Substituted piperazinyl amides and methods of use

• US 7,115,607 B2
• Filed: 07/24/2002
• Issued: 10/03/2006
• Est. Priority Date: 07/25/2001
• Status: Expired due to Fees

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Goldberg, Martin H., Smith, Duncan M., Norman, Mark H., Chen, Ning, Xi, Ning, Xu, Shimin, Kelly, Michael G., Liu, Qingyian, Han, Nianhe, Fotsch, Christopher H., Bo, Yunxin, Arasasingham, Premilla, Hsieh, Feng-Yin, Stec, Markian, Tamayo, Nuria
• Primary Examiner(s): Shameem, Golam M. M.
• Assistant Examiner(s): SACKEY, EBENEZER O
• Application Number:
  US10/202,823
• Publication Number:
  US 20030220324A1
• Time in Patent Office: 1,532 Days
• Field of Search: 544/363, 544/359, 544/365, 544/373, 544/376, 544/379, 514/253.05, 514/253.06, 514/252.13, 514/253.13, 514/254.09
• US Class Current: 514/252.13
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/09 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 215/48 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 217/06 with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 217/14 other than aralkyl radicals
• CPC Class Codes: C07D 217/26 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 295/185 : from aliphatic carboxylic acids
• CPC Class Codes: C07D 317/60 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 317/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 319/18 : Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : 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
• CPC Class Codes: C07D 451/02 : containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07K 5/06026 : the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/06139 : with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06147 : and His-amino acid; Derivatives thereof
• CPC Class Codes: C07K 5/06191 : containing heteroatoms different from O, S, or N

Abstract

Selected substituted piperazine compounds of Formula I
are effective for prophylaxis and treatment of diseases, such as obesity and the like. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving activation of the melanocortin receptor. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Claims

1. A compound of Formula II

wherein R¹⁰ is selected from H, chloro or fluoro;

wherein R¹² is

wherein R^13a and R^13b are independently selected from H, phenyl, fluoro, iodo, bromo, chloro, phenyl, C_1-2-alkyl, C_1-2-haloalkyl, and C_1-2-alkoxy;

or wherein R^13a and R^13b together form an C_1-4-alkenylenyl bridge;

wherein R¹⁴ is selected from R¹⁹R²⁰N—

, R¹⁹R²⁰N—

C_1-4-alkyl, (R21R22N—

) (O=)C-, C_1-4-haloalkyl, C_2-4-hydroxyalkyl, heterocyclyloxy-C_1-4-alkyl, aryloxy-C_1-4-alkyl and C_1-4-alkoxycarbonyl;

wherein R¹⁵ is selected from H, C_1-2-haloalkyl, C_1-4-alkyl, halo, —

OR¹⁷, and —

N(R¹⁷)₂;

wherein R¹⁶ is selected from 3-pyridyl, 4-pyridyl, 5-benzopyrrolyl, 2-benzofuran, 2-benzothienyl, 6-quinolyl, thienyl, 4-piperidyl, N-methyl-4-piperidyl, N-methyl-2-piperidyl, N-ethyl-4-piperidyl, N-isobutyl-4-piperidyl, 3-piperidyl and 3-azetidinyl optionally N-substituted with a substituent selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclohexylmethyl and benzyl;

wherein R¹⁷ is selected from H, C_1-4-alkyl, C_3-7-cyclhoalkyl-(CH₂)_n—

, and aryl-(CH₂)_n—

;

