Substituted piperidines and methods of use

• US 6,977,264 B2
• Filed: 07/24/2002
• Issued: 12/20/2005
• Est. Priority Date: 07/25/2001
• Status: Expired due to Fees

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Norman, Mark H., Xi, Ning, Xu, Shimin, Kelly, Michael G., Croghan, Michael, Fotsch, Christopher H., Doherty, Elizabeth M., Tamayo, Nuria, Smith, Duncan M.
• Primary Examiner(s): Davis, Zinna Northington
• Application Number:
  US10/205,649
• Publication Number:
  US 20040006067A1
• Time in Patent Office: 1,245 Days
• Field of Search: 514/330, 546/226
• US Class Current: 514/330
• 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 211/28 : to which a second hetero atom is attached
• CPC Class Codes: C07D 211/34 : with hydrocarbon 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 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07K 5/06139 : with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06191 : containing heteroatoms different from O, S, or N

Abstract

Selected substituted piperidine compounds 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 I

wherein Y is —

NH—

;

wherein R is phenyl ortho substituted with a radical selected from R⁴ and optionally substituted with a radical selected from R⁴;

wherein R^1a, R^1b, R^1c, R^1d, R^1e, and R^1f are independently selected from R⁴;

or wherein R^1a and R^1b or R^1d and R^1c form oxo;

wherein R² is selected from

a)—

(CH₂)_n—

C_3-6-cycloalkyl,

b)—

(CH₂)_n-phenyl,

c)—

(CH₂)_n-5-10-membered heterocyclyl, and

wherein the cycloalkyl and aryl groups are optionally substituted with 1 to 3 radicals selected from R⁴; and

the heterocyclyl groups are optionally substituted with 1 to 3 radicals selected from R⁴ and oxo;

wherein R³ is independently selected from H, chloro, bromo, iodo, phenyl, fluoro, amino, C_1-2-alkyl, C_1-2-haloalkyl, C_1-2-haloalkoxy, and C_1-2-alkoxy;

wherein R⁴ is selected from H, C_1-2-alkyl, —

(CH₂)_n—

C_5-6-cycloalkyl, —

(CH₂)_n-phenyl, —

(CH₂)_n-4-10-membered heterocyclyl, fluoro, chloro, —

(CH₂)_n—

OR^9a, —

NR^9aSO₂R⁷, —

NR^9aR^9b, C(O)NR^9aR^9b, —

NR^9aC(O)R⁷, cyano, nitro, —

(CH₂)_n—

C(O)R⁷, —

C(O)OR^9a, —

(CH₂)_n—

C(S)R⁷, —

(CH₂)_n—

C═

(NR^9a)R⁷, —

NR^9aC═

(NR^9a)N(R⁷)₂, —

[C(R⁷)₂]_pNR^9aR^9b, —

[CH₂]_pNR^9aSO₂R⁷, —

[CH₂]_pNR^9aC(O)R⁷, —

SO₂NR^9aR^9b, —

S(O)_mR⁷, —

C(R⁷)₂SO₂CF₃, C_1-2-hydroxyalkyl C_1-2-haloalkyl and C_1-2-haloalkoxy;

wherein R⁵ is selected from halo, —

OR^9a, —

NR^9aR^9b, —

[C(R⁷)₂]_nNR^9aR^9b, and —

SO₂NR^9aR^9b;

wherein R⁶ is naphthyl or phenyl optionally substituted with one or two R³;

wherein R⁷ is selected from H, C_1-4-alkyl, —

(CH₂)_n—

C_3-6-cycloalkyl, —

(CH₂)_n-4-10-membered heterocyclyl,

—

(CH₂)_n-phenyl, amino-C_1-4-alkyl, C_1-4-alkylamino, C_2-4-alkenyl, C_1-4-alkylthio-C_1-4-alkyl, C_1-4-alkylcarbonylamino-C_1-4-alkyl, C_1-4-alkylamino-C_1-4-alkyl, C_1-4-alkoxy-C_1-4-alkyl and C_1-4-alkoxy;

