Capsaicin receptor ligands

• US 6,723,730 B2
• Filed: 07/20/2001
• Issued: 04/20/2004
• Est. Priority Date: 07/20/2000
• Status: Expired due to Fees

• Current Assignee: Neurogen Corporation (Ligand Pharmaceuticals, Inc.)
• Original Assignee: Neurogen Corporation (Ligand Pharmaceuticals, Inc.)
• Inventors: White, Geoffrey G., Bakthavatchalam, Rajagopal, DeSimone, Robert W., Krause, James E., Hutchinson, Alan, Hodgetts, Kevin J.
• Primary Examiner(s): Berch, Mark L.
• Assistant Examiner(s): Habte, Kahsay
• Application Number:
  US09/910,442
• Publication Number:
  US 20020132853A1
• Time in Patent Office: 1,005 Days
• Field of Search: 544/363, 544/364, 544/365, 544/360, 544/368, 544/369, 544/370, 544/371, 544/372, 544/376, 544/379, 544/389, 544/390, 544/391, 544/284, 544/353, 544/355, 544/356, 544/357, 544/235, 206/570, 514/284, 514/354, 514/356, 514/357, 514/405, 514/400
• US Class Current: 514/284
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 217/22 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 241/20 Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Disclosed are diaryl piperazines and related compounds of the following Formula:

wherein the variables are as defined in the specification. These compounds are selective modulators of capsaicin receptors, including human capsaicin receptors, that are, therefore, useful in the treatment of a chronic and acute pain conditions, itch and urinary incontinence. Methods of treatment of such disorders and well as packaged pharmaceutical compositions are also provided. Compounds of the invention are also useful as probes for the localization of capsaicin receptors and as standards in assays for capsaicin receptor binding and capsaicin receptor mediated cation conductance. Methods of using the compounds in receptor localization studies are given.

Claims

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein;

A is absent or is selected from the group consisting of O, S, NR_A, NR_ACR_BR_B′

, CR_BR_B′

NR_A, —

CR_A═

CR_B—

, and C₃H₄;

where R_A, R_B, and R_B′

are independently selected at each occurrence from hydrogen or alkyl;

Z is oxygen or sulfur;

each R₃ and R₄ independently

(a) selected from the group consisting of hydrogen;

halogen;

hydroxy;

amino;

cyano;

nitro;

—

COOH;

—

CHO, optionally substituted alkyl;

optionally substituted alkenyl;

optionally substituted alkynyl;

optionally substituted alkoxy;

optionally substituted alkylthio;

optionally substituted alkyl ketone;

optionally substituted alkylester;

optionally substituted alkylsulfinyl;

optionally substituted alkylsulfonyl;

optionally substituted mono- or di-alkylcarboxamide;

optionally substituted —

S(O)_nNHalkyl;

optionally substituted —

S(O)_nN(alkyl)(alkyl);

optionally substituted —

NHC(═

O)alkyl;

optionally substituted —

NC(═

O)(alkyl)(alkyl);

optionally substituted —

NHS(O)_nalkyl;

optionally substituted —

NS(O)_n(alkyl)(alkyl);

optionally substituted saturated heterocyclic ring or partially unsaturated heterocycle of from 5 to 8 atoms, which saturated heterocyclic ring or partially unsaturated heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, and S;

optionally substituted aryl having from 1 to 3 rings;

or optionally substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms per ring independently selected from the group consisting of N, O, and S;

or

(b) joined to a R₃ and R₄ not attached to the same carbon may be joined to form an optionally substituted aryl ring, a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is optionally substituted, or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is optionally substituted and contains 1, 2, or 3 heteroatoms selected from N, O, and S;

Ar₁ is selected from the group consisting of;

(a) cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimdyl, pyrazinyl, benzimidazolyl naphthyl, indolyl, isoindolyl, benzfuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazoly, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with R₅; and

(b) bicyclic oxygen-containing groups of the formula;

 

optionally mono-, di-, or trisubstituted with R₅, where L represents point of attachment and may be at any point on the benzene ring, and the oxygen-containing ring of the bicyclic oxygen-containing group consists of from 5 to 8 ring atoms, contains 1 or 2 oxygen atoms and remaining ring atoms are carbon;

Ar₂ is selected from the group consisting of;

(a) cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolyl, furanyl thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimdyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazoly, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with R₅; and

(b) bicyclic oxygen-containing groups of the formula;

 

optionally mono-, di-, or trisubstituted with R₅, where L represents point of attachment and may be at any point on the benzene ring, and the oxygen-containing ring of the bicyclic oxygen-containing group consists of from 5 to 8 ring atoms, contains 1 or 2 oxygen atoms and remaining ring atoms are carbon;

R₅ is independently selected at each occurence from the group consisting of halogen, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆, C_2-6alkynyl substituted with 0-2 R₆, C_1-6alkoxy and Y;

R₆ is independently selected at each occurence from the group consisting of halogen, hydroxy, cyano C_1-4alkyl, C_1-4alkoxy, —

S(O)_n(C_1-4alkyl), halo(C_1-4)alkly, halo(C_1-4)alkoxy, CO(C_1-4alkyl), CONH(C_1-4alkyl), CON(C_1-4alkyl₁) (C_1-4alkyl₂) where alkyl₁ and alkyl₂ may be joined to form a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —

XR₇, and Y;

X is independently selected at each occurence from the group consisting of —

CH₂—

, —

CHR₈—

, —

O—

, —

S(O)_n—

, —

NH—

, —

NR₈—

, —

C(═

O)—

, —

C(═

O)O—

, —

C(═

O)NH—

, —

C(═

O)NR₈—

, —

S(O)_nNH—

, —

S(O)_nNR₈—

, NHC(═

O)—

, —

NR₈C(═

O)—

, —

NHS(O)_n—

, and —

NR₈S(O)_n—

;

R₇ and R₈ are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms is unsubsitituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —

O(alkyl), —

NH(alkyl), —

N(alkyl)(alkyl), —

NHC(O)(alkyl), —

N(alkyl)C(O)(alkyl), —

NHS(O)_n(alkyl), —

S(O)_n(alkyl), —

S(O)_nNH(alkyl), —

S(O)_nN(alkyl₃)(alkyl₄) where alkyl₃ and alkyl₄ are opitionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′

;

Y and Y′

are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, mono- or dialkylamino, and alkylthio;

wherein said 3- to 8-memberered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S;

n is independently chosen at each occurrence from 0, 1, and 2.

2. A compound or salt according to claim 1, wherein:

R_A, R_B, and R_B′

are independently selected at each occurrence from hydrogen and C_1-6alkyl;

each R₃ and R₄ is independently

(a) chosen from the group consisting of hydrogen halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆;

C_2-6alkynyl substituted with 0-2 R₆;

C_1-6alkoxy substituted with 0-2 R₆, —

NH(C_1-6alkyl) substituted with 0-2 R₆, —

N(C_1-6alkyl)(C_1-6alkyl) where each C_1-6alkyl is independently substituted with 0-2 R₆, —

XR₇, and Y;

or

(b) joined to a R₃ or R₄ not attached to the same carbon to form an aryl ring substituted with 0-3 R₆, a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is substituted with 0-2 R₆, or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is substituted with 0-2 R₆ and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;

R₇ and R₈ are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms is unsubsitituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —

O(alkyl), —

NH(alkyl), —

N(alkyl)(alkyl), —

NHC(O)(C_1-4alkyl), —

N(C_1-4alkyl)C(O)(C_1-4alkyl), —

NHS(O)_n(C_1-4alkyl), —

S(O)_n(C_1-4alkyl), —

S(O)_nNH(C_1-4alkyl), —

S(O)_nN(C_1-4alkyl₃)(C_1-4alkyl₄) where C_1-4alkyl₃ and C_1-4alkyl₄ are opitionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′

; and

Y and Y′

are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which are unsubsitiuted or substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, C_1-4alkyl, C_1-4alkoxy, halo(C_1-4)alkyl, halo(C_1-4)alkoxy, mono- or di(C_1-4)alkylamino, and C_1-4alkylthio;

wherein said 3- to 8-memberered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S.

3. A compound or salt according to claim 1, wherein Z is oxygen.

173. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or salt according to claim 1.

174. A package comprising a pharmaceutical composition of claim 173 in a container and further comprising indicia comprising instructions for using the composition to alleviate pain.

175. A package comprising a pharmaceutical composition of claim 173 in a container and further comprising indicia comprising instructions for using the composition to alleviate symptoms of exposure to capsaicin or tear gas.

176. A compound or salt of claim 1 wherein, in an in vitro assay of capsaicin receptor antagonism, the compound or salt exhibits capsaicin receptor antagonist activity, but in an in vitro assay of capsaicin receptor agonism the compound does not exhibit detectable agonist activity.

