran-2- yloxy)ethyl)piperidin-2-one.

Into a 500 mL Parr shaker bottle was placed Raney nickel 2800 (7.08 g, 120.64 mmol). The material was washed with water twice and the water decanted. The bottle was placed under N₂ and then ammonium hydroxide cone. (30 ml, 770.42 mmol) was added followed by 3C (8 g, 20.11 mmol) dissolved in EtOH (200 mL). The solution was placed under H₂ (50 psi). The reaction was then heated to 40⁰C with the use of a thermocouple and temperature controller on the Parr shaker overnight. After 18 hr, reaction had only proceeded to about 10% completion by LCMS. New catalyst added. The reaction was resubmitted to the Parr shaker (50 psi H2) for an additional 18 hr at 55°C. The reaction was filtered through Celite^® and the filter cake was washed with EtOH. The EtOH was removed on a rotary evaporator and the residue was extracted with EtOAC and NaHCO₃ solution. The organic layer was dried over Na₂SO₄, filtered, and concentrated. There was 5.1 g of crude material at this point. The residue was then purified by silica gel chromatography using as eluent a gradient of from 1 : 1 EtOAc/DCM to 1 : 1 EtOAC/DCM + 10% MeOH. The pure 3D (4.00 g, 55.9%) was obtained as a foamy solid after chromatography. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.51 (d, /=7.32 Hz, IH) 7.34- 7.42 (m, IH) 7.30 (t, /=8.85 Hz, IH) 7.06-7.18 (m, IH) 4.34 (dt, /=11.60, 3.66 Hz, IH) 3.55-3.68 (m, 2H) 3.28-3.44 (m, 3H) 3.10 (dd, /=10.38, 6.71 Hz, IH) 2.11-2.21 (m, 2H) 1.92-2.09 (m, 2H) 1.78-1.92 (m, /=14.19, 7.32, 7.32, 7.17 Hz, 2H) 1.63 (dd, /=8.55, 4.88 Hz, IH) 1.28-1.57 (m, 5H). Diastereomer mix. m/z (ES+) (M+Na)+ =378.12515; HPLC r, = 1.13 min (MSl). [258] Title compound: 2-(3-(3-chloro-4-fluorophenyl)piperidin-3-yl)ethanol.

3D (4.0 g, 11.24 mmol) was dissolved in THF (100 mL) under N₂ in a 500 mL flask equipped with a condenser and magnetic stirrer. To the stirring solution was added BH₃THF 1.0M in THF (28.1 mL, 28.10 mmol); the reaction was then heated to 70⁰C for 1 hr. The reaction was cooled to 0⁰C in an ice bath, quenched cautiously with 150 mL of MeOH, followed by 80 mL of 6N HCl. After addition was complete and reactivity had ceased, the reaction was heated to 60⁰C in an oil bath for 1 hr. The reaction was cooled and MeOH and THF were removed on a rotary evaporator. MeOH was azeotropically evaporated 2 additional times. The residue was cautiously taken to pH 9 by addition of saturated Na₂CO₃ with cooling. The aqueous layer was then extracted 3x with EtOAc, the organic layer was dried over Na₂SO₄, filtered and concentrated to give 2.8g of crude solid which contains about 15% des chloro compound by NMR. This material was then recrystallized from hot ACN. The 95% pure crystallized title compound (1.540 g, 53.2%) was a colorless powdery solid, m/z (ES+) (M+H)+ =258.10568; HPLC r, = 0.61 min (MSl). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.46 (d, /=7.32 Hz, IH) 7.33 (dd, /=7.93, 3.05 Hz, IH) 7.24 (t, /=8.85 Hz, IH) 3.80 (br. s., IH) 3.13 (t, /=7.32 Hz, 2H) 3.06 (d, /=12.82 Hz, IH) 2.81 (d, /=12.82 Hz, IH) 2.59-2.73 (m, 2H) 1.89 (dd, /=7.63, 4.58 Hz, IH) 1.82 (t, /=7.02 Hz, IH) 1.69-1.79 (m, 3H) 1.42-1.53 (m, / =13.43, 6.71, 3.36, 3.36 Hz, IH) 1.30 (dddd, /=12.67, 8.70, 8.55, 4.27 Hz, IH).

[259] Example 4. 2-(3-(3-chloro-4-fluorophenyl)piperidin-3-yl)ethanol (Isomer 1).

The Example 3 compound (2.5 g, 9.70 mmol) was purified by Prep LC using the Gemini NX column with eluent pH 9.0 (Chromatographic method D) to remove the des chloro impurity. The purified racemate was then resolved into the two enantiomers using prep CSP SFC with the IC column using 25% MeOH with 0.5% DMEA in CO₂ as eluent (Chromatographic method E). Peak 1 (r_t = 6.48 min) of 2-(3-(3-chloro-4- fluorophenyl)piperidin-3-yl)ethanol (1.688 g, 67.5%) is Isomer 1. The SFC analysis of the purified final solid shows that this material was obtained in >98% ee. Peak 2 (r_t = 7.58 min) of 2-(3-(3-chloro-4-fluorophenyl)piperidin-3-yl)ethanol (1.688 g, 67.5%) is Isomer 2 as described in Example 5. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.46 (d, /=6.71 Hz, IH) 7.33 (dd, /=10.99, 2.44 Hz, IH) 7.24 (t, /=8.85 Hz, IH) 3.81 (br. s., IH) 3.13 (t, /=7.32 Hz, 2H) 3.06 (d, /=12.82 Hz, IH) 2.89-2.96 (m, IH) 2.81 (d, /=12.21 Hz, IH) 2.59-2.73 (m, 2H) 1.89 (dd, /=7.93, 3.66 Hz, IH) 1.82 (t, /=7.02 Hz, IH) 1.74 (ddd, /=13.73, 7.32, 7.02 Hz, 2H) 1.49 (dddd, /=13.43, 7.17, 6.87, 3.66 Hz, IH) 1.30 (dddd, /=12.51, 8.54, 4.58, 4.27 Hz, IH). m/z (ES+) (M+H)+ = 258.10587; HPLC r, = 0.57 min (MSl). [260] Example 5. 2-(3-(3-chloro-4-fluorophenyl)piperidin-3-yl)ethanol (Isomer 2).

The Example 3 compound (2.5 g, 9.70 mmol) was purified by Prep LC using the Gemini NX column with eluent pH 9.0 (Chromatographic method D) to remove the des chloro impurity. The purified racemate was then resolved into the two enantiomers using prep CSP SFC with the IC column using 25% MeOH with 0.5% DMEA in CO₂ as eluent (Chromatographic method E). Peak 1 (r_t = 6.48 min) of 2-(3-(3-chloro-4- fluorophenyl)piperidin-3-yl)ethanol (1.688 g, 67.5%) is Isomer 1 as described in Example 4. Peak 2 (r_t = 7.58 min) of 2-(3-(3-chloro-4-fluorophenyl)piperidin-3-yl)ethanol (1.688 g, 67.5%) is Isomer 2. The SFC analysis of the final solid shows that isomer 2 was obtained in >98% ee. m/z (ES+) (M+H)+ =258.10587; HPLC r, = 0.57 min (MSl). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.46 (d, /=6.71 Hz, IH) 7.33 (dd, /=10.99, 2.44 Hz, IH) 7.24 (t, /=8.85 Hz, IH) 3.81 (br. s., IH) 3.13 (t, /=7.32 Hz, 2H) 3.06 (d, /=12.82 Hz, IH) 2.89- 2.96 (m, IH) 2.81 (d, /=12.21 Hz, IH) 2.59 -2.73 (m, 2H) 1.89 (dd, /=7.93, 3.66 Hz, IH) 1.82 (t, /=7.02 Hz, IH) 1.74 (ddd, /=13.73, 7.32, 7.02 Hz, 2H) 1.49 (dddd, /=13.43, 7.17, 6.87, 3.66 Hz, IH) 1.30 (dddd, /=12.51, 8.54, 4.58, 4.27 Hz, IH).

[261] Example 6. (S)-l-(3-(3,4-dichlorophenyl)piperidin-3-yl)-2- methylpropan-2-ol.

[262] Product 6A: (S)-2-(l-(tert-butoxycarbonyl)-3-(3,4- dichlorophenyl)piperidin-3-yl)acetic acid

To a solution of IA (1.000 g, 2.67 mmol) in DMF (15 niL) under nitrogen at 5°C was added PDC (6.03 g, 16.03 mmol) and the mixture stirred 24 hr at room temperature. The reaction mixture was cooled to 0⁰C, diluted with IN HCl and extracted with diethyl ether. Organic extracts were combined, dried (Na₂SO₄), filtered and evaporated to afford 6A (1.000 g, 96%) as a tan solid. This material was used directly in the next reaction without additional purification. ¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.48 (s, 9H) 1.51- 1.69 (m, 2H) 1.82-2.23 (m, 2H) 2.61 (s, 2H) 3.17-3.41 (m, 2H) 3.53-4.12 (m, 2H) 7.06- 7.24 (m, IH) 7.34-7.44 (m, IH) 7.44-7.60 (m, IH). m/z (ES+) (M+H)+ =388; HPLC r, = 0.86 min (MS2).

[263] Product 6B: (S)-methyl 2-(3-(3,4-dichlorophenyl)piperidin-3-yl)acetate.

To a solution of 6A (521 mg, 1.34 mmol) in MeOH (2 mL) under nitrogen at 25°C was added trimethylsilylchloride (0.221 mL, 1.74 mmol). The solution was stirred at 25°C for 24 hr then evaporated to afford 6B (405 mg, 1.34 mmol, 100% yield) as a tan foam solid, m/z (ES+) (M+l)+ = 302; HPLC r, = 0.50 min (MS2). [264] Product 6C: (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2-methoxy-2- oxoethyl)piperidine-l-carboxylate.

To a solution of 6B (405 mg, 1.34 mmol) in DCM (15 niL) at 25°C was added di-tert- butyl dicarbonate (292 mg, 1.34 mmol) and triethylamine (0.186 mL, 1.34 mmol). The mixture was stirred for 4 hr, diluted with EtOAc, washed sequentially with aqueous citric acid (10%) and saturated NaHCC>₃. The organic phase was dried over Na₂SO₄, filtered and evaporated. The residue was purified by flash chromatography on silica gel (25 g) eluting with an increasingly polar gradient of EtOAc in hexanes (10-70%). Product containing fractions were pooled and evaporated to afford 6C (491 mg, 1.22 mmol, 91% yield) as a dense colorless oil. m/z (ES+) (M-tBu)+ =346; HPLC r, = 0.98 min (MS2). ¹H NMR (500 MHz, MeOD) δ ppm 1.45 (br. s., 9H) 1.53-1.67 (m, 2H) 1.73-1.94 (m, IH) 2.13-2.35 (m, IH) 2.51-2.76 (m, 2H) 2.99-3.19 (m, IH) 3.18-3.29 (m, IH) 3.44 (s, 3H) 3.57-3.73 (m, IH) 4.27-4.45 (m, IH) 7.33 (dd, IH) 7.39- 7.52 (m, IH) 7.59 (d, IH). [265] Product 6D: (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2-hydroxy-2- methylpropyl)piperidine-l-carboxylate.