wherein R¹⁹ is selected from H, R²³SO₂—

, C_1-6-alkyl, C_3-7-cycloalkyl-(CH₂)_n—

, amino-C_1-6-alkyl, C_1-6-alkylamino-C_1-6-alkyl, C_3-7-cycloalkylamino-C_1-6-alkyl, C_3-7-cycloalkyl-C_1-6-alkylamino-C_1-6-alkyl, heteroarylamino-C_1-6-alkyl, heteroaryl-C_1-6-alkylamino-C_1-6-alkyl, arylamino-C_1-6-alkyl, aryl-C_1-6-alkylamino-C_1-6-alkyl, heteroaryloxy-C_1-6-alkyl, heteroaryl-C_1-6-alkyloxy-C_1-6-alkyl, aryloxy-C_1-6-alkyl, aryl-C_1-6-alkyloxy-C_1-6-alkyl, hydroxy-C_1-6-alkyl, C_1-6-alkylthio-C_1-6-alkyl, C_1-6-alkoxy-C_1-6-alkyl, C_1-6-alkylcarbonyl, C_1-6-alkoxycarbonyl, C_1-6-alkoxy-C_1-6-alkylcarbonyl, C_1-6-alkylaminocarbonyl, arylcarbonyl, aralkylcarbonyl, C_3-7-cycloalkylcarbonyl, C_3-7-cycloalkyl-C_1-6-alkylcarbonyl, heteroaryl-C_1-6-alkylcarbonyl and heteroarylcarbonyl;

wherein R²⁰ is selected from H, C_1-8-alkyl, C_3-7-cycloalkyl-(CH₂)_n—

, C_1-3-alkylsulfonyl, amino-C_1-3-alkylamino, heterocyclyl-(CH₂)_n—

, and aryl-(CH₂)_n—

;

alternatively R¹⁹ and R²⁰ together with the nitrogen atom form a 4-8 membered heterocyclic ring;

wherein R²¹ is selected from H, C_1-6-alkyl, C_2-6-alkenyl, C_1-6-alkylthio-C_1-6-alkyl, C_1-6-alkylcarbonylamino-C_1-6-alkyl, amino-C_1-6-alkyl, heterocyclyl-(CH₂)_n—

, C_3-7-cycloalkyl-(CH₂)_n—

, and aryl-(CH₂)_n—

;

wherein R²² is selected from H, C_1-6-alkyl, C_3-7-cycloalkyl-(CH₂)_n—

, heterocyclyl-(CH₂)_n— and

aryl-(CH₂)_n—

;

alternatively R²¹ and R²² together with the amide nitrogen atom form a 4-7 membered saturated heterocyclic ring;

wherein R²³ is selected from H, C_1-6-alkyl, C_3-7-cycloalkyl-(CH₂)_n—

, heterocyclyl-(CH₂)_n— and

aryl-(CH₂)_n—

;

wherein n is 0, 1, 2 or 3; and

wherein m is 0, 1 or 2;

wherein aryl, heterocyclyl are optionally substituted with one or more substituents selected from C_1-2-haloalkyl, C_1-3-alkyl, C_3-6-cycloalkyl-(CH₂)_n—

, chloro, fluoro, —

OR¹⁷, —

NR¹⁷CO₂R¹⁷, —

NR¹⁷SO₂R¹⁷, N(R¹⁷)₂, cyano, —

COR¹⁷, —

C(R¹⁷)₂N(R¹⁷)₂, nitro, —

SO₂N(R¹⁷)₂, —

S(O)_mR¹⁷, and C_1-3-haloalkoxy;

and a pharmaceutically-acceptable salt thereof.

2. Compound of claim 1 wherein R¹⁰ is H;

wherein R^13a is selected from H, phenyl, bromo, chloro, trifluoromethyl and methoxy;

wherein R^13b is H;

wherein R¹⁵ is selected from H and C_1-2-haloalkyl;

wherein R¹⁷ is selected from H, C_1-3-alkyl, —

(CH₂)_n—

C_3-6-cycloalkyl, and —

(CH₂)_n-phenyl;

wherein R¹⁹ is selected from H, R²³SO₂—

, C_1-6-alkyl, amino-C_1-3-alkyl, C_1-6-alkylamino-C_1-3-alkyl, C_3-5-cycloalkylamino-C_1-3-alkyl, C_3-5-cycloalkyl-C_1-3-alkylamino-C_1-3-alkyl, C_1-3-alkylthio-C_1-3-alkyl, C_1-3-alkoxy-C_1-3-alkyl, heteroarylamino-C_1-3-alkyl, 5-6 membered heteroaryl-C_1-3-alkylamino-C_1-3-alkyl, phenylamino-C_1-3-alkyl, phenyl-C_1-3-alkylamino-C_1-3-alkyl, 5-6 membered heteroaryloxy-C_1-3-alkyl, phenyloxy-C_1-3-alkyl, hydroxy-C_1-3-alkyl, phenyl-C_1-3-alkoxy-C_1-3-alkyl, C_1-6-alkylcarbonyl, C_1-3-alkoxycarbonyl, C_1-3-alkoxy-C_1-3-alkylcarbonyl, C_1-3-alkylaminocarbonyl, C_3-6-cycloalkylcarbonyl, C_3-6-cycloalkyl-C_1-3-alkylcarbonyl, phenylcarbonyl, phenyl-C_1-3-alkylcarbonyl, 5- or 6-membered heteroaryl-C_1-3-alkylcarbonyl, 5- or 6-membered heteroarylcarbonyl and —