177. A compound or salt of claim 1 wherein a dose of the compound or salt that is twice the minimum dose sufficient to provide analgesia in an animal model for determining pain relief does not produce sedation in an animal model assay of sedation.

4. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein;

A is absent or is selected from the group consisting of O, S, NR_A, CR_BR_B′

, NR_ACR_BR_B′

, CR_B R_B′

NR_A, —

CR_A═

CR_B—

, and C₃H₄;

where R_A, R_B, and R_B′

are independently selected at each occurrence from hydrogen or alkyl;

each R₃ and R₄ is independently;

(a) selected from the group consisting of hydrogen;

halogen;

hydroxy;

amino;

cyano;

nitro;

—

COOH;

—

CHO, optionally substituted alkyl;

optionally substituted alkenyl;

optionally substituted alkynyl;

optionally substituted alkoxy;

optionally substituted mono or dialkylamino;

optionally substituted alkylthio;

optionally substituted alkyl ketone;

optionally substituted alkylester;

optionally substituted alkylsulfinyl;

optionally substituted alkylsulfonyl;

optionally substituted mono- or di-alkylcarboxamide;

optionally substituted —

S(O)_nNHalkyl;

optionally substituted —

S(O)_nN(alkyl)(alkyl);

optionally substituted —

NHC(═

O)alkyl;

optionally substituted —

NC(═

O)(alkyl)(alkyl);

optionally substituted —

NHS(O)_nalkyl;

optionally substituted —

NS(O)_n(alkyl)(alkyl);

optionally substituted saturated heterocyclic ring or partially unsaturated heterocycle of from 5 to 8 atoms, which saturated heterocyclic ring or partially unsaturated heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, and S;

optionally substituted aryl having from 1 to 3 rings;

or optionally substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms per ring independently selected from the group consisting of N, O, and S;

or

(b) joined to a R₃ and R₄ not attached to the same carbon to form an optionally substituted aryl ring, a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is optionally substituted, or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is optionally substituted and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;

Ar₁ is selected from the group consisting of;

(a) cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolyl, furanyl thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazoly, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl;

wherein Ar₁ is optionally mono-, di-, or trisubstituted with R₅, and Ar₂ is optionally mono-, di-, or trisubstituted with R₉;

Ar₁ is selected from the group consisting of;

cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrim1dyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazoly, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl;

wherein Ar₁ is optionally mono-, di-, or trisubstituted with R₅, and Ar₂ is optionally mono-, di-, or trisubstituted with R₉; and

(b) groups of the formula;

 

optionally mono-, di-, or trisubstituted with R₅, where L represents point of attachment and may be at any point on the benzene ring, and the oxygen-containing ring of the bicyclic oxygen-containing group consists of from 5 to 8 ring atoms, contains 1 or 2 oxygen atoms and remaining ring atoms are carbon;

R₅ is independently selected at each occurence from the group consisting of cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alky substituted with 0-2 R₆, alkenyl substituted with 0-2 R₆, alkynyl substituted with 0-2 R₆, alkoxy and Y;

R₉ is independently selected at each occurrence from the group consisting of nitro, haloalkoxy, hydroxy, amino, alkyl substituted with 0-2 R₆, alkenyl substituted with 0-2 R₆, alkynyl substituted with 0-2 R₆, alkoxy substituted with 0-2 R₆, and Y;

R₆ is independently selected at each occurrence from the group consisting of halogen , hydroxy, cyano, alkyl, alkoxy, —

S(O)_n(alkyl), haloalkyl, haloalkoxy, CO(alkyl), CONH(alkyl), CON(alkyl₁)(alkyl₂) where alkyl₁ and alkyl₂ may be joined to from a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —

XR₇, and Y;

X is independently selected at each occurence from the group consisting of —

CH₂—

, —

CHR₈—

, —

O—

, —

S(O)_n—

, —

NH—

, —

NR₈—

, —

C(═

O)—

, —

C(═

O)O—

, —

C(═

O)NH—

, —

C(═

O)NR₈—

, —

S(O)_nNH—

, —

S(O)_nNR₈—

, NHC(═

O)—

, —

NR₈C(═

O)—

, —

NHS(O)_n—

, and —

NR₈S(O)_n—

;

R₇ and R₈ are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms is unsubstituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —

O(alkyl), —

NH(alkyl), —

N(alkyl)(alkyl), —

NHC(O)(alkyl), —

N(alkyl)C(O)(alkyl), —

NHS(O)_n(alkyl), —

S(O)_n(alkyl), —

S(O)_nNH(alkyl), —

S(O)_nN(alkyl₃)(alkyl₄) where alkyl₃ and alkyl₄ are opitionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′

;

Y and Y′

are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which are unsubstituted or substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, mono- or dialkylamino, and alkylthio;

wherein said 3- to 8-memberered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S;

n is independently chosen at each occurrence from 0, 1, and 2.

5. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein;

G, Q, T, and W are the same or different and are selected from the group consisting of N, CH, and CR₅, wherein T or W or both is N;

A is absent or is selected from the group consisting of O, S, NR_A, CR_BR_B′

, NR_ACR_BR_B′

, CR_B R_B′

NR_A, —

CR_A═

CR_B—

, and C₃H₄;

where R_A, R_B, and R_B′

are independently selected at each occurrence from hydrogen alkyl;

Z is oxygen or sulfur;

each R₃ and R₄ is independently

(a) selected from the group consisting of hydrogen;

halogen;

hydroxy;

amino;

cyano;

nitro;

—

COOH;

—

CHO, optionally substituted C_1-6alkyl;

optionally substituted C_2-6alkenyl;

optionally substituted C_2-6alkynyl;

optionally substituted C_1-6alkoxy;

optionally substituted mono or di(C_1-6)alkylamino;

optionally substituted C_1-6alkylthio;

optionally substituted C_1-6alkyl ketone;

optionally substituted C_1-6alkylester;

optionally substituted C_1-6alkylsulfinyl;

optionally substituted C_1-6alkylsulfonyl;

optionally substituted mono- or di(C_1-6)alkylcarboxamide;

optionally substituted —

S(O)_nNHC_1-6alkyl;

optionally substituted —

S(O)_nN(C_1-6alkyl)(C_1-6alkyl);

optionally substituted —

NHC(═

O)C_1-6alkyl;

optionally substituted —

NC(═

O)(C_1-6alkyl)(C_1-6alkyl);

optionally substituted —

NHS(O)_nC_1-6alkyl;

optionally substituted —

NS(O)_n(C_1-6alkyl)(C_1-6alkyl);

optionally substituted saturated heterocyclic ring or partially unsaturated heterocycle of from 5 to 8 atoms, which saturated heterocyclic ring or partially unsaturated heterocycle contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;

optionally substituted aryl having from 1 to 3 rings; and

optionally substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms per ring independently selected from the group consisting of N, O, and S;

or

(b) joined to a R₃ and R₄ not attached to the same carbon may be joined to form an optionally substituted aryl ring;

a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is optionally substituted;

or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is optionally substituted and contains 1, 2, or 3 heteroatoms selected from N, O, and S;

R₅ represents 1 to 3 substituents independently selected at each occurrence from the group consisting of cyano, hydroxy, amino, C_3-6 alkyl substituted with 0-2 R₆, C_2-6 alkenyl substituted with 0-2 R₆, C_2-6 alkynyl substituted with 0-2 R₆, C_3-6alkoxy, —

NH(C_1-6alkyl) substituted with 0-2 R₆, —

N(C_1-6alkyl)(C_1-6alkyl) where each alkyl is independently substituted with 0-2 R₆, —

XR₇, and Y;

R₉ represents 0 to 3 substituents and is independently selected at each occurrence from the group consisting of halogen, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆, C_2-6alkynyl substituted with 0-2 R₆, C_1-6alkoxy substituted with 0-2 R₆; and

Y;

R₆ is independently selected at each occurrence from the group consisting of halogen, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, —

S(O)_n(C_1-4alkyl), halo(C_1-4)alkyl, halo(C_1-4) alkoxy, CO(C_1-4alkyl), CONH(C_1-4alkyl), CON(C_1-4alkyl₁)(C_1-4alkyl₂) where alkyl₁ and alkyl₂ may be joined to form a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —

XR₇, and Y;

X is independently selected at each occurrence from the group consisting of —

CH₂—

, —

CHR₈—

, —

O—

, —

S(O)_n—

, —

NH—

, —

NR₈—

, —

C(═

O)—

, —

C(═

O)O—

, —

C(═

O)NH—

, —

C(═

O)NR₈—

, —

S(O)_nNH—

, —

S(O)_nNR₈—

, NHC(═

O)—

, —

NR₈C(═

O)—

, —

NHS(O)_n—

, and —

NR₈S(O)_n—

;

R₇ and R₈ are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms is unsubsitituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —

O(C_1-4alkyl), —

NH(C_1-4alkyl), —

N(C_1-4alkyl)(C_1-4alkyl), —

NHC(O)(C_1-4alkyl), —

N(C_1-4alkyl)C(O)(C_1-4alkyl), —

NHS(O)_n(C_1-4alkyl), —

S(O)_n(C_1-4alkyl), —

S(O)_nNH(C_1-4alkyl), —

S(O)_nN(C_1-4alkyl₃)(C_1-4alkyl₄) where C_1-4alkyl₃ and C_1-4alkyl₄ are opitionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′

;

Y and Y′

are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which are unsubstituted or substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, C_1-4alklyl, C_1-4alkoxy, halo(C_1-4)alklyl, halo(C_1-4)alkoxy, mono- or di(C_1-4)alklylamino, and C_1-4alklthio;

wherein said 3- to 8-membered heterocyclic group contain one or more heteroatom(s) independently selected from N, O, and S; and

n is independently chosen at each occurrence from 0, 1, and 2.