To a solution of 6C (215 mg, 0.53 mmol) in THF (5 mL) under nitrogen at 0⁰C was added methylmagnesium bromide (3M in ether) (0.374 mL, 1.12 mmol) and the mixture stirred for 3 hr. The reaction was quenched with aqueous NH₄Cl and extracted with ether. The organic extracts were combined, dried over Na₂SO₄, filtered and evaporated. The residue was purified by flash chromatography on basic alumina (24g) eluting with a MeOH in DCM gradient (1 to 10%). Product containing fractions were pooled and evaporated to afford 6D (211 mg, 0.52 mmol, 98% yield), m/z (ES+) (M-OtBu)+ =332; HPLC r, = 0.99 min (MS2). ¹H NMR (500 MHz, MeOD) δ ppm 0.80 (s, 3H) 0.94 (s, 3H) 1.19-1.38 (m, IH) 1.47 (br. s., 9H) 1.69-1.88 (m, 2H) 1.89-2.01 (m, IH) 2.04-2.42 (m, IH) 2.74-2.98 (m, IH) 2.97-3.23 (m, 2H) 3.63-3.95 (m, IH) 7.30-7.39 (m, IH) 7.38 (d, IH) 7.39-7.48 (m, IH) 7.65 (d, IH) 7.73- 7.74 (m, IH). [266] Title compound: (S)-l-(3-(3,4-dichlorophenyl)piperidin-3-yl)-2- methylpropan-2-ol.

A solution of 6D (200 mg, 0.50 mmol) in 1 :1 (v/v) CH₂Cl₂: TFA (10 mL) under nitrogen at 0⁰C was stirred for 10 min. The solvent was removed under reduced pressure below room temperature. The residue was suspended in aqueous saturated NaHCO₃ and extracted with EtOAc. The organic extracts were combined, dried over Na₂SO₄, filtered and evaporated. The residue was purified by flash chromatography on basic alumina (24 g) eluting with an increasingly polar gradient of MeOH in DCM (1% to 10% MeOH). Product containing fractions were pooled and evaporated to afford title compound (98 mg, 0.32 mmol, 65.2% yield) as a waxy off-white solid. ¹H NMR (500 MHz, MeOD) δ ppm 0.81 (s, 3H) 0.94 (s, 3H) 1.48 (dddd, IH) 1.69 (ddd, IH) 1.85-2.04 (m, 2H) 2.04- 2.15 (m, IH) 2.60-2.89 (m, 2H) 3.03-3.17 (m, IH) 3.20-3.30 (m, IH) 3.27 (d, IH) 7.35 (dd, IH) 7.47 (d, IH) 7.56 (d, IH). m/z (ES+) (M+H)+ =302.10693; HPLC r, = 0.88 min (MSl). [267] Example 7. (S)-2-(3-(4-chlorophenyl)piperidin-3-yl)ethanol.

[268] To a dry flask under N₂, with stir bar was added LAH in ether (10.94 mL, 10.94 mmol). THF (25 mL) and then MeOH (0.443 mL, 10.94 mmol) were added and gas evolved. After stirring 10 min, a solution of the compound of Example 31 (0.5 g, 1.82 mmol) in THF (15 mL) was added via syringe over 2 min. Some gas evolved, no exotherm. After 0.5 hr, another 27 ml IM LAH in ether was added. The reaction was stirred at room temperature for 2 days and then quenched by slowly adding solid Na₂SO₄-IOH₂O. After 2 hr, 80 ml of ether was added to form a thin slurry that was filtered through a 0.45 μm PTFE filter and washed with ether. After being evaporated, there was a small amount of water in the residue. The residue was redissolved in DCM, dried with MgSO₄, and filtered to obtain -100 mg product. Extracted aluminum salts with 2 to 1 CH₂Cl₂ and MeOH and combined all product fractions, which were dried over MgSO₄, filtered, and evaporated. The residue was dissolved/suspended in CH₂Cl₂ and filtered through 0.45 μm PTFE filter. The filtrate was evaporated to yield 200 mg semi-solid. This material was purified using preparative reverse phase HPLC (Chromatographic method D) to yield title compound (r, = 9.20 min, 18 mg, 4% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.35 (4H, d), 4.02-4.29 (IH, m), 2.95-3.12 (3H, m), 2.75-2.83 (IH, m), 2.54-2.73 (2H, m), 1.78-1.95 (2H, m), 1.65-1.78 (2H, m), 1.41-1.54 (IH, m), 1.27 (IH, m). m/z (ES+) (M+H)+= 240.1388; HPLC r, = 0.55 min (MSl).

[269] It is contemplated that (S)-2-(3-(4-chlorophenyl)piperidin-3-yl)ethanol also can be prepared in a manner analogous to that reported for the dichloro derivative in Example 31 below using the method generally described in Patent No. EP591040B1. It is further contemplated that the enantiomers in that method can be separated by fractional crystallization of diastereomeric salts or preparative chiral stationary phase supercritical fluid chromatography (CSP SFC). [270] Example 8. (S)-2-(3-(3-chlorophenyl)piperidin-3-yl)ethanol.

[271] The title compound was also obtained from the preparative reverse phase HPLC (Chromatographic method D) column purification of Example 7 (r_t = 8.25 min, 14 mg, 3% yield). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.12-7.45 (4H, m), 3.97-4.32 (IH, m), 2.97-3.09 (3H, m), 2.74- 2.83 (IH, m), 2.55-2.72 (2H, m), 1.79-1.95 (2H, m), 1.65- 1.77 (2H, m), 1.39-1.53 (IH, m). m/z (ES+) (M+H)+ =240.1387; HPLC r, = 0.47 min (MSl).

[272] Example 9. (S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethanamine.

[273] Product 9A: (S)-tert-butyl-3-(3,4-dichlorophenyl)-3-(2- (methylsulf onyloxy)ethyl)piperidine- 1 -carboxylate.

IA (1.44 g, 3.85 mmol) was dissolved in CH₂Cl₂ (100 mL). Then triethylamine (0.590 mL, 4.23 mmol) was added. To the stirring mixture was then added CHsSO₂Cl (0.328 mL, 4.23 mmol) in a dropwise fashion. After addition was complete the reaction was stirred at 25°C for 5 hr. The reaction was then poured into a separatory funnel, extracted with dilute HCl solution, NaHCO₃ solution, and then brine. The organic layer was then dried over Na₂SO₄, filtered, and then concentrated to obtain 9A (1.720 g, 99%) as a foamy gum. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.60 (d, /=2.44 Hz, IH) 7.54 (d, /=8.54 Hz, IH) 7.37 (dd, /=8.54, 2.44 Hz, IH) 4.04 (d, /=13.43 Hz, IH) 3.93 (td, /=6.87, 3.97 Hz, 2H) 3.49 (t, /=5.19 Hz, IH) 3.25 (d, /=14.04 Hz, IH) 3.11 (dd, /=13.12, 5.80 Hz, IH) 2.98 (s, 3H) 2.13 (d, /=13.43 Hz, IH) 2.00 (td, /=6.87, 2.75 Hz, 2H) 1.77 (ddd, /=13.73, 10.07, 3.66 Hz, IH) 1.54 (d, /=9.77 Hz, IH) 1.40 (s, 9H) 1.30 (dt, /=13.43, 3.97 Hz, IH). m/z (ES+)(M-tBu+H)+ =396.04340; HPLC r, = 1.41 min (MSl).

[274] Product 9B: (S)-tert-butyl 3-(2-azidoethyl)-3-(3,4- dichlorophenyl)piperidine-l-carboxylate.

9A (0.711 g, 1.57 mmol) was dissolved in dry DMSO (10 rnL). To this was added sodium azide (0.307 g, 4.71 mmol). The reaction was then heated using an oil bath under inert atmosphere at 45°C for 18 hr. The reaction was cooled and diluted with water and ether. The ether was extracted with NaHCO₃ solution, dried over Na₂SO₄, filtered, and concentrated to give 9B (0.610 g, 97%) as a gum. The material was taken to the azide reduction step without any further purification, m/z (ES+) (M-tBu+H)+ =343.07129; HPLC r, = 1.57 min (MSl).

[275] Product 9C: (S)-tert-butyl 3-(2-aminoethyl)-3-(3,4- dichlorophenyl)piperidine-l-carboxylate.

[276] 9B (610 mg, 1.53 mmol) was dissolved in THF (10 mL) to which water (1.00 mL) was added. To this was then added triphenylphosphine (801 mg, 3.06 mmol). The reaction was allowed to stir at 25°C for 3 hr. The THF (10 mL) was evaporated and the the residue dissolved in ether. The ether layer was washed with NaHCO₃ solution, and the product amine was extracted into the aqueous layer by washing the ether 3x with 0.05N HCl solution. The ether layer was discarded and the acidic aqueous fraction made basic (pH 9) with Na₂CO₃ solution. This fraction was then extracted with ether. The ether was dried over Na₂SO₄, filtered, and concentrated to give 407 mg of crude product that contained small amounts OfPH₃P and Ph₃PO. 9C (407 mg, 71.4%) was used without further purification, m/z (ES+) (M+H)+ = 373.14359; HPLC r, = 1.07 min (MSl). [277] Alternatively, 9B (887 mg, 2.22 mmol) was dissolved in THF (20 mL) to which water (2.00 mL) was added. To this was then added triphenylphosphine (1165 mg, 4.44 mmol). The reaction was allowed to stir at 25°C for 3 hr. At this time LCMS showed that all the azido compound was consumed and that the product amino compound had appeared. The THF (20 mL) and water (2.00 mL) was evaporated and dried under high vacuum to give crude product contaminated with PH₃P and with Ph₃PO. The crude 9C was purified by silica gel chromatography using an eluent with a gradient of 1 : 1 EA/DCM to 1 : 1 EA/DCM with 20% MeOH containing NH₃, to give pure amino product 9C after concentration as a foam (809 mg, 98%). m/z (ES+) (M+H)+ =373.14359; HPLC r, = 1.07 min (MSl). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.48 - 7.56 (m, 2H) 7.32 (dd, /=8.55, 2.44 Hz, IH) 3.99 (d, /=13.43 Hz, IH) 3.50 (dt, /=12.82, 4.88 Hz, IH) 3.18 (d, /=13.43 Hz, IH) 3.09 (ddd, /=12.97, 9.61, 3.66 Hz, IH) 2.92 (br. s., 2H) 2.19 - 2.34 (m, /=15.72, 15.72, 6.10, 5.80 Hz, 2H) 2.08 (d, /=13.43 Hz, IH) 1.70 (ddd, /=13.73, 10.38, 3.36 Hz, IH) 1.62 (ddd, /=12.67, 9.61, 6.41 Hz, 2H) 1.52 (dd, /=10.07, 3.97 Hz, IH) 1.40 (s, 9H) 1.27 (dd, /=9.46, 3.97 Hz, IH). [278] Product 9D: (S)-tert-butyl 3-(2-(tert-butoxycarbonylamino)ethyl)-3-

(3,4-dichlorophenyl)piperidine-l-carboxylate.