(CH₂)_n—

C_3-5-cycloalkyl optionally substituted with C_1-2-alkoxycarbonyl;

wherein R²⁰ is selected from H, C_1-7-alkyl, —

(CH₂)_n—

C_5-6-cycloalkyl, —

(CH₂)_n-5-6-membered heterocyclyl, C_1-3-alkylsulfonyl, amino-C_1-3-alkyl and —

(CH₂)_n-phenyl;

alternatively R¹⁹ and R²⁰ together with the nitrogen atom form a 4-8 membered heterocyclic ring;

wherein R²¹ is selected from H, C_1-3-alkyl, C_2-3-alkenyl, C_1-3-alkylthio-C_1-3-alkyl, C_1-3-alkylcarbonylamino-C_1-3-alkyl, amino-C_1-3-alkyl, —

(CH₂)_n-[5- or 6-membered heterocyclyl], —

(CH₂)_n—

C_5-6-cycloalkyl, and —

(CH₂)_n-phenyl;

wherein R²² is selected from H, C_1-3-alkyl, —

(CH₂)_n—

C_4-6-cycloalkyl, —

(CH₂)_n-[5- or 6-membered heterocyclyl] and —

(CH₂)_n-phenyl;

alternatively R²¹ and R²² together with the amide nitrogen atom form a 5-6 membered heterocyclic ring; and

wherein R²³ is selected from H, C_1-3-alkyl, —

(CH₂)_n—

C_4-6-cycloalkyl, —

(CH₂)_n-[5- or 6-membered heterocyclyl] and —

(CH₂)_n-phenyl;

wherein phenyl and heterocyclyl are optionally substituted with one or more substituents selected from C_1-2-haloalkyl, C_1-2-alkyl, —

(CH₂)_n—

C_4-6-cycloalkyl, chloro, fluoro, —

OR¹⁷, —

NR¹⁷CO₂R¹⁷, —

NR¹⁷SO₂R¹⁷, N(R¹⁷)₂, cyano, —

COR¹⁷, —

C(R¹⁷)₂N(R¹⁷)₂, nitro, —

SO₂N(R¹⁷)₂, —

S(O)_mR¹⁷, and C_1-2-haloalkoxy;

and pharmaceutically-acceptable salts thereof.

3. Compound of claim 2 wherein R^13a is selected from H, bromo and chloro;

wherein R^13b is H;

wherein R¹⁴ is selected from trifluoromethyl, 2-hydroxyethyl, 1-hydroxyethyl, R¹⁹R²⁰N—

, R¹⁹R²⁰N—

C_1-2-alkyl and (R²¹R²²N—

)(O═

)C—

;

wherein R¹⁵ is H or trifluoromethyl;

wherein R¹⁷ is selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, phenylpropyl, phenylethyl, benzyl and phenyl;

wherein R¹⁹ is selected from H, R²³SO₂—

, methyl, ethyl, propyl, isopropyl, isopentyl, 3-ethylbutyl, hydroxymethyl, hydroxyethyl, cyclopropylmethyl, 1-(ethoxycarbonyl)cycloprop-2-ylmethyl, R²³ SO₂—