6. A compound according to claim 5, which 4-(3-Chloro-2-pyridinyl)-N-[4(isopropyl)phenyl]-2- methylthio-1-piperazinecarboxamide, or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 5, wherein R₃ and R₄ are independently selected at each occurrence from the group consisting of hydrogen and C_1-6alkyl.

8. A compound according to claim 7, wherein G and Q are selected from the group consisting of CH and CR₅.

9. A compound according to claim 7, wherein G, Q, and W are independently selected at each occurrence from the group consisting of CH and CR₅;

and T is N.

10. A compound according to claim 9 wherein R₃ and R₄ are hydrogen;

and A is selected from the group consisting of NH, —

CH═

CH—

, and —

CH₂NH—

.

11. A compound or salt according to claim 10, wherein R₆ is independently selected at each occurrence from the group consisting of halogen, hydroxy, C_1-4 alkyl, C_1-4 alkoxy, —

NH(C_1-4alkyl), and —

N(C_1-4 alkyl)(C_1-4 alkyl).

12. A compound according to claim 10, which is 4-(3-Trifluoromethyl-2-pyridinyl)-N-(3-methoxy-4-hydroxyphenylmethyl)-1-piperazinecarboxamide, or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 10, which is 4-(3-Nitro-pyridinyl)-N-[4-(n-butyl)phenyl]-1-piperazinecarboxamide, or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 10, which is 4-(3-Trifluoromethyl-2-pyridinyl)-N-[4-(n-butyl)phenyl]-1-piperazinecarboxamide, or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 10, which is 4-(3-Methyl-2-pyridinyl)-N-[4-(isopropyl)phenyl]-1-piperazinecarboxamide, or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 10, which is 4-(3-Methyl-2-pyridinyl)-N-[4-(n-butyl)phenyl]-1-piperazinecarboxamide, or a pharmaceutically acceptable salt thereof.

17. A compound according to claim 10, which is 4-(3-Chloro-5-trifluoromethyl-2-pyridinyl)-N-[4-(isopropyl)phenyl]-1-piperazinecarboxamide, or a pharmaceutically acceptable salt thereof.

18. A compound according to claim 10, which is 4-(3-Chloro-2-pyridinyl)-N-[4-(isopropyl)phenyl]-1-piperazinecarboxamide, or a pharmaceutically acceptable salt thereof.

19. A compound according to claim 10, which is 4-(3,5-Dichloro-2-pyridinyl)-N-[4-(isopropyl)phenyl]-1-piperazinecarboxamide, or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 9, which is 4-(3-Chloro-2-pyridinyl)-N-[4-(isopropyl)phenyl]-2-methyl-1-piperazinecarboxamide.

21. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein;

A is selected from the group consisting of NH, —

CH═

CH—

, and CH₂NH;

R₄ is independently chosen from hydrogen and C_1-4 alkyl;

R₅ represents 0 to 2 substituents independently chosen at each occurrence from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆, C_2-6alkynyl substituted with 0-2 R₆, C_1-6alkoxy, —

NH(C_1-6alkyl) substituted with 0-2 R₆, and —

N(C_1-6alkyl)(C_1-6alkyl) where each C_1-6alkyl is independently substituted with 0-2 R₆;

R₉ represents 0 to 2 substituents and is independently chosen at each occurrence from the group consisting of halogen, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆, C_2-6alkynyl substituted with 0-2 R₆, and C_1-6alkoxy substituted with 0-2 R₆;

R_5A is independently selected from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6 alkyl, C_1-6 alkoxy, —

NH(C_1-6 alkyl), and —

N(C_1-6 alkyl)(C_1-6 alkyl)

R_9B is independently selected from the group consisting of halogen, nitro, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6 alkyl, and C_1-6 alkoxy; and

R₆ is independently selected at each occurrence the group consisting of halogen, hydroxy, C_1-4alkyl, C_1-4alkoxy, —

NH(C_1-4 alkyl), and —

N(C_1-4 alkyl)(C_1-4 alkyl).

22. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein;

A is selected from the group consisting of a single bond, S, NR_A, NR_ACHR_B, CHR_BNR_A, —

CR_A═

CR_B—

, and C₃H₄;

where R_A and R_B are independently selected at each occurrence from the group consisting of hydrogen and alkyl;

each R₃ and R₄ is independently

(a) selected from the group consisting of hydrogen;

halogen;

hydroxy;

amino;

cyano;

nitro;

—

COOH;

—

CHO, optionally substituted alkyl;

optionally substituted alkenyl;

optionally substituted alkynyl;

optionally substituted alkoxy;

optionally substituted mono or dialkylamino;

optionally substituted alkylthio;

optionally substituted alkyl ketone;

optionally substituted alkylester;

optionally substituted alkylsulfinyl;

optionally substituted alkylsulfonyl;

optionally substituted mono- or di-alkylcarboxamide;

optionally substituted —

S(O)_nNHalkyl;

optionally substituted —

S(O)_nN(alkyl)(alkyl);

optionally substituted —

NHC(═

O)alkyl;

optionally substituted —

NC(═

O)(alkyl)(alkyl);

optionally substituted —

NHS(O)_nalkyl;

optionally substituted —

NS(O)_n(alkyl)(alkyl);

optionally substituted saturated heterocyclic ring or partially unsaturated heterocycle of from 5 to 8 atoms, which saturated heterocyclic ring or partially unsaturated heterocycle contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;

optionally substituted aryl having from 1 to 3 rings; and

optionally substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 8 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms per ring independently selected from the group consisting of N, O, and S;

or

(b) joined to a R₃ or R₄ not attached to the same carbon to form an optionally substituted aryl ring;

a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is optionally substituted;

or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is optionally substituted and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;

R₅ represents 0-3 substituents independently selected at each occurrence from the group consisting of cyano, nitro, haloalkyl, haloalkoxy, C_2-6 alkenyl substituted with 0-2 R₆, and C_2-6 alkynyl substituted with 0-2 R₆;

R₉ represents 0-3 substituents independently selected at each occurrence from the group consisting of bromo, haloalkyl, haloalkoxy, hydroxy, C_2-6 alkyl substituted with 0-2 R₆, C_2-6 alkenyl substituted with 0-2 R₆, C_2-6 alkynyl substituted with 0-2 R₆, and C_2-6 alkoxy;

R₆ is independently selected at each occurrence from the group consisting of halogen, hydroxy, cyano, alkyl, alkoxy, —

S(O)_n(alkyl), haloalkyl, haloalkoxy, CO(alkyl), CONH(alkyl), CON(alkyl₁)(alkyl₂) where alkyl₁ and alkyl₂ may be joined to form a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —

XR₇, and Y;

X is independently selected at each occurrence from the group consisting of —

CH₂—

, —

CHR₈—

, —

O—

, —

S(O)_n—

, —

NH—

, —

NR₈—

, —

C(═

O)—

, —

C(═

O)O—

, —

C(═

O)NH—

, —

C(═

O)NR₈—

, —

S(O)_nNH—

, —

S(O)_nNR₈—

, NHC(═

O)—

, —

NR₈C(═

O)—

, —

NHS(O)_n—

, and —

NR₈S(O)_n—

;

R₇ and R₈ are independently selected at each occurrence from straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 3 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 3 to 8 carbon atoms is unsubstituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —

O(alkyl), —

NH(alkyl), —

N(alkyl)(alkyl), —

NHC(O)(alkyl), —

N(alkyl)C(O)(alkyl), —

NHS(O)_n(alkyl), —

S(O)_n(alkyl), —

S(O)_nNH(alkyl), —

S(O)_nN(alkyl₃)(alkyl₄) where alkyl₃ and alkyl₄ are optionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′

;

Y and Y′

are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which are unsubstituted or substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, mono- or dialkylamino, and alkylthio;

wherein said 3- to 8-membered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S; and

n is independently chosen at each occurrence from 0, 1, and 2.