9C (150 mg, 0.40 mmol) was dissolved in DCM (20 mL) then BOC-anhydride 1.0 M solution in THF (0.402 mL, 0.40 mmol) was added. The solution was stirred for 2 hr. The reaction was concentrated then chromatographed on silica gel using 30% EtOAc in

Hexanes as eluent. After concentration, the pure 9D (185 mg, 97%) was obtained as a foam, m/z (ES+) (M+Na)+ =495.17807; HPLC r, = 1.57 min (MSl). ¹H NMR (500 MHz, DMSO-dβ) δ ppm 7.54 (d, /=2.44 Hz, IH) 7.51 (d, /=8.55 Hz, IH) 7.32 (dd, /=8.55, 2.44 Hz, IH) 6.06 (d, /=3.05 Hz, IH) 3.90 (d, /=14.04 Hz, IH) 3.42-3.49 (m, IH) 3.22 (d, /=13.43 Hz, IH) 3.14 (ddd, /=12.67, 8.70, 3.66 Hz, IH) 2.61-2.68 (m, 2H) 2.08 (dd, /=5.19, 2.75 Hz, IH) 1.61-1.79 (m, 3H) 1.54 (dd, /=6.71, 3.66 Hz, IH) 1.40 (s, 9H) 1.32 (s, 9H) 1.28 (ddd, /=9.31, 4.88, 4.73 Hz, IH).

[279] Title compound: (S)-2-(3-(3,4-dichlorophenyl)piperidin-3- yl)ethanamine dihydrochloride.

9D (185 mg, 0.39 mmol) was dissolved in DCM (25.00 mL). HCl 1.0 M solution in ether (4.75 mL, 156.31 mmol) was added and the mixture allowed to stand overnight. The reaction was then concentrated to a crude solid and triturated with ether to give title compound (132 mg, 98%) as a pure solid di-HCl salt, m/z (ES+) (M+H)+ =273.09241; HPLC r, = 0.14min (MSl). ¹H NMR (500 MHz, DMSO-Cl₆) δ ppm 7.66-8.02 (m, 2H) 7.64 (d, /=2.44 Hz, IH) 7.61 (d, /= 8.55 Hz, IH) 7.40 (dd, /=8.55, 2.44 Hz, IH) 3.52 (d, /=13.43 Hz, IH) 3.35 (d, /=13.43 Hz, IH) 2.41-2.53 (m, 2H) 2.14 (dd, /=13.43, 4.27 Hz, 2H) 1.99 (dd, /=11.29, 5.80 Hz, IH) 1.78-1.93 (m, 2H) 1.66 (dq, /=18.54, 3.99 Hz, IH).

[280] Example 10. (S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)- 2,2,2-trifluoroacetamide

[281] Product 1OA: (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2-(2,2,2- trifluoroacetamido)ethyl)piperidine-l-carboxylate.

9C (777 mg, 2.08 mmol) was dissolved in DCM (25 niL) then triethylamine (0.725 niL, 5.20 mmol) was added. TFA anhydride (0.353 mL, 2.50 mmol) was then added dropwise over 10 min to the stirring mixture. The reaction was allowed to stir for 2 hr. At the end of this time the reaction was extracted with NaHCO₃ solution, the organic layer was dried over Na₂SO₄, filtered and concentrated. The crude product was purified using silica gel chromatography with 10% ether in DCM as eluent (development with UV (weak) and Iodine stain.) After concentrating and drying the product, 1OA (807 mg, 83%), was obtained as a foamy solid, m/z (ES+) (M-tbu)+= 413.06461; HPLC r, = 1.47 min (MSl). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.82 (br. s., IH) 7.53 (d, /=8.55 Hz, 2H) 7.34 (dd, /=8.55, 2.44 Hz, IH) 3.90 (d, /=13.43 Hz, IH) 3.43 (t, /=4.88 Hz, IH) 3.27 (d, /=13.43 Hz, IH) 3.18 (td, /=8.55, 4.27 Hz, IH) 2.88 - 2.97 (m, 2H) 2.08 (dd, /=6.10, 3.66 Hz, IH) 1.71 - 1.89 (m, 3H) 1.54 (td, /=7.02, 3.66 Hz, IH) 1.40 (s, 9H) 1.32 (dd, /=9.16, 4.27 Hz, IH).

[282] Title compound: (S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)- 2,2,2-trifluoroacetamide.

1OA (805 mg, 1.72 mmol) was dissolved in DCM (5 mL) then TFA (5.00 mL) was added. The reaction was allowed to stand at 25°C for 3 hr. The reaction was complete at the end of this time by LCMS analysis. The mixture was concentrated then redissolved in DCM and washed with 0.5N NaOH. The organic layer was dried over Na₂SO₄, filtered and concentrated to give title compound (616 mg, 97%) as a colorless solid after drying under high vacuum, m/z (ES+) (M+H)+ = 369.07462 ; HPLC r, = 0.86 min (MSl). ¹H NMR (500 MHz, DMSO-dβ) δ ppm 8.81 (br. s., IH) 7.50 (d, /=8.55 Hz, 2H) 7.35 (d, /=8.55 Hz, IH) 3.04 (d, /=12.21 Hz, IH) 2.86-2.90 (m, 2H) 2.83 (d, /=12.21 Hz, IH) 2.71 (dt, /=7.94, 3.97 Hz, IH) 2.64 (ddd, /=11.44, 7.17, 3.97 Hz, IH) 2.06-2.23 (br. S., IH) 1.94 (ddd, /=19.99, 13.89, 8.85 Hz, 2H) 1.83 (dd, /=9.16, 6.10 Hz, IH) 1.76 (ddd, /=13.43, 8.85, 4.58 Hz, IH) 1.45-1.56 (m, IH) 1.33 (ddd, /=12.97, 8.70, 3.97 Hz, IH).

[283] Example 11. (S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)- 2,2,2-trifluoroethanamine di-hydrochloride.

1OA (615 mg, 1.67 mmol) was dissolved in THF (40 mL) then borane THF complex, 1.0 M in THF (33.3 mL, 33.31 mmol) was added. The reaction was heated to reflux for 3 days in an oil bath at 80⁰C. At the end of this time the reaction was cautiously quenched with MeOH followed by IN HCl in ether solution. The residue was concentrated to the crude HCl salt. The residue was dissolved in DCM, washed with IN NaOH, filtered and concentrated. The residue was purified by chromatography using 5% MeOH with NH3 in DCM to give title compound after concentration (518 mg, 88%) as a clear oil. The product was converted to the solid di-HCl salt by redissolving in ether, adding IN HCl in ether, then collecting and drying the solids obtained, m/z (ES+) (M+H)+ = 355.09494 ; HPLC r, = 0.73 min (MSl). ¹H NMR (500 MHz, MeOD) δ ppm 7.60-7.70 (m, 2H) 7.42 (dd, /=8.55, 2.44 Hz, IH) 3.87 (q, / =8.95 Hz, 2H) 3.74 (d, /=13.43 Hz, IH) 3.45 (d, /=13.43 Hz, IH) 3.12-3.26 (m, 2H) 2.96 (td, /=12.06, 5.19 Hz, IH) 2.73 (td, /=11.90, 5.49 Hz, IH) 2.40 (dd, /=12.21, 4.88 Hz, IH) 2.18 (td, /=10.99, 4.88 Hz, 2H) 2.00 (dd, /=12.82, 7.32 Hz, 2H) 1.83 (dd, /=9.16, 4.88 Hz, IH).

Intermediates 12A-30B

[284] The following examples illustrate the preparation of various intermediates used in Examples 12-30 below. These intermediates were prepared in accordance with the following General Methods: [285] Method A (General Procedure).

[286] A solution of 9A (1 equiv.) in solvent (CH₂Cl₂, THF, DMSO) was treated with an appropriate amine, sulfonyl chloride, thiolate or cyanide (amine- up to 20 equiv. for commercial amines, thiolate- up to 10 equiv., sulfonyl chloride- up to 1.5 equiv., cyanide -up to 5 equiv.) and heated (RT to reflux) in a sealed apparatus (for volatile amines) for 5-96 hr. The usual work-up consisted of cooling the reaction to room temperature, removing solvent under vacuum, residue was taken up in ether or EtOAc and NaHCO₃ solution and the layers were separated. Cyanide reactions were also washed with bleach. The organic layer was dried over Na₂SO₄, filtered and concentrated to give crude product, which was purified using flash silica gel chromatography.

[287] Method B (General procedure).

[288] To a solution of 9C (1 equiv.) in pyridine (10-20 equiv.) was added an appropriate acylating agent (Acetic anhydride, etc.) (5-10 equiv.). The reaction was stirred at room temperature for 2-24 hr. The reaction was quenched with water, concentrated, then extracted with EtOAc, washed 2x with 0.5N HCl, NaHCO₃, and brine. The organic residues were concentrated, and then purified by silica gel chromatography.

[289] Method C (General procedure).

[290] To a solution of 13A (1 equiv.) in CH₂Cl₂ containing a base (such as Et₃N, DIPEA, 0-2 equiv.) was added an appropriate acylating agent (t-Boc anhydride, CH₃SO₂Cl etc.) (1-1.5 equiv.). The reaction was stirred at room temperature for 2-24 hr. The reaction was concentrated, then extracted with EtOAc, washed 2x with 0.5N HCl, NaHCO₃, and brine. The organic residues were concentrated and then purified by silica gel chromatography.

[291] Method D(General procedure). [292] 6A (1 equiv.) was dissolved in solvent (CH₂Cl₂, THF or DMF). An appropriate amine (1-6 equiv.) (methylamine, azetidine, etc.) was added, followed by an amide coupling reagent (EDC or TBTU, 1.5 equiv.) and Hunig's Base (2.0 equiv.). The reaction was stirred at 25°C for 3-18 hr. At the end of this time, the reaction was taken up in EtOAc and was washed 2x with 0.05N HCl solution, followed by NaHCO₃ solution then brine. The organic extracts were then dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel chromatography.

[293] Method E (General procedure).

[294] 9A (2.26 g, 5.00 mmol) was dissolved in DMSO (5 mL) and sodium tert- butoxide (1.440 g, 14.99 mmol) added to the solution. The reaction was stirred at 25°C for 3 hr. The reaction was diluted with water, extracted with EtOAc, and then washed with water. The organic layer was dried over Na₂SO₄, filtered and concentrated to give 17A (1.780 g, 100%) as a clear oil.

[295] Method F (General procedure). [296] 18A (1 equiv.) was dissolved in DCM and cooled to 0⁰C. To this was added solid NaHCO3 (95 mg, 1.13 mmol) and then the mixture was stirred vigorously, m- CPBA (1.05 for sulfoxide, up to 6 equiv. for sulfone) was added as a DCM suspension to the stirring mixture over 5 min. After the mixture stirred for 1 hr, analysis revealed a mixture of mostly sulfoxide and sulfone had formed. The reaction was poured into water and the organic layer washed 2x with NaHCO3 solution. The organic layer was dried over Na₂SO₄, filtered and concentrated. Flash silica gel chromatography gave three pure products as foamy solids. Typical product distribution for sulfoxide formation after flash silica gel chromatography was sulfoxide (major component 50-75%), sulfone (minor product 15-30%) and small amount of sulfide (5-10%). Typical product distribution for sulfone formation was > 90%.

[297] Method G (General procedure).