wherein R⁸ is selected from

a) amino-C_1-4-alkylamino,

b) amino-C_1-4-alkyl,

c) C_1-4-alkylamino-C_1-4-alkylamino,

d) C_1-4-alkylamino-C_1-4-alkyl,

e) phenyl-C_1-4-alkylamino-C_1-4-alkyl,

f) phenylamino-C_1-4-alkyl,

g) 4-10-membered heterocyclyl-C_1-4-alkylamino-C_1-4-alkyl,

h) N-(4-10-membered heterocyclyl-C_1-4-alkyl)amino,

i) C_1-4-alkyl,

j) C_3-6-cycloalkyl-(CH₂) n—

,

k) aryl-(CH₂)_n—

,

l) 4-10-membered heterocyclyl-(CH₂)_n—

,

m) R^9aO—

,

n) amino-C_1-4-alkoxy,

o) phenyl-C_1-4-alkyl where the alkyl portion is substituted with amino, hydroxy or C_1-4-alkylamino, and

p) 4-10-membered heterocyclyl-C_1-4-alkylenyl where the alkylenyl portion is substituted with amino, hydroxy or C_1-4-alkylamino;

wherein the cycloalkyl and aryl groups are optionally substituted with 1 to 3 groups selected from R⁴; and

the heterocyclyl groups are optionally substituted with 1 to 3 groups selected from R⁴ and oxo;

wherein R^9a is selected from H, C_1-6-alkyl, C_3-6-cycloalkyl-(CH₂)_n—

, 4-10-membered heterocyclyl-(CH₂)_n—

, and phenyl-(CH₂)_n—

;

wherein R^9b is selected from H, C_1-6-alkyl, C_2-6-alkenyl, C_3-6-cycloalkyl-(CH₂)_n—

, 4-10-membered heterocyclyl-(CH₂)_n—

, phenyl-(CH₂) _n—

, amino-C_1-6-alkyl, C_1-6-alkylcarbonylamino-C_1-6-alkyl, C_3-6-cycloalkylamino-C_1-6-alkyl, C_3-6-cycloalkyl-C_1-6-alkylamino-C_1-6-alkyl, 5-6-membered heteroarylamino-C_1-6-alkyl, 5-6-membered heteroaryl-C_1-6-alkylamino-C_1-6-alkyl, phenylamino-C_1-6-alkyl, phenyl-C_1-6-alkylamino-C_1-6-alkyl, 5-6-membered heteroaryloxy-C_1-6-alkyl, 5-6-membered heteroaryl-C_1-6-alkyloxy-C_1-6-alkyl, phenyl-C_1-6-alkyloxy-C_1-6-alkyl, phenyloxy-C_1-6-alkyl, C_1-6-alkylthio-C_1-6-alkyl, C_1-6-alkylamino-C_1-6-alkyl, C_1-6-hydroxyalkyl and C_1-6-alkoxy-C_1-6-alkyl;

wherein R^a are independently H or methyl;

wherein k is 1;

wherein m is 0, 1 or 2;

wherein n is 0, 1, 2 or 3;

wherein p is 1 or 2; and

wherein q is 1;

and a pharmaceutically-acceptable salt thereof;

provided R² is not —

CO₂(tert-butyl) when R⁴ is hydrogen or methoxy and when R⁶ is phenyl.

2. A compound of claim 1, wherein R is

wherein R^1a, R^1b, R^1c, R^1d, R^1e, and R^1f are H;

wherein R² is selected from

a)—

(CH₂)_n—

C_3-6-cycloalkyl,

b)—

(CH₂)_n-phenyl, and

c)—

(CH₂)_n-6-10-membered heterocyclyl;

wherein the cycloalkyl and aryl groups are optionally substituted with 1 to 2 groups selected from R^4b; and

the heterocyclyl group is optionally substituted with 1 to 2 groups selected from R^4b and oxo;

wherein R³ is independently selected from H, chloro, bromo, iodo, fluoro, amino, methyl, trifluoromethyl, trifluoromethoxy and methoxy;

wherein R^4a is selected from —

(CH₂)_n—

OR^9a, —

NR^9aSO₂R^7a, 4-6-membered heterocyclyl, —

[CH₂]_pNR^9aSO₂R^7a, —

NR^9aR^9b, —

C(O)NR^9aR^9b, —

NR^9bC(O)R^7a, —

[CH₂]_pNR^9bC(O)R^7a, —

(CH₂)_n—

C(O)R^7a, nitro, —

C(O)OR^9a, —

(CH₂)_n—

C(S)R^7a, —

[C(R^7a)₂]_pNR^9aR^9b, —

SO₂NR^9aR^9b, S(O)_mR^7aand —

C(R^7a)₂SO₂CF₃;