23. A compound or salt according to claim 22 in which R₃ and R₄ are independently selected at each occurrence from the group consisting of hydrogen and C_1-6 alkyl.

24. A compound or salt according to claim 22, wherein A is selected from the group consisting of NH, —

CH═

CH—

, and CH₂NH;

R₃ is hydrogen and R₄ is independently chosen at each occurrence from hydrogen and methyl; and

R₆ is independently selected at each occurrence from the group consisting of halogen, hydroxy, C_1-4 alkyl, C_1-4 alkoxy, —

NH(C_1-4 alkyl), and —

N(C_1-4 alkyl)(C_1-4 alkyl).

181. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or salt according to claim 22.

182. A compound or salt of claim 22 wherein, in an in vitro assay of capsaicin receptor antagonism, the compound or salt exhibits capsaicin receptor antagonist activity, but in an in vitro assay of capsaicin receptor agonism the compound does not exhibit detectable agonist activity.

183. A compound or salt of claim 22 wherein a dose of the compound or salt that is twice the minimum dose sufficient to provide analgesia in an animal model for determining pain relief does not produce sedation in an animal model assay of sedation.

184. A package comprising a pharmaceutical composition of claim 181 in a container and further comprising indicia comprising instructions for using the composition to alleviate pain.

185. A package comprising a pharmaceutical composition of claim 181 in a container and further comprising indicia comprising instructions for using the composition to alleviate symptoms of exposure to capsaicin or tear gas.

25. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein;

A is selected from the group consisting of NH, —

CH═

CH—

, and CH₂NH;

R₄ is independently selected at each occurrence from hydrogen and C_1-4alkyl;

R₅ represents 0 to 2 substituents independently selected at each occurrence from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, amino, C_2-6alkenyl substituted with 0-2 R₆, and C_2-6alkynyl substituted with 0-2 R₆;

R₉ represents 0 to 2 substituents and is independently selected at each occurrence from the group consisting of halogen, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆, C_2-6alkynyl substituted with 0-2 R₆, and C_1-6alkoxy substituted with 0-2 R₆;

R_5A is independently selected from the group consisting of halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C_1-6 alkyl, C_1-6 alkoxy, —

NH(C_1-6 alkyl), and —

N(C_1-6 alkyl)(C₁-C₆ alkyl);

R_9B is independently selected from the group consisting of trifluoromethoxy, hydroxy, C_2-6 alkyl, and C_2-6 alkoxy; and

R₆ is independently selected at each occurrence from the group consisting of halogen, hydroxy, C_1-4 alkyl, and C_1-4 alkoxy.

26. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt thereof exhibits an EC50 or K_i of 1 micromolar or less in a standard assay of capsaicin receptor mediated calcium mobilization; and

wherein

A is absent or is selected from the group consisting of O, S, NR_A, NR_ACR_BR_B′

, CR_BR_B′

NR_A, —

CR_A═

CR_B—

, and C₃H₄;

where

R_A, R_B, and R_B′

are independently selected at each occurrence from hydrogen and C_1-6 alkyl;

Z is oxygen or sulfur;

each R₃ and R₄ is independently

(a) selected from the group consisting of hydrogen, halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆;

C_2-6alkynyl substituted with 0-2 R₆;

C_1-6alkoxy substituted with 0-2 R₆, —

NH(C_1-6alkyl) substituted with 0-2 R₆, —

N(C_1-6alkyl)(C_1-6alkyl) where each C_1-6alkyl is independently substituted with 0-2 R₆, —

XR₇, and Y;

or

(b) joined to a R₃ or R₄ not attached to the same carbon to form an aryl ring substituted with 0-3 R₆, a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is substituted with 0-2 R₆, or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is substituted with 0-2 R₆ and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;

Ar₁ is selected from the group consisting of;

(a) cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with R₅; and

(b) bicyclic oxygen-containing groups of the formula;

 

optionally mono-, di-, or trisubstituted with R₅, where L represents point of attachment and may be at any point on the benzene ring, and the oxygen-containing ring of the bicyclic oxygen-containing group consists of from 5 to S ring atoms, contains 1 or 2 oxygen atoms and remaining ring atoms are carbon;

Ar₂ is selected from the group consisting of;

(a) cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl, each of which is optionally mono-, di-, or trisubstituted with R₅; and

(b) bicyclic oxygen-containing groups of the formula;

 

optionally mono-, di-, or trisubstituted with R₅, where L represents point of attachment and may be at any point on the benzene ring, and the oxygen-containing ring of the bicyclic oxygen-containing group consists of from 5 to 8 ring atoms, contains 1 or 2 oxygen atoms and remaining ring atoms are carbon;

R₅ is independently selected at each occurrence from the group consisting of halogen, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆, C_2-6alkynyl substituted with 0-2 R₆, C_1-6alkoxy and Y;

R₆ is independently selected at each occurrence from the group consisting of halogen, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, —

S(O)_n(C_1-4alkyl), halo(C_1-4)alkyl, halo(C_1-4)alkoxy, CO(C_1-4alkyl), CONH(C_1-4alkyl), CON(C_1-4alkyl₁)(C_1-4alkyl₂) where alkyl₁ and alkyl₂ may be joined to form a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —

XR₇, and Y;

X is independently selected at each occurrence from the group consisting of —

CH₂—

, —

CHR₈—

, —

O—

, —

S(O)_n—

, —

NH—

, —

NR₈—

, —

C(═

O)—

, —

C(═

O)O—

, —

C(═

O)NH—

, —

C(═

O)NR₈—

, —

S(O)_nNH—

, —

S(O)_nNR₈—

, NHC(═

O)—

, —

NR₈C(═

O)—

, —

NHS(═

O)_n—

, and —

NR₈S(O)_n—

;

R₇ and R₈ are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms is unsubstituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —

O(C_1-4alkyl), —

NH(C_1-4alkyl), —

NH(C_1-4alkyl)(C_1-4alkyl), —

NHC(O)(C_1-4alkyl), —

NH(C_1-4alkyl)C(O)(C_1-4alkyl), —

NHS(O)_n(C_1-4alkyl), —

S(O)_n(C_1-4alkyl), —

S(O)_nNH(C_1-4alkyl), —

S(O)_nN(C_1-4alkyl₃)(C_1-4alkyl₄) where C_1-4alkyl₃ and C_1-4alkyl₄ are optionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′

;

Y and Y′

are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, C_1-4alkyl, C_1-4alkoxy, halo(C_1-4)alkyl, halo(C_1-4)alkoxy, mono- or di(C_1-4)alkylamino, and C_1-4alkylthio;

wherein said 3- to 8-membered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S; and

n is independently chosen at each occurrence from 0, 1, and 2.

27. A compound of the Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F:

or a pharmaceutically acceptable salt of Formula A, Formula B, Formula C, Formula D, Formula E, or Formula F, wherein

A represents NH or O;

each R₃ and R₄ is independently

(a) selected from the group consisting of hydrogen, halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆;

C_2-6alkynyl substituted with 0-2 R₆;

C_1-6alkoxy substituted with 0-2 R₆, —

NH(C_1-6alkyl) substituted with 0-2 R₆, —

N(C_1-6alkyl)(C_1-6alkyl) where each C_1-6alkyl is independently substituted with 0-2 R₆, —

XR₇, and Y;

or

(b) joined to a R₃ or R₄ not attached to the same carbon to form an aryl ring substituted with 0-3 R₆, a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is substituted with 0-2 R₆, or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is substituted with 0-2 R₆ and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;

R₅ represents from 1 to 3 substituents independently selected at each occurrence from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆, C_2-6alkynyl substituted with 0-2 R₆, C_1-6alkoxy, —

NH(C_1-6alkyl) substituted with 0-2 R₆, —

N(C_1-6alkyl)(C_1-6alkyl) where each C_1-6alkyl is independently substituted with 0-2 R₆, —

XR₇, and Y;

R₉ represents from 1 to 3 substituents independently selected at each occurrence from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆, C_2-6alkynyl substituted with 0-2 R₆, C_1-6alkoxy substituted with 0-2 R₆, and Y;

R₆ is independently selected at each occurrence from the group consisting of halogen, hydroxy, cyano, C_1-4alkyl, C_1-4alkoxy, —

S(O)_n(C_1-4alkyl), halo(C_1-4)alkyl, halo(C_1-4)alkoxy, CO(C_1-4alkyl), CONH(C_1-4alkyl), CON(C_1-4alkyl₁)(C_1-4alkyl₂) where alkyl₁ and alkyl₂ may be joined to form a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —

XR₇, and Y;

X is independently selected at each occurrence from the group consisting of —

CH₂—

, —

CHR₈—

, —

O—

, —

S(O)_n—

, —

NH—

, —

NR₈—

, —

C(═

O)—

, —

C(═

O)O—

, —

C(═

O)NH—

, —

C(═

O)NR₈—

, and —

NR₈S(O)_n—

;

R₇ and R₈ are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms is unsubstituted or substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —

O(C_1-4alkyl), —

NH(C_1-4alkyl), —

N(C_1-4alkyl)(C_1-4alkyl), —

NHC(O)(C_1-4alkyl), —

N(C_1-4alkyl)C(O)(C_1-4alkyl), —

NHS(O)_n(C_1-4alkyl), —

S(O)_n(C_1-4alkyl), —

S(O)_nNH(C_1-4alkyl), —

S(O)_nN(C_1-4alkyl₃)(C_1-4alkyl₄) where C_1-4alkyl₃ and C_1-4alkyl₄ are optionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′

;

Y and Y′

are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, C_1-4alkyl, C_1-4alkoxy, halo(C_1-4)alkyl, halo(C_1-4)alkoxy, mono- or di(C_1-4)alkylamino, and C_1-4alkylthio;

wherein said 3- to 8-membered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S; and

n is independently chosen at each occurrence from 0, 1, and 2.