[298] IA (1 equiv.) was dissolved in THF. NaH (60% disp. in oil, 1.2 equiv.) was added to the solution at 0⁰C. After 10 min, methyl iodide (1.2-5 equiv.) was added to the reaction and the mixture was heated to 35-55°C for 4-18 hr. The reaction was cooled in an ice bath, quenched with NaHCO₃ solution, and THF evaporated. The residue was dissolved in EtOAc and the layers separated. The organic layer was washed with NaHCO₃ solution, then brine, followed by drying over Na₂SO₄, filtration and concentration. The crude product was purified by silica gel chromatography. [299] Method H (General procedure). [300] To a solution of 24C (1 equiv.) in dry CH₂Cl₂ was added Et₃N (0.4 equiv.) at 0⁰C. The solution was stirred at 0⁰C for 5 min, and then methyl isocyanate (1.7 equiv.) was added. The solution was stirred at room temperature overnight. Water was added and the mixture extracted with CH₂Cl₂ (2x). Combined organic layers were dried over Na₂SO₄, filtered and cone. Residue was purified by flash silica gel chromatography. [301] Method I (General procedure).

[302] To a solution of 3OA (1 equiv.) in MeOH and ammonia in MeOH (50 equiv.) was added Raney®-Nickel (50% by weight) and hydrogenated under 50 psig for 5 hr. Filtered off catalyst and evaporated. Purified using flash silica gel chromatography. [303] Intermediate 26C. (3S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2- (methylsulfinyl)methyl)piperidine-l-carboxylate

26B (158 mg, 0.39 mmol) was dissolved in DCM (50 mL) at 25°C. To this was added a solution of 3-(4-nitrophenyl)-2-(phenylsulfonyl)-l ,2-oxaziridine, which was prepared in accordance with J. Org. Chem., 1982, 47 (9) 1774-1775 (120 mg, 0.39 mmol) in DCM. The mixture was then stirred vigorously. After 1 hr, the reaction was quenched with a drop of dimethysulfide then poured into water and the organic layer was washed with NaHCO3 solution and sodium thiosulfate solution. The organic layer was dried over Na₂SO₄, filtered and concentrated. Flash silica gel chromatography using a gradient of 1 :1 EA/DCM to 10% MeOH 1 : 1 EA/DCM gave 26C (154 mg, 94%) as a possible unknown mixture of stereoisomers at the sulfoxide chiral center as a foamy solid. Physical data is set forth in Table 1.

Examples 12-23

[304] The following Table 2 below shows various compounds that were prepared by the general route illustrated in Examples 1-9. Table 2 also provides the intermediate from Table 1 that was used to prepare each compound. Yields in the reactions varied from approximately 20-80%.

[305] Example 24. (S)-(3-(3,4-dichlorophenyl)piperidin-3-yl)methyl dimethylcarbamate.

[306] Product 24A: (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-vinylpiperidine-l- carboxylate.

9A (2.26 g, 5.00 mmol) was dissolved in DMSO (5 niL) then sodium tert-butoxide (1.440 g, 14.99 mmol) was added to the solution. The reaction was then stirred at 25°C for 3 hr. The reaction was quenched with water, washed with EtOAc then extracted with water (slow due to emulsion formation). The organic layer was dried over Na₂SO₄, filtered and concentrated to give 24A (1.780 g, 100%) as a clear oil. m/z (ES+) (M-tBu)+= 300.05569; HPLC r, = 1.56 min (MSl). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.45-7.60 (m, 2H) 7.32 (d, /=8.55 Hz, IH) 5.84 (dd, /=17.09, 10.99 Hz, IH) 5.12 (d, /=10.99 Hz, IH) 4.97 (d, /=17.70 Hz, IH) 3.81 (d, /=13.43 Hz, IH) 3.47 (d, /=13.43 Hz, IH) 3.34-3.42 (m, IH) 3.26 (dd, /= 12.51, 4.58 Hz, IH) 2.13 (dd, /=6.71, 3.66 Hz, IH) 1.87 (dd, /=9.16, 3.66 Hz, IH) 1.56 (dt, /=10.38, 3.05 Hz, IH) 1.40 (s, 9H) 1.26 (br. s., IH). [307] Product 24B: (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-formylpiperidine- 1-carboxylate.

24A (1.69 g, 4.74 mmol) was placed in a 250 mL flask and dissolved in DCM (75 niL). The reaction was placed under nitrogen with stirring and then cooled to -78 ⁰C using a dry ice acetone bath. Ozone (0.250 g, 5.22 mmol) was bubbled through the solution until a blue color persisted. The reaction was purged with nitrogen and the resulting ozonides formed from addition to the alkene were quenched with dimethyl sulfide (3.51 mL, 47.43 mmol). The reaction was allowed to warm to room temperature and then concentrated to give crude 24B (1.71O g, 101%). The crude product was carried forward to the aldehyde reduction without further purification, m/z (ES+) (M-tBu)+ = 302.03348; HPLC r_t = 1.44 min (MSl). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.51 (s, IH) 7.61 (d, /=8.55 Hz, IH) 7.56 (d, /=2.44 Hz, IH) 7.33 (dd, /=8.55, 2.44 Hz, IH) 4.01 (d, /=14.04 Hz, IH) 3.79 (d, /=13.43 Hz, IH) 3.39 (dd, / =6.71, 4.27 Hz, IH) 3.26 (td, /=8.55, 3.66 Hz, IH) 2.22 (td, /=8.70, 3.97 Hz, IH) 2.06 (ddd, /=13.28, 8.70, 4.27 Hz, IH) 1.55 (ddd, /=12.97, 8.70, 4.58 Hz, IH) 1.46-1.51 (m, IH) 1.40 (s, 9H).

[308] Product 24C: (S)-tert-butyl 3-(3,4-dichlorophenyl)-3- (hydroxymethyl)piperidine- 1 -carboxylate.

The crude 24B (1.71 g, 4.77 mmol) was dissolved in EtOH (75 mL) and then cooled to 0⁰C on an ice bath. When the solution had reached temperature, solid NaBH₄ (0.181 g, 4.77 mmol) was added and the solution stirred for 30 min. The reaction was quenched with 0.5 rnL of acetone, and allowed to warm to room temperature. Most of the EtOH was removed on the rotary evaporator. The product was redissolved in EtOAc and partitioned between EtOAc and NaHCθ₃ solution. The organic layer was dried over Na₂SO₄, filtered and concentrated yielding a white solid. Trituration with DCM/Hexanes followed by collection of the solids by filtration and washing with hexanes gave pure 24C (1.260 g, 73.3%) as a powdery white solid, m/z (ES+) (M-tBu)+ =304.04987; HPLC r, = 1.33 min (MSl). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.59 (s, IH) 7.49 (d, /=8.55 Hz, IH) 7.35 (dd, /=8.55, 2.44 Hz, IH) 4.33 (br. s., IH) 4.13 (d, /=12.82 Hz, IH) 3.61 (ddd, /=12.97, 4.88, 4.73 Hz, IH) 3.40 (t, /=6.10 Hz, 2H) 3.13 (d, /=14.04 Hz, IH) 2.95-3.02 (m, IH) 2.01 (dd, /=5.80, 2.75 Hz, IH) 1.74 (d, /=3.66 Hz, IH) 1.51 (td, /=9.46, 4.27 Hz, IH) 1.40 (s, 9H) 1.22 - 1.30 (m, IH).

[309] Product 24D: (S)-tert-butyl 3-(3,4-dichlorophenyl)-3- ((dimethylcarbamoyloxy)methyl)piperidine-l-carboxylate.

To a solution of 24C (0.086 g, 0.24 mmol) in pyridine (1 mL) was added dimethylcarbamic chloride (0.220 mL, 2.39 mmol). The solution was heated at 92 ⁰C overnight. Solvent was evaporated and saturated NaHCO₃ was added. The mixture was extracted with EtOAc (3x). Combined organic layers were dried over Na₂SO₄, filtered and cone, to give 24D (0.089 g, 86%) as a yellow oil, which was carried to the next step without purification, m/z (ES+) (M+Na)+= 453; HPLC r, = l.OOmin (MS2). [310] Product 24E: (S)-(3-(3,4-dichlorophenyl)piperidin-3-yl)methyl dimethylcarbamate.

To a solution of 24D (0.089 g, 0.21 mmol) in EtOAc (1.547 ml) was added HCl (0.516 ml, 2.06 mmol). The solution was stirred at room temperature overnight. Saturated NaHCO₃ was added and the mixture was extracted with EtOAc (2x). Combined organic layers were dried over Na₂SO₄, filtered, cone, and purified by ISCO silica gel column (4g, 230nm), eluting with 0-10% MeOH/DCM to give 24E (0.036 g, 52.7%) as a light yellow oil. m/z (ES+) (M+l)+ = 331.09790; HPLC r, = 0.85 min (MSl). ¹H NMR (300 MHz, CHLOROFORM-J) δ ppm 1.43-1.72 (m, 2H) 1.80-1.92 (m, IH) 1.97-2.09 (m, IH) 2.23 (br. s., 2H) 2.71-2.91 (m, 7H) 3.05 (d, /=12.86 Hz, IH) 3.30 (d, /=12.86 Hz, IH) 4.04- 4.11 (m, IH) 4.17-4.24 (m, IH) 7.23 (dd, /=8.54, 2.21 Hz, IH) 7.41 (d, /=8.43 Hz, IH) 7.49 (d, /=2.32 Hz, IH).

Examples 25-30

[311] The following Table 3 below shows various compounds that were prepared by the general route illustrated in Examples 1-9 and 24. Table 3 also provides the intermediate from Table 1 that was used to prepare each compound.

[312] Example 31. (S)-(-)-2-(3-(3,4-dichloro-phenyl)-piperidine-3-yl)ethanol.

This compound was prepared according to the method described in Patent No. EP591040B1. m/z (ES+) (M+l)+ =274.07529; HPLC r, = 0.69 min (MSl). [a]_D= -8.7° (C=I, MeOH). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.53 (d, /=2.44 Hz, IH) 7.48 (d, /=8.55 Hz, IH) 7.33 (d, /=8.55 Hz, IH) 3.14 (t, /=7.32 Hz, 2H) 3.08 (d, /=12.82 Hz, IH) 2.92 (s, 2H) 2.80 (d, /= 12.21 Hz, IH) 2.66 (dq, /=11.60, 11.39 Hz, 2H) 1.91 (dd, /=11.90, 3.97 Hz, IH) 1.81 (t, /= 7.02 Hz, IH) 1.68-1.77 (m, 2H) 1.43-1.54 (m, /=13.43, 9.77, 3.66, 3.66 Hz, IH) 1.29 (dddd, /=12.82, 8.85, 4.58, 4.27 Hz, IH).

[313] Example 32. (S)-3-(2-(3-(3,4-dichlorophenyl)piperidin-3- yl)ethylamino)propanenitrile citrate salt.

[314] Product 32A: (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2- oxoethyl)piperidine-l-carboxylate.