, aminomethyl, aminoethyl, dimethylaminoethyl, diethylaminoethyl, dipropylaminoethyl, di-isobutylaminoethyl, di-tert-butylmethylaminoethyl, di(3-ethylbutyl)aminoethyl, furylmethylaminoethyl, thienylmethylaminoethyl, benzylaminoethyl, di(furylmethyl)aminoethyl, di(cyclohexylmethyl)aminoethyl, di(cyclopropylmethyl)aminoethyl, di(thienylmethyl)aminoethyl, di(benzyl)aminoethyl, phenylmethoxyethyl, pyridyloxymethyl, methylthiopropyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, butylcarbonyl, cyclopentylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclohexylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, ethoxycarbonyl, propoxycarbonyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, optionally substituted thienylmethylcarbonyl, optionally substituted benzylcarbonyl, optionally substituted phenylethylcarbonyl, optionally substituted phenylcarbonyl and optionally substituted pyridylcarbonyl;

wherein R²⁰ is selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclohexyl, methylsulfonyl, aminoethyl, optionally substituted phenyl, optionally substituted imidazolyl, optionally substituted imidazolylmethyl, optionally substituted thienylmethyl, optionally substituted furylmethyl, optionally substituted pyrrolidinylmethyl, optionally substituted pyridylmethyl, optionally substituted thienylmethyl, optionally substituted benzyl, optionally substituted phenylethyl and optionally substituted phenylpropyl;

alternatively R¹⁹ and R²⁰ together with the nitrogen atom form a heterocyclic ring selected from triazolyl, tetrazolyl, 2-pyridone, oxo-pyrrolidinyl, 2-oxo-piperidinyl, 4,5-dihydro-2-oxo-oxazolyl, 1,1-dioxo-isothiazolidin-2-yl, 2-oxo-imidazolin-1-yl, 3-methyl-2-oxo-imidazolin-1-yl, piperidinyl optionally

 

substituted with one or more substituents selected from methyl, ethyl, propyl, and isopropyl,

piperazinyl optionally substituted with one or more substituents selected from methyl, ethyl, propyl, and isopropyl,

imidazolyl optionally substituted with one or more substituents selected from methyl, ethyl, propyl, and isopropyl, and

pyrrolidinyl optionally substituted with one or more substituents selected from methyl, ethyl, propyl, and isopropyl;

wherein R²¹ is selected from H, methyl, ethyl, propyl, isopropyl, allyl, methylthioethyl, methylthiomethyl, methylcarbonylaminoethyl, methylcarbonylaminomethyl, aminomethyl, aminoethyl, 1-methylpyrrolidinylethyl, piperidinylethyl, pyridyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, 4-chlorophenylmethyl, 4-phenoxyphenylethyl, benzyl and phenylethyl;

wherein R²² is H or methyl;

alternatively R²¹ and R²² together form a ring selected from pyrrolidinyl, morpholino, piperidinyl, piperazinyl, 4-acetylpiperazinyl and 4-methylpiperazinyl; and

wherein R²³ is selected from H, methyl, ethyl, propyl, optionally substituted thienyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted phenylethyl and optionally substituted phenylpropyl;

wherein phenyl and heterocyclyl are optionally substituted with one or more substituents selected from trifluoromethyl, methyl, nitro, cyano, chloro, methoxy, phenyloxy, acetyl, amino, dimethylamino and aminomethyl;

and pharmaceutically-acceptable salts thereof.

4. Compound of claim 3 wherein R¹⁴ is selected from N-pyrrolidinylcarbonyl, N-morpholinocarbonyl, N-piperidinylethylaminocarbonyl, benzylaminocarbonyl, N-methyl-N-benzylaminocarbonyl, aminoethylaminocarbonyl, pyridylaminocarbonyl, methylthioethylaminocarbonyl, methylcarbonylaminoethylaminocarbonyl, 1-methylpyrrolidinylethylaminocarbonyl, phenethylaminocarbonyl, phenylaminocarbonyl, cyclohexylmethylaminocarbonyl, N-methyl-N-phenethylaminocarbonyl, N,N-dimethylaminocarbonyl, 4-chlorophenylmethylaminocarbonyl, phenoxyphenethylaminocarbonyl, allylaminocarbonyl, 4-methylpiperazinylcarbonyl, 4-acetylpiperazinylcarbonyl, isopropylaminocarbonyl,