28. A compound or salt according to claim 27, wherein A represents NH.

29. A compound or salt according to claim 27, wherein:

A represents NH; and

R₃ and R₄ are independently chosen at each occurrence from the group consisting of hydrogen, halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy substituted with 0-2 R₆, —

NH(C_1-6alkyl), and —

N(C_1-6alkyl)(C_1-6alkyl).

30. A compound or salt according to claim 27, wherein:

A represents NH;

R₃ represents hydrogen; and

R₄ is independently chosen at each occurrence from hydrogen and C_1-6 alkyl.

31. A compound or salt according to claim 27, wherein:

A represents NH;

R₃ represents hydrogen; and

R₄ is independently chosen at each occurrence from hydrogen and methyl.

32. A compound or salt according to claim 27, wherein:

A represents NH;

R₃ represents hydrogen;

R₄ is independently chosen at each occurrence from hydrogen and methyl; and

represents from 1 to 3 substituents independently selected at each occurrence from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, —

NH(C_1-6alkyl), —

N(C_1-6alkyl)(C_1-6alkyl), and C_3-8 cycloalkyl; and

R₉ represents from 1 to 3 substituents independently selected at each occurrence from the group consisting of halogen, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, and C_3-8 cycloalkyl.

39. A compound or salt according to claim 32 of Formula D-1:

wherein;

R₅ is selected from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, —

NH(C_1-6alkyl), —

N(C_1-6alkyl)(C_1-6alkyl), and C_3-8 cycloalkyl;

R₉ is selected from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, and C_3-8 cycloalkyl; and

R_5B and R_9B each represent from 0 to 2 substituents independently selected at each occurrence from hydrogen, halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, hydroxy, amino, C_1-3alkyl, C_1-3alkoxy, —

NH(C_1-3alkyl), and —

N(C_1-6alkyl)(C_1-6alkyl).

40. A compound or salt according to claim 39, wherein:

R₅ is C_3-6 alkyl;

C_3-6 alkoxy;

halo(C_1-3)alkyl, halo(C_1-3)alkoxy, or C_3-8 cycloalkyl;

R₉ is chloro or trifluoromethyl; and

R_5B and R_9B are hydrogen.

33. A compound or salt of the Formula A-1

wherein

R₄ is hydrogen or methyl;

R₅ and R₉ are independently selected from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, —

NH(C_1-6alkyl), —

N(C_1-6alkyl)(C_1-6alkyl), and C_3-8 cycloalkyl; and

R_5B and R_9B each represent from 0 to 2 substituents independently selected at each occurrence from hydrogen, halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, hydroxy, amino, C_1-3alkyl, C_1-3alkoxy, —

NH(C_1-3alkyl), and —

N(C_1-6alkyl)(C_1-6alkyl).

34. A compound or salt according to claim 33, wherein:

R₅ is C_3-6 alkyl;

C_3-6 alkoxy;

halo(C_1-3)alkyl, halo(C_1-3)alkoxy, or C_3-8 cycloalkyl;

R₉ is chloro or trifluoromethyl; and

R_5B and R_9B are hydrogen.

167. A compound according to claim 33, which is (2R)-N-(4-tert-butylcyclohexyl)-4-(3-chloropyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

168. A compound according to claim 33, which is (2R)-4-(3-chloropyridin-2-yl)-N-(4-isopropylcyclohexyl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

169. A compound according to claim 33, which is (2R)-N-(4-isopropylcyclohexyl)-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

35. A compound or salt of Formula B-1:

wherein

R₄ is hydrogen or methyl;

R₅ and R₉ are independently selected from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, —

NH(C_1-6alkyl), —

N(C_1-6alkyl)(C_1-6alkyl), and C_3-8 cycloalkyl; and

R_5B and R_9B each represent from 0 to 2 substituents independently selected at each occurrence from hydrogen, halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, hydroxy, amino, C_1-3alkyl, C_1-3alkoxy, —

NH(C_1-3alkyl), and —

N(C_1-6alkyl)(C_1-6alkyl).

36. A compound or salt according to claim 35, wherein:

R₅ is C_3-6alkyl;

C_3-6 alkoxy;

halo(C_1-3)alkyl, halo(C_1-3)alkoxy, or C_3-8 cycloalkyl;

R₉ is chloro or trifluoromethyl; and

R_5B and R_9B are hydrogen.

145. A compound according to claim 35, which is (2R)-N-(4-tert-butylphenyl)-4-(3-chloropyrazin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

146. A compound according to claim 35, which is (2R)-4-(3-chloropyrazin-2-yl)-N-(4-isopropylphenyl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

147. A compound according to claim 35, which is (2R)-4-(3-chloropyrazin-2-yl)-2-methyl-N-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

148. A compound according to claim 35, which is (2R)-4-(3-chloropyrazin-2-yl)-2-methyl-N-{4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl}piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

149. A compound according to claim 35, which is (2R)-4-(3-chloropyrazin-2-yl)-2-methyl-N-{4-cyclopentyl-phenyl}piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

150. A compound according to claim 35, which is (2R)-4-(3-chloropyrazin-2-yl)-2-methyl-N-{4-cyclohexyl-phenyl}piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

37. A compound or salt of Formula C-1:

wherein;

R₄ is hydrogen or methyl;

R₅ and R₉ are independently selected from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, —

NH(C_1-6alkyl), —

N(C_1-6alkyl)(C_1-6alkyl), and C_3-8 cycloalkyl; and

R_5B and R_9B each represent from 0 to 2 substituents independently selected at each occurrence from hydrogen, halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, hydroxy, amino, C_1-3alkyl, C_1-3alkoxy, —

NH(C_1-3alkyl), and —

N(C_1-6alkyl)(C_1-6alkyl).

38. A compound or salt according to claim 37, wherein:

R₅ is C_3-6 alkyl;

C_3-6 alkoxy;

halo(C_1-3)alkyl, halo(C_1-3)alkoxy, or C_3-8 cycloalkyl;

R₉ is chloro or trifluoromethyl; and

R_5B and R_9B are hydrogen.

151. A compound according to claim 37, which is 4-(3-chloropyridin-2-yl)-N-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

152. A compound according to claim 37, which is (2R)-4-(3-chloropyridin-2-yl)-2-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

153. A compound according to claim 37, which is (2R)-4-(3-chloropyridin-2-yl)-2-methyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

41. A compound or salt of Formula E-1:

wherein;

R₄ is hydrogen or methyl;

R₅ and R₉ are independently selected from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, —

NH(C_1-6alkyl), —

N(C_1-6alkyl)(C_1-6alkyl), and C_3-8 cycloalkyl; and

R_5B and R_9B each represent from 0 to 2 substituents independently selected at each occurrence from hydrogen, halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, hydroxy, amino, C_1-3alkyl, C_1-3alkoxy, —

NH(C_1-3alkyl), and —

N(C_1-6alkyl)(C_1-6alkyl).

42. A compound or salt according to claim 41, wherein:

R₅ is C_3-6 alkyl;

C_3-6 alkoxy;

halo(C_1-3)alkyl, halo(C_1-3)alkoxy, or C_3-8 cycloalkyl;

R₉ is chloro or trifluoromethyl; and

R_5B and R_9B are hydrogen.

44. A compound or salt according to claim 42, wherein:

R₅ is C_3-6 alkyl;

C_3-6 alkoxy;

halo(C_1-3)alkyl, halo(C_1-3)alkoxy, or C_3-8 cycloalkyl;

R₉ is chloro or trifluoromethyl; and

R_5B and R_9B are hydrogen.