IA (3.35 g, 8.95 mmol) was dissolved in a small amount of DCM. This solution was then added over 10 min to a stirring mixture of 32 g of silica gel and PCC (5.79 g, 26.85 mmol) suspended in DCM (400 mL). The reaction was then allowed to stir for 18 hr. At the end of this time the reaction was complete by LCMS. The reaction was diluted with Et₂O then filtered through a pad of celite. The filter cake was washed with Et₂O. The filtrate was concentrated and the residue was chromatographed on silica gel using 5% EtOAC in DCM as eluent. The desired fractions were dried under high vacuum to give 56A (3.03 g, 91%) as a clear oil. m/z (ES+) (M-tbu)+ = 316.05002 ; HPLC r, = 0.73 min (MSl). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.45 (t, /=2.29 Hz, IH) 7.49-7.66 (m, 2H) 7.39 (dd, /=8.55, 2.44 Hz, IH) 4.00 (d, /=13.43 Hz, IH) 3.44 (d, /=13.43 Hz, 2H) 3.23 (td, /=8.62, 4.12 Hz, IH) 2.70 (dd, /=17.40, 2.44 Hz, 2H) 2.09 - 2.18 (m, IH) 1.87 (ddd, /=13.58, 9.46, 3.81 Hz, IH) 1.56 (dd, /=7.02, 3.36 Hz, IH) 1.40 (s, 9H) 1.36 (td, /=9.00, 4.58 Hz, IH).

[315] Product 32B: (S)-tert-butyl 3-(2-(2-cyanoethylamino)ethyl)-3-(3,4- dichlorophenyl)piperidine-l-carboxylate.

3-Aminopropanenitrile fumarate (150 mg, 0.81 mmol) was suspended in ACN (4.00 mL) then sodium acetate (187 mg, 2.28 mmol) was added and the mixture was allowed to stir for 30 min. Then 32A (250 mg, 0.67 mmol) was added as a solution in ClCH₂CH₂Cl (20 mL) and this mixture was allowed to stir an additional 30 min. Following this time sodium triacetoxyhydroborate (427 mg, 2.01 mmol) was added as a solid and the reaction allowed to stir at 25°C for 18 hr. The reaction was quenched with Na₂CO₃ solution, then dissolved in DCM and washed with IN NaOH. The organic layers were dried over Na₂SO₄, filtered and concentrated to give a crude residue. This material was purified by silica gel chromatography using 3% MeOH with NH₃ in DCM as eluent to give 32B (108 mg, 37.7%) as a clear oil. m/z (ES+) (M+H)+ =426.17068 ; HPLC r, = 1.10 min (MSl). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.50 (d, /=8.55 Hz, 2H) 7.33 (dd, /=8.55, 2.44 Hz, IH) 3.99 (d, /=14.04 Hz, IH) 3.50 (dt, /=12.82, 4.88 Hz, IH) 3.20 (d, /=13.43 Hz, IH) 3.10 (ddd, /=13.12, 9.77, 3.36 Hz, IH) 2.62 (t, /=6.71 Hz, 2H) 2.40 (t, /=6.71 Hz, 2H) 2.18-2.31 (m, 2H) 2.09 (d, /=13.43 Hz, IH) 1.59-1.77 (m, 3H) 1.50 (dd, /=14.65, 6.71 Hz, 2H) 1.40 (s, 9H) 1.28 (td, /=13.89, 5.19 Hz, IH).

[316] Title compound: (S)-3-(2-(3-(3,4-dichlorophenyl)piperidin-3- yl)ethylamino)propanenitrile citrate salt.

32B (105 mg, 0.25 mmol) was dissolved in DCM (4 niL) then TFA (4.00 niL) was added. The reaction was allowed to stir for 2 hr at 25°C. At the end of this time the reaction was complete by LCMS. The reaction was then concentrated to remove excess TFA. The residue was redissolved in DCM then washed with IN NaOH solution. The organic layer was dried over Na₂SO₄, filtered, then chromatographed on silica gel using 5% MeOH with NH₃ in DCM as eluent. The product containing fractions were concentrated to give title compound (64.0 mg, 80%) as a clear oil. In order to obtain a solid, the product was redissolved in MeOH then citric acid was added. The MeOH was removed and the residue triturated with ether. The resultant solids were collected then dried under high vacuum, m/z (ES+) (M+H)+ = 326.11819 ; HPLC r, = 0.19 min (MSl). ¹H NMR (SOO MHz, MeOD) δ ppm 7.58 (d, /=8.55 Hz, 2H) 7.35 (dd, /=8.55, 2.44 Hz, IH) 3.60 (d, /=13.43 Hz, IH) 3.43 (d, /=12.82 Hz, IH) 3.09 (t, /=6.71 Hz, 2H) 3.00 (t, /=8.24 Hz, IH) 2.80 (t, /=6.71 Hz, 2H) 2.62 (d, /=8.55 Hz, 2H) 2.14-2.25 (m, 2H) 2.01-2.13 (m, 3H) 1.83 (dd, /=9.77, 3.66 Hz, IH) 1.74 (m, IH). [317] Example 33. (S)-N-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)- l,l,l-trifluoropropan-2-amine di HCl salt

[318] Product 33A : (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2-((S)-l,l,l- trifluoropropan-2-ylamino)ethyl)piperidine-l-carboxylate.

(S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2-oxoethyl)piperidine-l-carboxylate, 32A (3.00 g, 8.06 mmol), was dissolved in ClCH₂CH₂Cl (100 niL). (S)-l,l,l-trifluoropropan-2-amine (1.185 g, 10.48 mmol) was added, and then the mixture was stirred for 30 min Afterward, sodium triacetoxyborohydride (4.27 g, 20.15 mmol) was added as a solid, and the resulting mixture was stirred at 25°C for 18 hr. The reaction was complete at this time (monitored by LCMS). The reaction was then quenched with Na₂CO₃ solution, and the product was dissolved in DCM and washed with IN NaOH solution. The organic layers were dried over Na₂SO₄, filtered, and concentrated to afford a crude product. The crude product was purified by silica gel chromatography using 15% EtOAc in DCM as eluent to afford (S)- tert-butyl 3-(3,4-dichlorophenyl)-3-(2-((S)- 1,1,1 -trifluoropropan-2- ylamino)ethyl)piperidine-l-carboxylate 33A (3.40 g, 90%) as a clear oil. m/z (ES+) (M+H)+ = 469.1625; HPLC r, = 1.66 min (MSlA). ¹H NMR (500 MHz, DMSO-Cl₆) δ ppm 7.55 (s, IH) 7.51 (d, /=8.54 Hz, IH) 7.33 (dd, /=8.54, 2.44 Hz, IH) 4.02 (d, /=13.43 Hz, IH) 3.46 - 3.54 (m, IH) 3.19 (d, /=13.43 Hz, IH) 3.00 - 3.13 (m, 2H) 2.33 (t, /=6.71 Hz, 2H) 2.03 - 2.12 (m, IH) 1.61 - 1.74 (m, 3H) 1.47 - 1.57 (m, IH) 1.40 (s, 9H) 1.27 (ddd, /=9.00, 4.43, 4.27 Hz, IH) 1.05 (d, /=6.71 Hz, 3H). ¹⁹F NMR (471 MHz, DMSO- dβ) δ ppm -75.43 (s, 3 F)

[319] Title Compound. (S)-N-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3- yl)ethyl)-l,l,l-trifluoropropan-2-amine di HCl salt.

(S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2-((S)-l,l,l-trifluoropropan-2- ylamino)ethyl)piperidine-l-carboxylate, 33A (3.4 g, 7.24 mmol), was dissolved in DCM (8 niL). TFA (8 mL) was then added. The mixture was stirred for 2 hr at 25°C. At this point, the reaction was complete (monitored by LCMS). The mixture was concentrated to remove the excess TFA. The residue was redissolved in DCM and washed with IN NaOH solution. The organic layer was dried over Na₂SO₄, filtered, concentrated, and dried to afford the crude product. The crude product was further purified by silica gel chromatography using 2% of a 7N ammonia in methanol solution in DCM as eluent. Concentration of the fractions afforded the title compound (2.60 g, 97%) as a free amine in the form of a clear oil. To obtain a solid, the oily product was redissolved in 25 mL of ether and treated with 25 mL IN HCl in ether solution to obtain the solid di-HCl salt (mild exotherm). The solids were collected and dried under high vacuum for 18 hr to afford the dry di HCl salt, m/z (ES+) (M+H)+ = 369.1109; HPLC r, = 1.09 min (MSlA). ¹H NMR (500 MHz, MeOD) δ ppm 7.67 (d, /=2.44 Hz, IH) 7.64 (d, /=8.54 Hz, IH) 7.42 (dd, /=8.54, 2.44 Hz, IH) 4.03 (d, /=6.71 Hz, IH) 3.77 (d, /=13.43 Hz, IH) 3.46 (d, /=13.43 Hz, IH) 3.11 - 3.26 (m, 2H) 2.89 (dt, /=11.60, 5.80 Hz, IH) 2.77 (td, /=11.75, 5.19 Hz, IH) 2.35 - 2.45 (m, IH) 2.10 - 2.23 (m, 2H) 1.94 - 2.06 (m, 2H) 1.76 - 1.89 (m, IH) 1.45 (d, /=6.71 Hz, 3H). ¹⁹F NMR (471 MHz, MeOD) δ ppm -75.24 (s, 3 F). [320] Example 34 : (S)-N-(2-(3-(4-chlorophenyl)piperidin-3-yl)ethyl)- 1,1,1- trifluoro-2-methylpropan-2-amine.

[321] Product 34A: (S)-tert-butyl 3-(4-chlorophenyl)-3-(2- hydroxyethyl)piperidine-l-carboxylate

(S)-2-(3-(4-chlorophenyl)piperidin-3-yl)ethanol (330 mg, 1.38 mmol) was dissolved in tetrahydrofuran (20 mL). To this was added di-tert-butyl dicarbonate (1.45 niL, 1.45 mmol) at 25°C. The resulting mixture was stirred under N₂ for 18 hr. The mixture was then concentrated, extracted with DCM and NaHCO₃ solution, dried over Na₂SO₄, filtered, concentrated, and purified using flash silica gel chromatography with 25% EtOAc/DCM as eluent (TLC development with UV (weak) and Iodine stain). This resulted in (S)-tert- butyl 3-(4-chlorophenyl)-3-(2-hydroxyethyl)piperidine-l-carboxylate (465 mg, 105 %) as a clear gum. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.28 - 7.40 (m, 4H) 4.64 (br. s., IH) 3.90 (d, /=13.43 Hz, IH) 3.36 - 3.45 (m, IH) 3.29 (d, /=14.04 Hz, IH) 3.18 (ddd,

/=12.82, 8.85, 3.97 Hz, IH) 3.13 (t, /=7.32 Hz, 2H) 1.99 - 2.09 (m, IH) 1.69 - 1.80 (m, 3H) 1.53 (dd, /=7.32, 3.66 Hz, IH) 1.39 (s, 9H) 1.32 (ddd, /=13.58, 9.31, 4.58 Hz, IH). m/z (ES+) (M-tBu)+ = 284.10391; HPLC r_t = 1.57 min (MSlA). [322] Product 34B: (S)-tert-butyl 3-(4-chlorophenyl)-3-(2- oxoethyl)piperidine-l-carboxylate