1-(N-cyclopropylmethylamino)ethyl, 1-(N-methyl-N-methylcarbonylamino)ethyl, 1-(N-isopropylamino)ethyl, 1-(N-isobutyl-N-methylamino)ethyl, N-cyclopropylmethyl-N-propylaminomethyl, N,N-dicyclopropylmethylaminomethyl, 1-(N-propyl-N-methylamino)ethyl, 1-(N-methyl-N-methylsulfonylamino)ethyl, triazolylmethyl, imidazol-1-ylmethyl, 2-isopropylimidazol-1-yl-methyl, 2-propylimidazol-1-yl-methyl, 2-oxo-pyrid-1-yl-methyl, 3-pyridyl-oxymethyl, 2-methylimidazol-1-yl-methyl, tetrazolylmethyl, 2,5-dimethylpyrrolidin-1-ylmethyl, 2-oxo-pyrrolidin-1-yl-methyl, 2-oxo-piperidin-1-yl-methyl, 4,5-dihydro-2-oxo-oxazol-3-yl-methyl, pyrrolidin-1-ylmethyl, 2,6-dimethylpiperidin-1-ylmethyl, piperazin-1-yl-methyl, 4-methylpiperazin-1-yl-methyl, piperidin-1-yl-methyl, 1-(N-ethyl-N-methylamino)ethyl, 1-(N,N-dipropylamino)ethyl, 1-(N,N-diisopropylamino)ethyl, 1-(N-(1-ethoxycarbonyl)cycloprop-2-ylmethyl-N-methylamino)ethyl, 1-(N-(2-methylbutyl)-N-methylamino)ethyl, 1-(N-(4-methylcarbonylaminophenyl)methyl-N-methylamino)ethyl, 1-(N-methylamino)ethyl, 1-(N,N-dimethylamino)ethyl, N,N-dimethylaminomethyl, N-cyclopropylmethyl-N-methylsulfonylaminomethyl, 1-(N-(3-thienyl)methyl-N-methylamino)ethyl, 1-(N-phenylmethoxyethyl-N-methylamino)ethyl, 1-(N-(2-methoxyphenyl)methyl-N-methylamino)ethyl, 1-(N-(4-pyridyl)methyl-N-methylamino)ethyl, 1-(N-(2-pyrrolidinyl)methyl-N-methylamino)ethyl, 1-(N-(3-methoxyphenyl)methyl-N-methylamino)ethyl, 1-(N-(4-methoxyphenyl)methyl-N-methylamino)ethyl, 1-(N-benzyl-N-methylamino)ethyl, 1-(N-methyl-N-aminoethylamino)ethyl, 1-(N-cyclohexylmethyl-N-methylamino)ethyl, N,N-dimethylaminomethyl, N-(1-hydroxyethyl)-N-methylaminomethyl, N-(1-hydroxyethyl)-N-methylaminomethyl,

N-propyl-N-methylsulfonylamino, N-(methylsulfonyl)-N-propylamino, N-(methylsulfonyl)-N-cyclopropylmethylamino, N-(methylsulfonyl)-N-aminoethylamino, N-(methylsulfonyl)-N-(N′

,N′

-dimethylaminoethyl)amino, N-(N′

,N′

-diethylaminoethyl)-N-methylsulfonylamino, N-(N′

,N′

-dipropylaminoethyl)-N-methylsulfonylamino, N-(N′

,N′

-diisobutylaminoethyl)-N-methylsulfonylamino, N-(N′

,N′

-di-tert-butylmethylaminoethyl)-N-methylsulfonylamino, N-(N′

,N′

-di(cyclopropylmethyl)aminoethyl)-N-methylsulfonylamino, N-(N′

,N′

-di(2-furylmethyl)aminoethyl)-N-methylsulfonylamino, N-(N′

,N′

-di(3-thienylmethyl)aminoethyl)-N-methylsulfonylamino, N-(N′

,N′

-di(benzyl)aminoethyl)-N-methylsulfonylamino, N-(methylsulfonyl)-N-isobutylamino, N-(methylsulfonyl)-N-methylamino, N-(methylsulfonyl)-N-phenethylamino, N-(methylsulfonyl)amino, N-(benzylsulfonyl)amino, N-(propylsulfonyl)amino, N-(phenylsulfonyl)amino, N-(methylsulfonyl)-N-phenylpropylamino, thienylsulfonylamino, (2-nitrophenyl)methylsulfonylamino, (2,4,6-trimethylphenyl)sulfonylamino, (2-cyanophenyl)sulfonylamino,