43. A compound of salt of Formula F-1:

wherein;

R₄ is hydrogen or methyl;

R₅ and R₉ are independently selected from the group consisting of halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, —

NH(C_1-6alkyl), —

N(C_1-6alkyl)(C_1-6alkyl), and C_3-8 cycloalkyl; and

R_5B and R_9B each represent from 0 to 2 substituents independently selected at each occurrence from hydrogen, halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, hydroxy, amino, C_1-3alkyl, C_1-3alkoxy, —

NH(C_1-3alkyl), and —

N(C_1-6alkyl)(C_1-6alkyl).

45. A compound of the Formula:

or a pharmaceutically acceptable salt thereof, wherein;

A is absent or is selected from the group consisting of O, S, NR_A, CR_BR_B′

, NR_ACR_BR_B′

, CR_BR_B′

NR_A, —

CR_A═

CR_B—

, and C₃H₄;

where R_A, R_B, and R_B′

are independently selected at each occurrence from hydrogen and C_1-6 alkyl;

each R₃ and R₄ is independently

(a) selected from the group consisting of hydrogen, halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆;

C_2-6alkynyl substituted with 0-2 R₆;

C_1-6alkoxy substituted with 0-2 R₆, —

NH(C_1-6alkyl) substituted with 0-2 R₆, —

N(C_1-6alkyl)(C_1-6alkyl) where each C_1-6alkyl is independently substituted with 0-2 R₆, —

XR₇, and Y;

or

(b) joined to a R₃ or R₄ not attached to the same carbon to form an aryl ring substituted with 0-3 R₆, a saturated or partially unsaturated carbocyclic ring of from 5 to 8 members, which carbocyclic ring is substituted with 0-2 R₆, or a saturated, partially unsaturated, or aromatic heterocyclic ring of from 5 to 8 members, which heterocyclic ring is substituted with 0-2 R₆ and contains 1, 2, or 3 heteroatoms independently selected from N, O, and S;

R₅ is selected from the group consisting of bromo, fluoro, iodo, halo(C_1-6)alkyl, halo(C_3-6)alkoxy, C_3-6alkyl substituted with 0-3 R₆, C_2-6alkenyl substituted with 0-3 R₆, C_2-6alkynyl substituted with 0-3 R₆, C_3-6alkoxy, (C_3-8cycloalkyl)C_1-4alkyl, —

NH(C_1-6alkyl) substituted with 0-2 R, —

N(C_1-6alkyl)(C_1-6alkyl) where each C_1-6alkyl is substituted with 0-2 R₆, Y, —

(C═

O)Y, —

(CH₂)Y, and —

(CH(CN))Y;

R₉ is selected from the group consisting of halogen, cyano, —

N(SO₂C_1-6alkyl)(SO₂C_1-6alkyl), —

SO₂NH₂, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, C_1-6alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆, C_2-6alkynyl substituted with 0-2 R₆, and C_1-6alkoxy substituted with 0-2 R₆;

R_5B represents from 0 to 2 substituents independently selected at each occurrence from the group consisting of

(a) halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, (C_3-8cycloalkyl)C_1-4alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆, C_2-6alkynyl substituted with 0-2 R₆, C_1-6alkoxy, —

NH(C_1-6alkyl) substituted with 0-2 R₆, —

N(C_1-6alkyl)(C_1-6alkyl) where each C_1-6alkyl is independently substituted with 0-2 R₆, and Y; and

(b) groups that are joined to R₅ to form a C_3-8cycloalkyl group or a saturated heterocyclic ring or partially unsaturated heterocycle, each of which is optionally substituted by from 1 to 5 substituents independently chosen from cyano, halogen, hydroxy, C_1-4alkyl, C_1-4alkoxy, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)(C_1-4alkyl) halo(C_1-4)alkyl, and halo(C_1-4)alkoxy, wherein the saturated heterocyclic ring or partially unsaturated heterocycle contains from 4 to 3 ring atoms of which 1, 2, or 3 are heteroatoms independently selected from N, O, and S;

R_9B represents from 0 to 2 substituents independently selected at each occurrence from halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl substituted with 0-2 R₆, (C_3-8cycloalkyl)C_1-4alkyl substituted with 0-2 R₆, C_2-6alkenyl substituted with 0-2 R₆, C_2-6alkynyl substituted with 0-2 R₆, C_1-6alkoxy substituted with 0-2 R₆, and Y;

R₆ is independently selected at each occurrence from the group consisting of cyano, halogen, hydroxy, C_1-4alkyl, C_1-4alkoxy, —

S(O)_n(C_1-4alkyl), halo(C_1-4)alkyl, halo(C_1-4)alkoxy, CO(C_1-4alkyl), CONH(C_1-4alkyl), CON(C_1-4alkyl₁)(C_1-4alkyl₂) where alkyl₁ and alkyl₂ may be joined to form a saturated heterocyclic ring of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, —

XR₇, and Y;

X is independently selected at each occurrence from the group consisting of —

CH₂—

, —

CHR₈—

, —

O—

, —

S(O)_n—

, —

NH—

, —

NR₈—

, —

C(═

O)—

, —

C(═

O)NH—

, —

C(═

O)NH₈—

, —

S(═

O)_nNH—

, —

S(O)_nNR₈—

, NHC(═

O)—

, —

NR₈C(═

O)—

, —

NHS(O)_n—

, and —

NH₈S(O)_n—

;

R₇ and R₈ are independently selected at each occurrence from hydrogen, and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, said straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups consisting of 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, —

O(C_1-4alkyl), NH(C_1-4alkyl), —

N(C_1-4alkyl)(C_1-4alkyl) —

NHC(O)(C_1-4alkyl), —

N(C_1-4alkyl)C(O)(C_1-4alkyl) —

NHS(O)_n(C_1-4alkyl), —

S(O)_n(C_1-4alkyl), —

S(O)_nNH(C_1-4alkyl), —

S(O)_nN(C_1-4alkyl₃)(C_1-4alkyl₄) where C_1-4alkyl₃ and C_1-4alkyl₄ are optionally joined to form a saturated heterocyclic ring consisting of from 5 to 8 ring atoms and containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and Y′

;

Y and Y′

are independently selected at each occurrence from 3- to 8-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, C_1-4alkyl, C_1-4alkoxy, halo(C_1-4)alkyl, halo(C_1-4)alkoxy, mono- or di(C_1-4)alkylamino, and C_1-4alkylthio;

wherein said 3- to 8-membered heterocyclic groups contain one or more heteroatom(s) independently selected from N, O, and S; and

n is independently chosen at each occurrence from 0, 1, and 2.

46. A compound or salt according to claim 45, wherein:

A as O or NR_A, wherein R_A is hydrogen or methyl.

47. A compound or salt according to claim 45, wherein:

A is O or NR_A, wherein R_A is hydrogen or methyl; and

R₃ and R₄ are independently chosen at each occurrence from the group consisting of hydrogen, halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, —

NH(C_1-6alkyl), and —

N(C_1-6alkyl)(C_1-6alkyl).

48. A compound or salt according to claim 45, wherein:

A is O or NR_A, wherein R_A is hydrogen or methyl;

R₃ is hydrogen; and

R₄ is independently chosen at each occurrence from the group consisting of hydrogen, halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, —

NH(C_1-6alkyl), and —

N(C_1-6alkyl)(C_1-6alkyl).

49. A compound or salt according to claim 45, wherein:

A is O or NR_A, wherein R_A is hydrogen or methyl;

R₃ is hydrogen; and

R₄ is independently chosen at each occurrence from hydrogen and C_1-6alkyl.

50. A compound or salt according to claim 45, wherein:

A is NR_A, wherein R_A is hydrogen or methyl;

R₃ is hydrogen; and

R₄ is independently chosen at each occurrence from hydrogen, halo(C_1-3)alkyl, and C_1-6alkyl.

51. A compound or salt according to claim 45, wherein:

A is NR_A, wherein R_A is hydrogen or methyl;

R₃ is hydrogen; and

R₄ is independently chosen at each occurrence from hydrogen and C_1-4alkyl.

52. A compound or salt according to claim 45 of the Formula:

wherein;

R₄ is independently chosen at each occurrence from hydrogen and C_1-4alkyl.

53. A compound or salt according to claim 52 of the formula:

wherein

R_5B and R_9B are independently chosen from hydrogen, halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, amino, C_1-4alkyl, and C_1-2alkoxy; and

R₁₀ is independently chosen at each occurrence from hydrogen, halogen, and C_1-4 alkyl.

54. A compound or salt according to claim 53 wherein:

R₉ is selected from the group consisting of halogen, cyano, —

N(SO₂CH₃)₂, —

SO₂NH₂, halo(C_1-3)alkyl, and C_1-3alkoxy.