34A (465 mg, 1.38 mmol) was dissolved in DMSO (5 mL). The reaction flask was placed into a cooling bath to maintain the temperature at 25°C. Triethylamine (1.20 mL, 8.65 mmol) was then added while the mixture was stirred. Afterward, pyridine sulfur trioxide complex (688 mg, 4.33 mmol) was dissolved in DMSO (5 mL) (endothermic) and then added dropwise over 10 min. The resulting mixture was then allowed to stir for an additional 10 min while in the cooling bath. At the end of this time, the completion of the reaction was confirmed by LCMS. The mixture was then poured into 0.5 N HCl solution and extracted with EtOAc (caution: mild exotherm). The organic layer was washed with 0.5 N HCl and then with 1% NaHCO₃ solution. Afterward, the organic layer was dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by chromatography on silica gel using a gradient of 20-35% EtOAC in hexanes as eluent (TLC development with UV (weak) and Iodine stain). The desired fractions were dried under high vacuum to form (S)-tert-butyl 3-(4-chlorophenyl)-3-(2-oxoethyl)piperidine-l- carboxylate (398 mg, 99 %) as a clear oil. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.42 (s, IH) 7.43 (d, /=8.54 Hz, 2H) 7.32 - 7.37 (m, 2H) 3.84 (d, /=13.43 Hz, IH) 3.57 (d, /=13.43 Hz, IH) 3.27 - 3.39 (m, 2H) 2.66 (dd, /=7.02, 2.75 Hz, 2H) 2.08 (td, /=8.85, 4.27 Hz, IH) 1.91 (td, /=8.85, 4.27 Hz, IH) 1.53 - 1.63 (m, IH) 1.40 - 1.45 (m, IH) 1.39 (s, 9H). m/z (ES+) (M-tBu)+ = 282.08868 ; HPLC r_t = 1.58 min (MSlA). [323] Product 34C: (S)-tert-butyl 3-(4-chlorophenyl)-3-(2-(l,l,l-trifluoro-2- methylpropan-2-amine) piperidine-1-carboxylate

34B (200 mg, 0.59 mmol) was dissolved in ClCH₂CH₂Cl (20 niL). Afterward, 1,1,1- trifluoro-2-methylpropan-2-amine (94 mg, 0.74 mmol) was added. The resulting mixture was allowed to stir for 30 min. Afterward, sodium triacetoxyborohydride (314 mg, 1.48 mmol) was added as a solid, and the mixture was stirred at 25°C for 18 hr. At the end of this time, completion of the reaction was confirmed by LCMS. The reaction was then quenched with Na₂CO₃ solution. The resulting product was dissolved in DCM and washed with IN NaOH solution. The organic layers were dried over Na₂SO₄, filtered, and concentrated to give a crude product. This material was purified by silica gel chromatography using 15% EtOAc in DCM as eluent (TLC development with UV (weak) and iodine stain) to form (S)-tert-butyl 3-(4-chlorophenyl)-3-(2-(l,l,l-trifluoro-2- methylpropan-2-amine) ethyl) piperidine-1-carboxylate (240 mg, 90 %) as a clear oil. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.28 - 7.40 (m, 4H) 3.85 (d, /=13.43 Hz, IH) 3.35 - 3.42 (m, IH) 3.32 (d, /=13.43 Hz, IH) 3.22 (ddd, /=12.82, 8.54, 4.27 Hz, IH) 2.21 - 2.35 (m, 2H) 1.97 - 2.07 (m, IH) 1.74 (ddd, /=13.73, 9.46, 3.66 Hz, IH) 1.62 - 1.69 (m, 2H) 1.49 - 1.58 (m, IH) 1.42 - 1.49 (m, IH) 1.40 (s, 9H) 1.33 (dddd, /=13.05, 9.00, 8.77, 3.97 Hz, IH) 1.04 (s, 6H). 19F NMR (471 MHz, DMSO-d₆) δ ppm -77.88 (s, 3 F). m/z (ES+) (M+H)+ = 449.21811; HPLC r_t = 1.62 min (MSlA). [324] Title Compound : (S)-N-(2-(3-(4-chlorophenyl)piperidin-3-yl)ethyl)- l,l,l-trifluoro-2-methylpropan-2-amine

34C (240 mg, 0.53 mmol) was dissolved in DCM (2 niL). Afterward, TFA (2 rnL) was added. The resulting mixture was stirred for 2 hr at 25°C. Completion of the reaction was confirmed by LCMS. The mixture was then concentrated to remove excess TFA. The residue was redissolved in DCM, and then washed with IN NaOH solution. The organic layer was dried over Na₂SO₄, filtered, concentrated, and dried to form a crude product, which was further purified by silica gel chromatography using 2% of a 7N ammonia in methanol solution in DCM as eluent (TLC development with UV (weak) and Iodine stain). Concentration of the fractions produced (S)-N-(2-(3-(4-chlorophenyl)piperidin-3- yl)ethyl)- l,l,l-trifluoro-2-methylpropan-2-amine (174 mg, 93 %) as a colorless solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.34 (s, 4H) 3.19 (d, /=13.43 Hz, IH) 2.90 (d, /=13.43 Hz, IH) 2.69 - 2.83 (m, 2H) 2.36 (dt, /=10.38, 5.19 Hz, IH) 2.29 (td, /=10.22, 5.80 Hz, IH) 2.13 (ddd, /=13.12, 3.97, 3.66 Hz, IH) 1.69 - 1.87 (m, /=10.38, 10.07, 9.92, 9.92 Hz, 3H) 1.62 (ddd, /=13.73, 6.41, 3.66 Hz, IH) 1.51 (td, /=8.54, 4.27 Hz, IH) 1.09 (s, 6H). 19F NMR (471 MHz, DMSO-Cl₆) δ ppm -80.11 (s, 3 F). m/z (ES+) (M+H)+ = 349.16443; HPLC r_t = 1.01 min (MSlA).

Examples 35-58 in the following Table 4 show additional compounds made in accordance with this invention using methods similar to those illustrated above from commerically available starting materials.

Example 118. Biological Evaluation

[325] At least one compound of Formula (I), including the compounds described in the Examples hereof, when tested in at least one in vitro assay described below is active towards norepinephrine transport receptors and/or dopamine transport receptors. Particularly, at least one compound of the invention is an effective norepinephrine transport receptor and/or dopamine transport receptor ligand. The in vitro activity may be related to in vivo activity but may not be linearly correlated with binding affinity. In the in vitro assay, a compound can be tested for its activity toward norepinphrine transport receptors and dopamine transport receptors, and Ki values can be obtained to determine the activity for a particular compound towards both of these receptors.

[326] Norepinephrine and Dopamine Transport Inhibition Assay. [327] Compounds in accordance with Formula (I) are evaluated in an eleven point IC50 curve for ability to inhibit uptake of a fluorescent substrate (dye) that mimics biogenic amine neurotransmitters. A stable population of HEK293F cells transfected with the human transporter (NET: norepinephrine, DAT: dopamine) are cryopreserved, then plated and used on the day of the assay. Cells are at 60K/well. Final dye concentration is 7% (NET) or 50% (DAT) of the vendor-recommended reconstitution concentration (100%). At least one compound in accordance with Formula (I) is diluted 1 :20 in buffer and incubated with the cells for 30 min prior to adding dye. In this fluorescence intensity assay, plates are read after a 20 min (NET or DAT) dye incubation to determine percent effect with respect to total signal (0.5% DMSO, final) and background signal (NET: lOμM desipramine, DAT: lOμM GBR12909). The IC₅₀, half of the control response, is converted to Ki using the standard Cheng-Prusoff equation.

Ki values [328] At least one compound in accordance with Formula (I) has a Ki value of less than about 1.5 μM at NET and DAT. In a further embodiment, at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of between about 0.1 nM to about 1.5 μM. In an even further embodiment, at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of between about 0.1 nM to about 700 nM. In yet a further embodiment, at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of between about 0.1 nM and 200 nM. In still a further embodiment, at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of between about 0.1 nM and 100 nM. In one embodiment, at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of less than about 1200 nM. In another embodiment, at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of less than about 100 nM. In yet another embodiment, at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of less than about 50 nM. In yet another embodiment, a compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of less than about 10 nM. [329] Set forth in Table 5 below are Ki values for the compounds of Example 1-117 that were generated in accordance with the Norepinephrine and Dopamine Transport Inhbition Assay as essentially described above.

Table 5

[330] Unless otherwise indicated, the following apply in this patent:

[331] The modifier "C_m_C_n" means that the modified group contains from m to n carbon atoms. For example, the term "Ci.C_δ-alkyl" means an alkyl group containing from

1 to 6 carbon atoms.

[332] The chemical nomenclature used in this patent generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979. Compound names in the above examples were generated using AutoNom 2000 within ISIS/Draw or ChemDraw Ultra 8.0. AutoNom (Automatic Nomenclature) is a chemical-name-generating program that assigns systematic IUPAC (International Union of Pure and Applied Chemistry) chemical names to drawn structures at the press of a button.

[333] The term "hydrocarbon" refers to a chemical structure comprising only carbon and hydrogen atoms.

[334] The term "alkyl" means a straight or branched chain alkane (hydrocarbon) radical. In some embodiments, the alkyl comprises from 1 to 12 carbon atoms. In some embodiments, the alkyl comprises from 1 to 6 carbon atoms. And in some embodiments, the alkyl comprises from 1 to 3 carbon atoms. Examples of alkyl groups include, for example, methyl; ethyl; propyl; isopropyl; 1-methylpropyl; 2-methylpropyl; n-butyl, t-butyl; isobutyl; 3-methylbutyl; pentyl; hexyl; isohexyl; heptyl; 4,4-dimethylpentyl; diethylpentyl; octyl; 2,2,4-trimethylpentyl; nonyl; decyl; undecyl; and dodecyl. [335] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group.

The cycloalkyl may comprise one or more rings. In some embodiments, the cycloalkyl comprises a single ring. In some embodiments, the cycloalkyl comprises from 3 to 10 carbons. In other embodiments, the cycloalkyl comprises from 3 to 6 carbons. Examples of cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[336] The term "heterocycloalkyl" refers to a saturated or partially unsaturated hydrocarbon ring in which at least one ring carbon (and any associated hydrogen atoms) are independently replaced with at least one atom(s) selected from O, N, NH, and S. In some embodiments, the at least one ring carbon (and any associated hydrogen atoms) is replaced with an atom(s) selected from O, N, and NH. In some embodiments, the at least one ring carbon (and any associated hydrogen atoms) is replaced with an atom selected from O and N. In some embodiments, at least two carbon atoms (and any associated hydrogen atoms) are replaced with atoms independently selected from O, N, NH, and S. In some embodiments, at least two carbon atoms (and any associated hydrogen atoms) are replaced with atoms independently selected from O, N, and S.

[337] The term "aryl" refers to an aromatic (i.e., fully unsaturated) hydrocarbon ring structure. In some embodiments, the aryl comprises one ring (i.e., the aryl is phenyl).

[338] The terms "halogen" and "halo" means chlorine, bromine, fluorine, or iodine. In some embodiments, the halogen atoms in a molecule are selected from the group consisting of chlorine or fluorine. In some embodiments, the halogen atoms in a molecule are chlorine. And in some embodiments, the halogen atoms in a molecule are fluorine.

[339] The term "haloalkyl" refers to an alkyl bonded to a single halogen or multiple halogens. Examples of haloalkyls include -CHCl₂, -CHF₂, and -CF₃.