N-methoxymethylcarbonyl-N-cyclopropylmethylamino, N-methylcarbonyl-N-cyclopropylmethylamino, N-phenylcarbonyl-N-cyclopropylmethylamino, N-(3-methoxyphenylcarbonyl-N-cyclopropylmethylamino, N-benzylcarbonyl-N-cyclopropylmethylamino, N-phenylethyl-N-cyclopropylmethylamino, N-(2-imidazolyl)-N-cyclopropylmethylamino, N-(4-methyl-5-imidazolyl)-N-cyclopropylmethylamino, N-(2-thienylmethyl)-N-cyclopropylmethylamino, N-(3-thienylmethyl)-N-cyclopropylmethylamino, N-(3-furylmethyl)-N-cyclopropylmethylamino, N-(4-imidazolyl)-N-cyclopropylmethylamino, N-cyclopentylcarbonyl-N-cyclopropylmethylamino, N-cyclohexylcarbonyl-N-cyclopropylmethylamino, N-methylthiopropyl-N-cyclopropylmethylamino, N-ethylcarbonyl-N-cyclopropylmethylamino, N-isopropylcarbonyl-N-cyclopropylmethylamino, N-isobutylcarbonyl-N-cyclopropylmethylamino, N-ethyl-N-cyclopropylmethylamino, N-isobutyl-N-cyclopropylmethylamino, N-cyclopropylcarbonyl-N-cyclopropylmethylamino, N,N-di(cyclopropylmethyl)amino,

N-methoxymethylcarbonyl-N-aminoethylamino, N-ethylcarbonyl-N-aminoethylamino, N-isopropylcarbonyl-N-aminoethylamino, N-isobutylcarbonyl-N-aminoethylamino, N-tert-butylcarbonyl-N-aminoethylamino, N-propylcarbonyl-N-aminoethylamino, N-pentylcarbonyl-N-aminoethylamino, N-ethyl-N-aminoethylamino, N-propyl-N-aminoethylamino, N-cyclopropyl-N-aminoethylamino, N-cyclopropylmethyl-N-aminoethylamino, N-cyclobutylmethyl-N-aminoethylamino, N-butyl-N-aminoethylamino, N-pentyl-N-aminoethylamino, N-hexyl-N-aminoethylamino, N-heptyl-N-aminoethylamino, N-(3-ethylbutyl)-N-aminoethylamino, N-cyclohexylcarbonyl-N-aminoethylamino, N-phenylcarbonyl-N-aminoethylamino, N-(3-methoxyphenyl)carbonyl-N-aminoethylamino, N-benzylcarbonyl-N-aminoethylamino, N-phenylethylcarbonyl-N-aminoethylamino, N-pyridylcarbonyl-N-aminoethylamino, N-thienylmethyl-N-aminoethylamino,

aminoethylamino, pyridylcarbonylamino, N-cyclopropylmethylamino, methylcarbonylamino, methoxycarbonylamino, trifluoromethyl, 2-hydroxyethyl, 1-hydroxyethyl, methylaminocarbonylamino, 1,1-dioxo-isothiazolidin-2-yl, 2-oxo-imidazolin-1-yl and 3-methyl-2-oxo-imidazolin-1-yl;

and pharmaceutically-acceptable salts thereof.

5. Compound of claim 1 wherein R¹⁶ is selected from pyridyl, 4-pyridyl, 5-benzopyrrolyl, 2-benzofuran, 2-benzothienyl, 6-quinolyl, and thienyl,

and pharmaceutically-acceptable salts thereof.

6. Compound of claim 1 wherein R¹⁶ is selected from 3-azetidinyl optionally N-substituted with a substituent selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclohexylmethyl and benzyl;

and pharmaceutically-acceptable salts thereof.

7. Compound of claim 1 wherein R¹⁶ is selected from 5-benzopyrrolyl, 2-benzofuran, 2-benzothienyl, and 4-quinolyl;

and pharmaceutically-acceptable salts thereof.

8. Compound of claim 1 wherein R¹⁶ is selected from 4-pyridyl, 3-pyridyl and thienyl;

and pharmaceutically-acceptable salts thereof.

9. Compound of claim 1 wherein R¹⁶ is selected from 4-piperidyl, N-methyl-4-piperidyl, N-methyl-2-piperidyl, N-ethyl-4-piperidyl, N-isobutyl-4-piperidyl, and 3-piperidyl;

and pharmaceutically-acceptable salts thereof.