55. A compound or salt according to claim 52, wherein:

R_5B and R_9B are independently chosen from hydrogen, halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, amino, C_1-4alkyl, and C_1-2alkoxy.

56. A compound or salt according to claim 52, wherein:

R_5B represents 0 or 1 substituents chosen from halogen, cyano, nitro, halo(C_1-2alkyl, halo(C_1-2)alkoxy, amino, C_1-4alkyl, and C_1-2alkoxy; and

R_9B represents 0 or 1 substituents chosen from halogen, cyano, nitro, halo(C_1-2)alkyl, and C_1-2alkyl, and C_1-2alkoxy.

57. A compound or salt according to claim 52, wherein:

R₉ is selected from the group consisting of halogen, cyano, —

N(SO₂CH₃)₂, —

SO₂NH₂, halo(C_1-3)alkyl, and C_1-3alkoxy;

R_5B represents 0 or 1 substituents chosen from halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, amino, C_1-4alkyl, and C_1-2alkoxy; and

R_9B represents 0 or 1 substituents chosen from halogen, cyano, nitro, halo(C_1-2)alkyl, C_1-2alkyl, and C_1-2alkoxy.

58. A compound or salt according to claim 52, wherein:

R₅ is selected from the group consisting of bromo, fluoro, iodo, halo(C_1-6)alkyl, halo(C_3-6)alkoxy, C_3-6alkyl substituted with 0-3 R₆, C_2-6alkenyl substituted with 0-3 R₆, Y, —

(C═

O)Y, —

(CH₂)Y, and —

(CH(CN))Y;

R₉ is selected from the group consisting of halogen, cyano, —

N(SO₂CH₃)₂, —

SO₂NH₂, halo(C_1-2alkyl, C_1-3alkoxy;

R_5B represents 0 or 1 substituents chosen from halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, amino, C_1-4alkyl, and C_1-2alkoxy; and

R_9B represents 0 or 1 substituents chosen from halogen, cyano, nitro, halo(C_1-2)alkyl, C_1-2alkyl, and C_1-2alkoxy.

59. A compound or salt according to claim 58, wherein:

R₆ is independently selected at each occurrence from the group consisting of cyano, halogen, hydroxy, C_1-4alkyl, C_1-4alkoxy, —

NH(C_1-4alkyl), and —

N(C_1-4alkyl)(C_1-4alkyl) and Y; and

Y is independently selected at each occurrence from C_3-8 cycloalkyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, morpholinyl, thiomorpholinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, and imidazolyl, each of which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, C_1-4alkyl, C_1-4alkoxy, halo(C_1-4)alkyl, halo(C_1-4)alkoxy, mono- or di(C_1-4)alkylamino, and C_1-4alkylthio.

60. A compound or salt according to claim 58, wherein:

R₉ is cyano, trifluoromethyl, chloro, or iodo; and

R_9B is hydrogen.

61. A compound according to claim 45, which is N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

62. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-N-(4-cyclohexylphenyl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

63. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-2-methyl-N-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

64. A compound according to claim 45, which is (2R)-N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

65. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-N-(4-isopropylphenyl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

66. A compound according to claim 45, which is (2S)-4-(3-chloropyridin-2-yl)-N-(4-trifluoromethylphenyl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

67. A compound according to claim 45, which is (2S)-N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

68. A compound according to claim 45, which is (2S)-4-(3-chloropyridin-2-yl)-N-(4-isopropylphenyl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

69. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-2-methyl-N-(4-piperidin-1-ylphenyl)piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

70. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-N-[2-fluoro-4-(trifluoromethyl)phenyl]-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

71. A compound according to claim 45, which is (2R)-2-methyl-N-[4-(trifluoromethyl)phenyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

72. A compound according to claim 45, which is (2R)-N-(4-tert-butylphenyl)-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

73. A compound according to claim 45, which is (2R)-N-(4-isopropylphenyl)-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

74. A compound according to claim 45, which is 4-(3-chloropyridin-2-yl)-2,6-dimethyl-N-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

75. A compound according to claim 45, which is N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-2,6-dimethylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

76. A compound according to claim 45, which is 4-(3-chloropyridin-2-yl)-N-(4-isopropylphenyl)-2,6-dimethylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

77. A compound according to claim 45, which is (2R)-N-(4-cyclohexylphenyl)-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

78. A compound according to claim 45, which is 4-(3-chloropyridin-2-yl)-N-(4-cyclohexylphenyl)-2,6-dimethylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

79. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-N-(4-cyclopentylphenyl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

80. A compound according to claim 50, which is (2R)-N-(4-cyclopentylphenyl)-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

81. A compound according to claim 45, which is (2R)-N-(4-tert-butylphenyl)-4-(3-methoxypyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

82. A compound according to claim 45, which is (2R)-4-(3-methoxypyridin-2-yl)-2-methyl-N-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

83. A compound according to claim 45, which is (2R)-N-(4-cyclohexylphenyl)-4-(3-methoxypyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

84. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-N-[4-(3,6-dihydro-2H-pyran-4-yl)phenyl]-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

85. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-2-methyl-N-(4-tetrahydro-2H-pyran-4-ylphenyl)piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

86. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-N-[4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl]-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

87. A compound according to claim 45, which is (2R)-N-[4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl]-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

88. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-2-methyl-N-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

89. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-N-[4-(2-ethyl-1,3-thiazol-4-yl)phenyl]-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

90. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-N-[4-(2-methoxy-1,1-dimethylethyl)phenyl]-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

91. A compound according to claim 45, which is (2R)-N-[4-(2-methoxy-1,1-dimethylethyl)phenyl]-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

92. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-N-[4-(1-cyano-1-methylethyl)phenyl]-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

93. A compound according to claim 45, which is (2R)-N-[4-(1-cyano-1-methylethyl)phenyl]-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

94. A compound according to claim 45, which is N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-2-ethylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

95. A compound according to claim 45, which is 4-(3-chloropyridin-2-yl)-2-ethyl-N-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

96. A compound according to claim 45, which is 4-(3-chloropyridin-2-yl)-2-ethyl-N-(4-isopropylphenyl)piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

97. A compound according to claim 45, which is N-(4-tert-butylphenyl)-2-ethyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

98. A compound according to claim 45, which is 2-ethyl-N-[4-(trifluoromethyl)phenyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

99. A compound according to claim 45, which is 2-ethyl-N-(4-isopropylphenyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

100. A compound according to claim 45, which is 2-tert-butyl-N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

101. A compound according to claim 45, which is 2-tert-butyl-N-[4-(trifluoromethyl)phenyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

102. A compound according to claim 45, which is N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-2-isopropylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

103. A compound according to claim 45, which is N-(4-tert-butylphenyl)-2-isopropyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

104. A compound according to claim 45, which is 2-isopropyl-N-[4-(trifluoromethyl)phenyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

105. A compound according to claim 45, which is 2-isopropyl-N-(4-isopropylphenyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

106. A compound according to claim 45, which is (2R)-4-(3-fluoropyridin-2-yl)-2-methyl-N-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

107. A compound according to claim 45, which is (2R)-N-(4-tert-butylphenyl)-4-(3-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

108. A compound according to claim 45, which is (2R)-4-(3-fluoropyridin-2-yl)-N-(4-isopropylphenyl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

109. A compound according to claim 45, which is (2R)-N-(4-cyclohexylphenyl)-4-(3-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

110. A compound according to claim 45, which is (2R)-N-(4-cyclopentylphenyl)-4-(3-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

111. A compound according to claim 45, which is (2R)-N-(4-tert-butylphenyl)-4-(3-cyanopyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

112. A compound according to claim 45, which is (2R)-4-(3-cyanopyridin-2-yl)-2-methyl-N-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

113. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-N-{4-[cyano(phenyl)methyl]phenyl}-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

114. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-2-methyl-N-[3-methyl-4-(trifluoromethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

115. A compound according to claim 45, which is (2R)-4-(3-fluoropyridin-2-yl)-2-methyl-N-[3-methyl-4-(trifluoromethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

116. A compound according to claim 45, which is (2R)-4-{3-[bis(methylsulfonyl)amino]pyridin-2-yl}-N-(4-tert-butylphenyl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

117. A compound according to claim 45, which is (2R)-2-methyl-N-[3-methyl-4-(trifluoromethyl)phenyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

118. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-2-methyl-N-{4-[1-(trifluoromethyl)vinyl]phenyl}piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

119. A compound according to claim 45, which is (2R)-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[1-(trifluoromethyl)vinyl]phenyl}piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

120. A compound according to claim 45, which is (2R)-4-(3-fluoropyridin-2-yl)-2-methyl-N-{4-[1-(trifluoromethyl)vinyl]phenyl}piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

121. A compound according to claim 45, which is (2R)-N-(4-sec-butylphenyl)-4-(3-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