[340] The term "alkoxy" means -O-alkyl. Examples of alkoxys include methoxy, ethoxy, propoxy, and butoxy.

[341] The term "optionally substituted" means that the modified group, structure, or molecule may be either: (1) substituted with a substituent at one or more substitutable positions, or (2) not substituted.

[342] The term "pharmaceutically acceptable" is used to characterize a moiety (e.g., a salt, dosage form, carrier, diluent, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[343] References made in the singular may also include the plural. For example, "a" and "an" may refer to either one or more than one.

[344] The words "comprise," "comprises," and "comprising" in this patent (including the claims) are to be interpreted inclusively rather than exclusively. This interpretation is intended to be the same as the interpretation that these words are given under United States patent law.

[345] The term "ACN" means acetonitrile.

[346] The term "BH₃.THF" means borane tetrahydrofuran. [347] The term "CH₂Cl₂" means dichloromethane.

[348] The term "CH₃SO₂Cl" means methanesulfonyl chloride.

[349] The term "CO₂" means carbon dioxide.

[350] The term "DAT" means dopamine transport receptor.

[351] The term "DCM" means dichloromethane. [352] The term "DIPEA" means N,N-diisopropylethylamine.

[353] The term "DMF" means N,N-dimethylformamide.

[354] The term "DMSO" means dimethyl sulfoxide.

[355] The term "DMSO-d6" means deuterated dimethyl sulfoxide.

[356] The term "EDC" means l-ethyl-3-(3-dimethylaminopropyl) carbodiimide. [357] The term "ee" means enantiomeric excess.

[358] The term "equiv." means equivalents.

[359] The term "Et₃N" means triethylamine.

[360] The term "EtOAc" means ethyl acetate. [361] The term "EtOH" means ethanol.

[362] The term "¹H NMR" means proton nuclear magnetic resonance.

[363] The term "H₂O" means water.

[364] The term "HCl" means hydrochloric acid.

[365] The term "HPLC" means high performance liquid chromatography. [366] The term "hr" means hr or hr.

[367] The term "K₂CO₃" means potasssium carbonate.

[368] The term "LAH" means Lithium aluminum hydride.

[369] The term "LCMS" means liquid chromatography mass spectral detection.

[370] The term "LDA" means lithium diisopropyl amide. [371] The term "m-CPBA" means meta-chloroperbenzoic acid.

[372] The term "m/z" means mass to charge ratio.

[373] The term "MeOH" means methanol.

[374] The term "MgSO₄" means magnesium sulfate.

[375] The term "min" means minute or minutes. [376] The term "MS" means mass spectrum.

[377] The term "N₂" means nitrogen gas.

[378] The term "NaBH₄" means sodium borohydride.

[379] The term "NaH" means sodium hydride.

[380] The term "NaHCO₃" means sodium bicarbonate. [381] The term "NaOH" means sodium hydroxide.

[382] The term "Na₂SO₄" means sodium sulfate.

[383] The term "NET" means norepinephrine transport receptor.

[384] The term "NH₄Cl" means ammonium chloride.

[385] The term "NMR" means nuclear magnetic resonance. [386] The term "PCC" means pyridinium chlorochromate.

[387] The term "PDC" means pyridinium dichromate.

[388] The term "psig" means pound per square inch.

[389] The term "r_t" means retention time.

[390] The term "SFC" means supercritical fluid chromatography. [391] The term "TBTU" means O-(benzotriazol-l-yl)-N,N,N',N'- tetramethy luronium tetrafluoroborate .

[392] The term "TFA" means trifluoroacetic acid.

[393] The term "THF" means tetrahydrofuran. [394] The term "UV" means ultraviolet.

[395] The above detailed description of preferred embodiments is intended only to acquaint others skilled in the art with the invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This invention, therefore, is not limited to the above embodiments, and may be variously modified.

Claims

We claim:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Formula (I) corresponds to:

1 0

R and R are each independently selected halogen; as to R³ and R⁴:

R³ and R⁴ are each independently selected from H, -OH, and Ci_₃alkyl, or

R³ and R⁴, together with the carbon to which they are both attached, form C₃_₆cycloalkyl;

R⁵ is selected from -CN, -CF₃, -C₂-C₆alkenyl, -OR⁷, -S(=O)R⁶, -S(=O)₂R⁶, -SR⁶, -S(=O)₂NR⁷R⁸, -C(=O)NR⁷R⁸, -NR⁷C(=O)R¹², -NR⁷R⁸, -NR⁷C(=O)OR⁸, -NR⁷S(=O)₂R⁹, -NR⁷(C=O)NR⁷R⁸, and -0(C=O)NR⁷R⁸; R⁶ is Ci-Cealkyl; as to R⁷ and R⁸:

R⁷ and R⁸ are each independently selected from H and Ci-Cβalkyl, wherein: the Ci-Cβalkyl is optionally substituted by lor 2 substituents selected from haloalkyl, Ci-C₃alkyl,

-CC=O)NR , 1¹O⁰rR, 1¹1¹, -OH, -CN, and Ci-C₃alkoxy, or when R⁵ is -C(=O)NR⁷R⁸, -NR⁷R⁸, -NR⁷C(=O)OR⁸, or -S(=O)₂NR⁷R⁸, R⁷ and R⁸, together with the atom(s) to which they are both attached, may form a 3-, A-, 5-, or 6-membered heterocycloalkyl, wherein: the 3-, A-, 5-, or 6-membered heterocycloalkyl optionally contains at least one ring heteroatom selected from O and N in addition to: the N to which both R⁷ and R⁸ are both attached where R⁵ is -C(=O)NR⁷R⁸,

-NR⁷R⁸, or -S(=O)₂NR⁷R⁸, or the N to which R⁷ is attached and the O to which R is attached where R is -NR⁷C(=O)OR⁸; R⁹ is selected from H, Ci-C₆alkyl, -NR⁷R⁸, and haloalkyl;

R¹⁰ and R¹¹ are each independently selected from H and Ci-Cβalkyl; R¹² is selected from H, Ci-Cβalkyl, and haloalkyl; n is selected from zero and 1 ; p is selected from zero, 1, 2, and 3; p is not zero when R⁵ is -OR⁷; and the compound of Formula (I) is not 2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethanol.

2. A compound or salt according to claim 1, wherein R¹ is chlorine.

3. A compound or salt according to claim 1 or 2, wherein n is zero.

4. A compound or salt according to any one of claims 1-3, wherein p is 2.

5. A compound or salt according to any one of claims 1-4, wherein R³ and R⁴ are each H.

6. A compound or salt according to any one of claims 1-5, wherein R⁵ is -NR⁷R⁸.

7. A compound or salt according to any one of claims 1-6, wherein R⁷ is Ci_₆alkyl substituted with haloalkyl.

8. A compound or salt according to any one of claims 1-7, wherein R is hydrogen.

9. A compound or salt according to any one of claims 1-8, wherein: R⁷ is Ci_₆alkyl substituted with haloalkyl, and

R⁸ is hydrogen.

10. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

(S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl dimethylcarbamate;

(S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl methylcarbamate; 2-(3-(3-chloro-4-fluorophenyl)piperidin-3-yl)ethanol;

(S)-l-(3-(3,4-dichlorophenyl)piperidin-3-yl)-2-methylpropan-2-ol;

(S)-2-(3-(4-chlorophenyl)piperidin-3-yl)ethanol;

(S)-2-(3-(3-chlorophenyl)piperidin-3-yl)ethanol;

(S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethanamine; (S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)-2,2,2-trifluoroacetamide;

(S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)-2,2,2-trifluoroethanamine;

(S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)acetamide;

(S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)-N-methylethanamine;

(S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)-N- methylmethanesulfonamide;

(S)-l-(azetidin-l-yl)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethanone;

(S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)-N-methylacetamide;

(S)-3-(3,4-dichlorophenyl)-3-vinylpiperidine;

(3S)-3-(3,4-dichlorophenyl)-3-(2-(methylsulfinyl)ethyl)piperidine; (S)-3-(3,4-dichlorophenyl)-3-(2-(methylsulfonyl)ethyl)piperidine;

(S)-3-(3,4-dichlorophenyl)-3-(2-(methylthio)ethyl)piperidine;

(S)-2-(3-(3,4-dichlorophenyl)piperidin-3-yl)-N-methylacetamide;

(S)-3-(3,4-dichlorophenyl)-3-(2-methoxyethyl)piperidine;

(S)-3-(3-(3,4-dichlorophenyl)piperidin-3-yl)propanenitrile; (S)-(3-(3,4-dichlorophenyl)piperidin-3-yl)methyl dimethylcarbamate;

(S)-(3-(3 ,4-dichlorophenyl)piperidin-3 -yl)methyl methylcarbamate;

(3 S)-tert-butyl 3 -(3 ,4-dichlorophenyl)-3 -(methylsulfϊnylmethyl)piperidine- 1 - carboxylate; (S)-tert-butyl 3 -(3 ,4-dichlorophenyl)-3 -(methylsulfonylmethyl)piperidine- 1 - carboxylate;

(S)-3-(3,4-dichlorophenyl)-3-(methoxymethyl)piperidine;

(S)-(3-(3 ,4-dichlorophenyl)piperidin-3 -yl)methanol; (R)-3-(3-(3,4-dichlorophenyl)piperidin-3-yl)propan-l -amine;

(S)-(-)-2-(3-(3,4-dichloro-phenyl)piperidine-3-yl)ethanol;

2-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethylamino)-N,N- dimethylacetamide;

(S)-N-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)- 1,1,1- trifluoromethanesulfonamide;

N'-{2-[(3S)-3-(3,4-dichlorophenyl)piperidin-3-yl]ethyl}-N,N-dimethylsulfamide; N-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)-2,2-difluoroethanamine;

N-(((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)methyl)propan-2-amine;

N-(((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)methyl)-2,2,2-trifluoroethanamine; methyl 2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethylcarbamate;

3-((R)-3-(3,4-dichlorophenyl)piperidin-3-yl)-N-methylpropan-l-amine; (S)-N-(3-(3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-N- methy lmethanesulfonamide ;

3-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)- 1,1,1 -trifluoropropan-2-ol;

N-(3-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-N-methylacetamide;

2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl carbamate; 2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)-N-(2-methoxyethyl)ethanamine;

2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)-N-ethylethanamine;

(S)-3-(2-(tert-butylsulfonyl)ethyl)-3-(3,4-dichlorophenyl)piperidine;

4-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)morpholine;

2-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethylamino)ethanol; N-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethyl)propan-2-amine;

2-(2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)ethoxy)ethanol;

2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)-N,N-dimethylacetamide;

2-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)-N,N-dimethylethanamine;

3-((S)-3-(3,4-dichlorophenyl)piperidin-3-yl)propan-l-ol; and (S)-3-(2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethylamino)propanenitrile.

11. A compound or salt according to claim 1 , wherein the compound is selected from:



12. A compound or salt according to any one of claims 1-11 for use as a medicament.

13. The use of a compound or salt according to any one of claims 1-11 in the manufacture of a medicament for the therapy of a disorder comprising a disorder selected from major depressive disorders, attention-deficit and disruptive behavior disorders, and cocaine-related disorders.