10. Compound of claim 1 and pharmaceutically acceptable salts thereof selected from

N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]azetidin-3-ylcarboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]((2S) (2-piperidyl))carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]-4-piperidylcarboxamide;

((2R)azetidin-2-yl)-N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]-3-pyridylcarboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]-4-pyridylcarboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl)-6-quinolylcarboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]azetidin-3-ylcarboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]-3-piperidylcarboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl](1-methyl(2-piperidyl))carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl](1-methyl(4-piperidyl))carboxamide;

N-[(1S)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]azetidin-3-ylcarboxamide;

quinoline-6-carboxylic acid [1-(4-chloro-benzyl)-2-(4-{2-[1-(cyclopropylmethyl-amino)-ethyl]-phenyl}-piperazin-1-yl)-2-oxo-ethyl]-amide;

quinoline-6-carboxylic acid [2-(4-{2-(1-(bis-cyclopropylmethyl-amino)-ethyl]-phenyl}-piperazin-1-yl)-1-(4-chloro-benzyl)-2-oxo-ethyl]-amide;

quinoline-6-carboxylic acid [2-(4-{2-[(bis-cyclopropylmethyl-amino)methyl]phenyl}-piperazin-1-yl)-1-(4-chlorobenzyl)-2-oxo-ethyl]amide;

quinoline-6-carboxylic acid [1-(4-chlorobenzyl)-2-(4-{2-[(cyclopropylmethyl-propylamino)methyl]phenyl}-piperazin-1-yl)-2-oxo-ethyl]amide;

N-[1-(4-chlorobenzyl)-2-(4-{2-[(cyclopropylmethyl-propyl-amino)-methyl]-4-fluorophenyl}-piperazin-1-yl)-2-oxo-ethyl]-3-piperidin-1-yl-propionamide;

azetidine-3-carboxylic acid {1-(4-chlorobenzyl)-2-oxo-2-[4-(2-[1,2,3]triazol-2-ylmethylphenyl)piperazin-1-yl]ethyl}amide;

quinoline-6-carboxylic acid {1-(4-chlorobenzyl)-2-[4-(2-{1-[cyclopropylmethyl-(3-methylbutyl)amino]ethyl}-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-amide;

quinoline-6-carboxylic acid [1-(4-chlorobenzyl)-2-(4-{2-[1-(cyclohexylmethyl-cyclopropylmethyl-amino)-ethyl]-phenyl}-piperazin-1-yl)-2-oxo-ethyl]-amide;

quinoline-6-carboxylic acid {1-(4-chlorobenzyl)-2-[4-(2-{1-[cyclopropylmethyl-(3-methylsulfanylpropyl)amino]-ethyl}phenyl)-piperazin-1-yl]-2-oxo-ethyl}-amide;

quinoline-6-carboxylic acid [1-(4-chlorobenzyl)-2-(4-{2-[1-(cyclopropylmethyl-thiophen-3-ylmethylamino)-ethyl]-phenyl}-piperazin-1-yl)-2-oxo-ethyl}-amide;

quinoline-6-carboxylic acid (1-(4-chlorobenzyl)-2-{4-[2-(cyclopropylmethyl-methylsulfonylamino)-phenyl]-piperazin-1-yl}-2-oxo-ethyl)-amide;

1-isobutyl-azetidine-3-carboxylic acid (1-(4-chloro-benzyl)-2-{4-[2-(cyclopropylmethyl-methylsulfonyl-amino)-phenyl]-piperazin-1-yl}-2-oxo-ethyl)-amide;

1-(2,2-dimethylpropyl)-azetidine-3-carboxylic acid (1-(4-chlorobenzyl)-2-{4-[2-(cyclopropylmethyl-methylsulfonylamino)phenyl]-piperazin-1-yl}-2-oxo-ethyl)-amide;

1-cyclopropylmethyl-azetidine-3-carboxylic acid (1-(4-chlorobenzyl)-2-{4-[2-(cyclopropylmethyl-methylsulfonylamino)phenyl]piperazin-1-yl}-2-oxo-ethyl)-amide; and

piperidine-4-carboxylic acid (1-(4-chlorobenzyl)-2-{4-[2-(cyclopropylmethyl-methanesulfonylamino)phenyl]-piperazin-1-yl}-2-oxo-ethyl)amide.

12. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound as in claim 1.

13. A method of treating obesity in a subject, said method comprising administering an effective amount of a compound of claim 1.

14. A method of treating diabetes mellitus in a subject, said method comprising administering an effective amount of a compound of claim 1.

11. A compound and pharmaceutically acceptable salts thereof selected from

quinoline-6-carboxylic acid [1-(4-chloro-benzyl)-2-(4-{2-[1-(cyclopropylmethyl-amino)-ethyl]-phenyl)-piperazin-1-yl)-2-oxo-ethyl]-amide;

quinoline-6-carboxylic acid [2-(4-{2-[1-(bis-cyclopropylmethyl-amino)-ethyl]-phenyl}-piperazin-1-yl)-1-(4-chloro-benzyl)-2-oxo-ethyl]-amide;

quinoline-6-carboxylic acid [2-(4-{2-[(bis-cyclopropylmethyl-amino)methyl]phenyl}-piperazin-1-yl)-1-(4-chlorobenzyl)-2-oxo-ethyl]amide;

quinoline-6-carboxylic acid [1-(4-chlorobenzyl)-2-(4-{2-[(cyclopropylmethyl-propylamino)methyl]phenyl}-piperazin-1-yl)-2-oxo-ethyl]amide;

N-[1-(4-chlorobenzyl)-2-(4-{2-[(cyclopropylmethyl-propyl-amino)-methyl]-4-fluorophenyl}-piperazin-1-yl)-2-oxo-ethyl]-3-piperidin-1-yl-propionamide;

azetidine-3-carboxylic acid {1-(4-chlorobenzyl)-2-oxo-2-[4-(2-[1,2,3]triazol-2-ylmethylphenyl)piperazin-1-yl]ethyl}amide;

quinoline-6-carboxylic acid {1-(4-chlorobenzyl)-2-[4-(2-{1-[cyclopropylmethyl-(3-methylbutyl)amino]ethyl}-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-amide;

quinoline-6-carboxylic acid [1-(4-chlorobenzyl)-2-(4-{2-[1-(cyclohexylmethyl-cyclopropylmethyl-amino)-ethyl]-phenyl}-piperazin-1-yl)-2-oxo-ethyl]-amide;

quinoline-6-carboxylic acid [1-(4-chlorobenzyl)-2-[4-(2-{1-[cyclopropylmethyl-(3-methylsulfanylpropyl)amino]-ethyl}phenyl)-piperazin-1-yl]-2-oxo-ethyl}-amide;

quinoline-6-carboxylic acid [1-(4-chlorobenzyl)-2-(4-(2-[1-(cyclopropylmethyl-thiophen-3-ylmethylamino)-ethyl]-phenyl)-piperazin-1-yl)-2-oxo-ethyl]-amide;

quinoline-6-carboxylic acid [1-(4-chlorobenzyl)-2-{4-[2-(cyclopropylmethyl-methylsulfonylamino)-phenyl]-piperazin-1-yl}-2-oxo-ethyl)-amide;

1-isobutyl-azetidine-3-carboxylic acid {1-(4-chloro-benzyl)-2-{4-[2-(cyclopropylmethyl-methylsulfonyl-amino)-phenyl]-piperazin-1-yl}-2-oxo-ethyl)-amide;

1-(2,2-dimethylpropyl)-azetidine-3-carboxylic acid (1-(4-chlorobenzyl)-2-}4-[2-(cyclopropylmethyl-methylsulfonylamino)phenyl]-piperazin-1-yl{-2-oxo-ethyl)-amide;

1-cyclopropylmethyl-azetidine-3-carboxylic acid (1-(4-chlorobenzyl)-2-[4-[2-(cyclopropylmethyl-methylsulfonylamino)phenyl]piperazin-1-yl}-2-oxo-ethyl)-amide; and

piperidine-4-carboxylic acid [1-(4-chlorobenzyl)-2-{4-[2-(cyclopropylmethyl-methylsulfonylamino)phenyl]-piperazin-1-yl}-2-oxo-ethyl)amide.