122. A compound according to claim 45, which is (2R)-2-methyl-N-[4-(2,2,2-trifluoro-1-methylethyl)phenyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

123. A compound according to claim 45, which is (2R)-4-(3-fluoropyridin-2-yl)-2-methyl-N-[4-(2,2,2-trifluoro-1-methylethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

124. A compound according to claim 45, which is (2R)-4-(3-chloro-5-nitropyridin-2-yl)-2-methyl-N-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

125. A compound according to claim 45, which is (2R)-4-(5-amino-3-chloropyridin-2-yl)-2-methyl-N-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

126. A compound according to claim 45, which is (2R)-4-(3-fluoropyridin-2-yl)-N-[3-fluoro-4-(trifluoromethyl)phenyl]-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

127. A compound according to claim 45, which is (2R)-N-[3-fluoro-4-(trifluoromethyl)phenyl]-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

128. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-2-methyl-N-[4-(2,2,2-trifluoro-1-methylethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

129. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-2-methyl-N-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

130. A compound according to claim 45, which is (2R)-4-(3-fluoropyridin-2-yl)-2-methyl-N-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

131. A compound according to claim 45, which is (2R)-2-methyl-N-(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

132. A compound according to claim 45, which is (2R)-4-[3-(aminosulfonyl)pyridin-2-yl]-N-(4-tert-butylphenyl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

133. A compound according to claim 45, which is (2R)-N-(4-benzoylphenyl)-4-(3-chloropyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

134. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-N-(4-iodophenyl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

135. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-2-methyl-N-{4-[2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethyl]phenyl}piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

136. A compound according to claim 45, which is (2R)-2-methyl-N-{4-[2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethyl]phenyl}-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

137. A compound according to claim 45, which is (2R)-N-(4-butylphenyl)-4-(3-chloropyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

138. A compound according to claim 45, which is 2-(fluoromethyl)-N-[4-(trifluoromethyl)phenyl]-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

139. A compound according to claim 45, which is (2R)-N-[4-bromo-3-(trifluoromethyl)phenyl]-4-(3-chloropyridin-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

140. A compound according to claim 45, which is (2R)-N-[4-bromo-3-(trifluoromethyl)phenyl]-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

141. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

142. A compound according to claim 45, which is (2R)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

143. A compound according to claim 45, which is (2R)-4-(3-chloropyridin-2-yl)-2-methyl-N-{4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl}piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

144. A compound according to claim 45, which is (2R)-2-methyl-N-{4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl}-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

170. A compound or salt of claim 45 wherein the compound or salt is not addictive.

154. A compound of the Formula:

or a pharmaceutically acceptable salt thereof, wherein;

A is absent or is selected from the group consisting of O, S, NR_A, CR_BR_B′

, NR_ACR_BR_B′

, CR_BR_B′

NR_A, —

CR_A═

CR_B—

, and C₃H₄;

where R_A, R_B, and R_B′

are independently selected at each occurrence from hydrogen and C_1-6 alkyl;

R₃ and R₄ are independently chosen at each occurrence from the group consisting of hydrogen, halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, —

NH(C_1-6alkyl), and —

N(C_1-6alkyl)(C_1-6alkyl);

R₅ is selected from the group consisting of halogen, halo(C_1-6)alkyl, C_3-6alkyl substituted with 0-3 R₆, C_2-6alkenyl substituted with 0-3 R₆, (C_3-8cycloalkyl)C_1-4alkyl substituted with 0-3 R₆, and Y;

R_5B and R_9B each represent from 0 to 2 substituents and are independently chosen from halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, amino, C_1-4alkyl, and C_1-2alkoxy;

R₆ is independently selected at each occurrence from the group consisting of cyano, halogen, hydroxy, C_1-4alkyl, C_1-4alkoxy, —

NH(C_1-4alkyl), —

N(C_1-4alkyl)(C_1-4alkyl) and Y;

Y is independently selected at each occurrence from C_3-8 cycloalkyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl,morpholinyl, thiomorpholinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, and imidazolyl, each of which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, nitro, cyano, C_1-4alkyl, C_1-4alkoxy, halo(C_1-4)alkyl, halo(C_1-4)alkoxy, mono- or di(C_1-4)alkylamino, and C_1-4alkylthio.

155. A compound or salt according to claim 154 of the Formula:

wherein

R₄ is independently selected at each occurrence from hydrogen and C_1-4alkyl.

156. A compound or salt according to claim 155, wherein:

R₅ is selected from the group consisting of halo(C_1-6)alkyl, C_3-6alkyl, (C_3-8cycloalkyl)C_1-4alkyl, and Y;

R_5B and R_9B each represent from 0 to 1 substituents and are independently chosen from halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, amino, C_1-4alkyl, and C_1-2alkoxy;

Y is selected from C_3-8 cycloalkyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, morpholinyl, thiomorpholinyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, thiazolyl, thienyl, and imidazolyl.

157. A compound according to claim 154, which is (2R)-4-isoquinolin-1-yl-2-methyl-N-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

158. A compound according to claim 154, which is (2R)-N-(4-tert-butylphenyl)-4-isoquinolin-1-yl-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

159. A compound according to claim 154, which is (2R)-N-(4-isopropylphenyl)-4-isoquinolin-1-yl-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

160. A compound according to claim 154, which is (2R)-N-(4-cyclopentylphenyl)-4-isoquinolin-1-yl-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

161. A compound according to claim 154, which is (2R)-N-(4-cyclohexylphenyl)-4-isoquinolin-1-yl-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

162. A compound of the Formula:

or a pharmaceutically acceptable salt thereof, wherein;

A is absent or is selected from the group consisting of O, S, NR_A, CR_BR_B′

, NR_ACR_BR_B′

, CR_BR_B′

NR_A, —

CR_A═

CR_B—

, and C₃H₄;

where R_A, R_B, and R_B′

are independently selected at each occurrence from hydrogen and C_1-6 alkyl;

R₃ and R₄ are independently chosen at each occurrence from the group consisting of hydrogen, halogen, cyano, nitro, halo(C_1-6)alkyl, halo(C_1-6)alkoxy, hydroxy, amino, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkoxy, —

NH(C_1-6alkyl), and —

N(C_1-6alkyl)(C_1-6alkyl);

R_5B, R_5C, and R_9B each represent from 0 to 2 substituents and are independently chosen from halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, amino, C_1-4alkyl, and C_1-2alkoxy; and

R₉ is selected from the group consisting of halogen, cyano, —

N(SO₂CH₃)₂, —

SO₂NH₂, halo(C_1-3)alkyl, C_1-3alkoxy, —

NH(C_1-3alkyl), and —

N(C_1-3alkyl)(C_1-3alkyl).

163. A compound or salt according to claim 162 of the Formula:

wherein

R₄ is independently selected at each occurrence from hydrogen and C_1-4alkyl.

164. A compound or salt according to claim 163, wherein:

R₉ is selected from the group consisting of halogen and halo(C_1-2)alkyl; and

R_5B and R_9B each represent from 0 to 1 substituents and are independently chosen from halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, amino, C_1-4alkyl, and C_1-2alkoxy.

165. A compound according to claim 162, which is (2R)-4-(3-chloropyridin-2-yl)-N-(9H-fluoren-2-yl)-2-methylpiperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

166. A compound according to claim 162, which is (2R)-N-(9H-fluoren-2-yl)-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxamide, or a pharmaceutically acceptable salt thereof.

171. A compound of the Formula:

or a pharmaceutically acceptable salt thereof wherein;

R₄ is methyl or hydrogen;

R_9B represents 0-2 substituents independently chosen from;

halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, amino, C_1-4alkyl, and C_1-2alkoxy; and

Ar₁ is 2,4-dichlorphenyl or 3-nitro-4-chlorophenyl.

172. A compound of the Formula:

or a pharmaceutically acceptable salt thereof wherein;

R₉ is chloro or trifluoromethyl; and

R_5B and R_9B independently represent from 0-2 substituents on each of the rings on which they occur and are independently chosen from;

halogen, cyano, nitro, halo(C_1-2)alkyl, halo(C_1-2)alkoxy, amino, C_1-4alkyl, and C_1-2alkoxy.

178. 4-(3-Chloro-2-pyridinyl)-N-[4-(isopropyl)phenyl]-1-piperazinecarboxamide or a pharmaceutically acceptable salt thereof.

179. (2R)-N-(4-tert-butylphenyl)-4-[3-(dimethylamino)pyridin-2-yl]-2-methylpiperazine-1-carboxamide or a pharmaceutically acceptable salt thereof.

180. (2R)-4-[3-(dimethylamino)pyridin-2-yl]-2-methyl-N-[4-(trifluoromethyl)phenyl]piperazine-1-carboxamide or a pharmaceutically acceptable salt thereof.