14. A compound or salt according to any one of claims 1-11 for the treatment of a disorder comprising a disorder selected from atypical depression, melancholy depression, cocaine abuse, and attention deficit hyperactivity disorder.

15. A pharmaceutical composition, wherein the composition comprises: a compound or salt according to any one of claims 1-11, and a pharmaceutically acceptable carrier or diluent.

16. A method for treating a disorder comprising a disorder selected from a major depressive disorders, attention-deficit and disruptive behavior disorders, and cocaine-related disorders in a warm-blooded animal in need of such treatment, wherein: the method comprises administering to the animal a therapeutically effective amount a compound of Formula (I) or a pharmaceutically acceptable salt thereof; Formula (I) corresponds to:

R¹ and R² are each independently selected halogen; as to R³ and R⁴:

R³ and R⁴ are each independently selected from H, -OH, and

Ci_₃alkyl, or

R³ and R⁴, together with the carbon to which they are both attached, form C₃-₆cycloalkyl;

R⁵ is selected from -CN, -CF₃, -C₂-C₆alkenyl, -OR⁷, -S(=O)R⁶, -S(=O)₂R⁶, -SR⁶, -S(=O)₂NR⁷R⁸, -C(=O)NR⁷R⁸, -NR⁷C(=O)R¹², -NR⁷R⁸, -NR⁷C(=O)OR⁸, -NR⁷S(=O)₂R⁹, -NR⁷(C=O)NR⁷R⁸, and -0(C=O)NR⁷R⁸;

R⁶ is Ci-Cealkyl; as to R⁷ and R⁸:

R and R are each independently selected from H and Ci-Cβalkyl, wherein: the Ci-Cβalkyl is optionally substituted by lor 2 substituents selected from haloalkyl, Ci-Csalkyl, -CC=O)NR¹⁰R¹ \ -OH, -CN, and -Ci-Csalkoxy, or when R⁵ is -C(=O)NR⁷R⁸, -NR⁷R⁸, -NR⁷C(=O)OR⁸, or -S(=O)₂NR⁷R⁸, R⁷ and R⁸, together with the atom(s) to which they are both attached, may form a 3-, 4-, 5-, or 6-membered heterocycloalkyl, wherein: the 3-, 4-, 5-, or 6-membered heterocycloalkyl optionally contains at least one ring heteroatom selected from O and N in addition to: the N to which both R⁷ and R⁸ are both attached where R⁵ is -C(=O)NR⁷R⁸, -NR⁷R⁸, or -S(=O)₂NR⁷R⁸, or the N to which R⁷ is attached and the O to which R8 is attached where R⁵ is

-NR⁷C(=O)OR⁸;

R⁹ is selected from H, Ci-C₆alkyl, -NR⁷R⁸, and haloalkyl; R¹⁰ and R¹¹ are each independently selected from H and Ci-Cβalkyl; R¹² is selected from H, Ci-Cβalkyl, and haloalkyl; n is selected from zero and 1; p is selected from zero, 1, 2, and 3; p is not zero when R⁵ is -OR⁷; and the compound of Formula (I) is not 2-((R)-3-(3,4-dichlorophenyl)piperidin-3- yl)ethanol.

17. A method for treating a disorder comprising a disorder selected from melancholy depression, atypical depression, cocaine abuse, and ADHD in a warm-blooded animal in need of such treatment, wherein: the method comprises administering to the animal a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; Formula (I) corresponds to:

R and R are each independently selected halogen; as to R³ and R⁴: R³ and R⁴ are each independently selected from H, -OH, and

Ci_₃alkyl, or R³ and R⁴, together with the carbon to which they are both attached, form a C₃_₆cycloalkyl;

R and R are each independently selected from H and Ci-Cβalkyl, wherein: the Ci-Cβalkyl is optionally substituted by lor 2 substituents selected from haloalkyl, Ci-Csalkyl, -CC=O)NR¹⁰R¹ \ -OH, -CN, and -Ci-C₃alkoxy, or when R⁵ is -C(=O)NR⁷R⁸, -NR⁷R⁸, -NR⁷C(=O)OR⁸, or -S(=O)₂NR⁷R⁸, R⁷ and R⁸, together with the atom(s) to which they are both attached, may form a 3-, 4-, 5-, or 6-membered heterocycloalkyl, wherein: the 3-, 4-, 5-, or 6-membered heterocycloalkyl optionally contains at least one ring heteroatom selected from O and N in addition to: the N to which both R⁷ and R⁸ are both attached where R⁵ is -C(=O)NR⁷R⁸,

-NR⁷R⁸, or -S(=O)₂NR⁷R⁸, or the N to which R⁷ is attached and the O to which R8 is attached where R⁵ is -NR⁷C(=O)OR⁸; R⁹ is selected from H, Ci-C₆alkyl, -NR⁷R⁸, and haloalkyl;

R¹⁰ and R¹¹ are each independently selected from H and Ci-Cβalkyl; R¹² is selected from H, Ci-Cβalkyl, and haloalkyl; n is selected from zero and 1 ; p is selected from zero, 1, 2, and 3; p is not zero when R⁵ is -OR⁷; and the compound of Formula (I) is not 2-((R)-3-(3,4-dichlorophenyl)piperidin-3- yl)ethanol.

18. A method for treating a major depressive disorder in a warm-blooded animal in need of such treatment, wherein: the method comprises administering to the animal a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof;

Formula (I) corresponds to:

1 0

R and R are each independently selected halogen; as to R³ and R⁴:

R³ and R⁴ are each independently selected from H, -OH, and Ci-₃alkyl, or

R³ and R⁴, together with the carbon to which they are both attached, form a C₃_₆cycloalkyl;

R⁷ and R⁸ are each independently selected from H and Ci-Cβalkyl, wherein: the Ci-Cβalkyl is optionally substituted by lor 2 substituents selected from haloalkyl, Q-Csalkyl, -C(O)NR¹⁰R¹ \ -OH, -CN, and -Ci-C₃alkoxy, or when R⁵ is -C(=O)NR⁷R⁸, -NR⁷R⁸, -NR⁷C(=O)OR⁸, or -S(=O)₂NR⁷R⁸, R⁷ and R⁸, together with the atom(s) to which they are both attached, may form a 3-, 4-, 5-, or 6-membered heterocycloalkyl, wherein: the 3-, A-, 5-, or 6-membered heterocycloalkyl optionally contains at least one ring heteroatom selected from O and N in addition to: the N to which both R⁷ and R⁸ are both attached where R⁵ is -C(=O)NR⁷R⁸,

19. A method for treating a disorder in which modulating norepinephrine transport receptors and/or dopamine transport receptors is beneficial, wherein: the method comprises administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof;

Formula (I) corresponds to:

R¹ and R² are each independently selected halogen; as to R³ and R⁴: R³ and R⁴ are each independently selected from H, -OH, and Ci_₃alkyl, or

R³ and R⁴, together with the carbon to which they are both attached, form a C₃_₆cycloalkyl; R⁵ is selected from -CN, -CF₃, -C₂-C₆alkenyl, -OR⁷, -S(=O)R⁶, -S(=O)₂R⁶, -SR⁶,

-S(=O)₂NR⁷R⁸, -C(=O)NR⁷R⁸, -NR⁷C(=O)R¹², -NR⁷R⁸, -NR⁷C(=O)OR⁸, -NR⁷S(=O)₂R⁹, -NR⁷(C=O)NR⁷R⁸, and -0(C=O)NR⁷R⁸; R⁶ is Ci-C₆alkyl; as to R⁷ and R⁸: R⁷ and R⁸ are each independently selected from H and Ci-Cβalkyl, wherein: the Ci-Cβalkyl is optionally substituted by lor 2 substituents selected from haloalkyl, Ci-Csalkyl, -C(O)NR¹⁰R¹ \ -OH, -CN, and -Ci-C₃alkoxy, or when R⁵ is -C(=O)NR⁷R⁸, -NR⁷R⁸, -NR⁷C(=O)OR⁸, or

-S(=O)₂NR⁷R⁸, R⁷ and R⁸, together with the atom(s) to which they are both attached, may form a 3-, A-, 5-, or 6-membered heterocycloalkyl, wherein: the 3-, A-, 5-, or 6-membered heterocycloalkyl optionally contains at least one ring heteroatom selected from O and N in addition to: the N to which both R⁷ and R⁸ are both attached where R⁵ is -C(=O)NR⁷R⁸, -NR⁷R⁸, or -S(=O)₂NR⁷R⁸, or the N to which R⁷ is attached and the O to which R8 is attached where R⁵ is

-NR⁷C(=O)OR⁸;

20. A compound according to Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disorder comprising a disorder selected from atypical depression, melancholy depression, cocaine abuse, and attention deficit hyperactivity disorder, wherein:

Formula (I) corresponds to:

Ci_₃alkyl, or

R⁵ is selected from -CN, -CF₃, -C₂-C₆alkenyl, -OR⁷, -S(=O)R⁶, -S(=O)₂R⁶, -SR⁶, -S(=O)₂NR⁷R⁸, -C(=O)NR⁷R⁸, -NR⁷C(=O)R¹², -NR⁷R⁸, -NR⁷C(=O)OR⁸, -NR⁷S(=O)₂R⁹, -NR⁷(C=O)NR⁷R⁸, and -0(C=O)NR⁷R⁸; R⁶ is Ci-C₆alkyl; as to R⁷ and R⁸:

R⁷ and R⁸ are each independently selected from H and Ci-Cβalkyl, wherein: the Ci-Cβalkyl is optionally substituted by lor 2 substituents selected from haloalkyl, Ci-Csalkyl, -C(O)NR¹⁰R¹ \ -OH, -CN, and -Ci-C₃alkoxy, or when R⁵ is -C(=O)NR⁷R⁸, -NR⁷R⁸, -NR⁷C(=O)OR⁸, or -S(=O)₂NR⁷R⁸, R⁷ and R⁸, together with the atom(s) to which they are both attached, may form a 3-, A-, 5-, or 6-membered heterocycloalkyl, wherein: the 3-, A-, 5-, or 6-membered heterocycloalkyl optionally contains at least one ring heteroatom selected from O and N in addition to: the N to which both R⁷ and R⁸ are both attached where R⁵ is -C(=O)NR⁷R⁸,

21. A compound according to Formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament, wherein: Formula (I) corresponds to:

Ci_₃alkyl, or R³ and R⁴, together with the carbon to which they are both attached, form a C₃-₆cycloalkyl;

R¹⁰ and R¹¹ are each independently selected from H and Ci-Cβalkyl; R¹² is selected from H, Ci-Cβalkyl, and haloalkyl; n is selected from zero and 1 ; p is selected from zero, 1, 2, and 3 p is not zero when R⁵ is -OR⁷; and the compound of Formula (I) is not 2-((R)-3-(3,4-dichlorophenyl)piperidin-3- yl)ethanol.

22. The use of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the therapy of a disorder comprising a disorder selected from major depressive disorders, attention-deficit and disruptive behavior disorders, and cocaine-related disorders, wherein:

Formula (I) corresponds to:

R and R are each independently selected halogen; as to R³ and R⁴:

R³ and R⁴ are each independently selected from H, -OH, and Ci-₃alkyl, or