wherein R^4b is selected from H, C_1-2-alkyl, —

(CH₂)_n—

C_5-6-cycloalkyl, —

(CH₂)_n-phenyl, —

(CH₂)_n-4-10-membered heterocyclyl, fluoro, chloro, —

OR^9a(CH₂)_n—

OR^9a, —

NR^9aSO₂R^7a, —

NR^9aR^9b, —

C(O)NR^9aR^9b, —

NR^9aC(O)R^7b, —

(CH₂)_n—

C(O)R^7a, nitro, —

C(O)R^9a, —

(CH₂)_n—

C(S)R^7a, —

[C(R^7a)₂]_pNR^9aR^9b, —

SO₂NR^9aR^9b, —

S(O)_mR^7a, —

C(R^7a)₂SO₂CF₃, cyano, C_1-2-haloalkyl and C_1-2-haloalkoxy;

wherein R^7a is selected from H, C_1-3-alkyl, —

(CH₂)_n—

C_3-6-cycloalkyl, —

(CH₂)_n-4-10-membered heterocyclyl and —

(CH₂)_n-phenyl;

wherein R^7b is selected from H, amino-C_1-3-alkyl, C_1-3-alkoxy, C_1-3-alkylamino, C_2-3-alkenyl, C_1-3-alkylthio-C_1-3-alkyl, C_1-3-alkylamino-C_1-3-alkyl, C_1-3-alkoxy-C_1-3-alkyl, H, C_1-3-alkyl, —

(CH₂)_n—

C_3-6-cycloalkyl, —

(CH₂)_n-4-10-membered heterocyclyl and —

(CH₂)_n-phenyl;

wherein R^9a is selected from H, C_1-6-alkyl, C_5-6-cycloalkyl-(CH₂)_n—

, 4-10-membered heterocyclyl-(CH₂)_n—

, and phenyl-(CH₂)_n—

;

wherein R^9b is selected from H, C_1-6-alkyl, C_5-6-cycloalkyl-(CH₂)_n—

, 4-10-membered heterocyclyl-CH₂)_n—

, phenyl-(CH₂)_n—

, amino-C_1-3-alkyl, C_1-3-alkylcarbonylamino-C_1-3-alkyl, C_5-6-cycloalkylamino-C_1-3-alkyl, C_5-6-cycloalkyl-C_1-3-alkylamino-C_1-3-alkyl, 5-6-membered 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, 5-6-membered heteroaryl-C_1-3-alkyloxy-C_1-3-alkyl, phenyl-C_1-3-alkyloxy-C_1-3-alkyl, phenyloxy-C_1-3-alkyl, C_1-3-alkylthio-C_1-3-alkyl, C_1-3-alkylamino-C_1-3-alkyl, C_1-3-hydroxyalkyl and C_1-3-alkoxy-C_1-3-alkyl;

wherein R^a are H;

wherein k is 1;

wherein m is 2;

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

wherein p is 1 or 2;

and a pharmaceutically-acceptable salt thereof.

3. A compound of claim 2, wherein R is

wherein R² is selected from indolyl(CH₂)_n—

, phenyl(CH₂)_n—

, benzoxazolyl(CH₂)_n—

, oxazolo[4,5-b]pyridyl(CH₂)_n—

, oxazolo[5,4-b]pyridyl(CH₂)_n—

, benzoxazolyl(CH₂)_n—

, 1,2,3,4-tetrahydro-isoquinolyl (CH₂)_n—

, pyridyl(CH₂)_n— and

2,3-dihydro-benzo[1,4]dioxanyl(CH₂)_n—

;

wherein R² is optionally substituted with 1 to 2 groups selected from R^4b;

wherein R³ is independently selected from H, chloro, bromo, amino, methyl, trifluoromethyl and methoxy;

wherein R^4a is selected from 4-5-membered heterocyclyl, —

NR^9aSO₂R^7a, —

NR^9aR^9b, —

C(O)NR^9aR^9b, —

C_1-3—

NR^9aSO₂R^7a, —

C_1-3—

NR^9aC(O)R^7b, —

NR^9bC(O)R^7a and —

C_1-3—

NR^9aR^9b;

wherein R⁶ is phenyl optionally substituted with one or two R³;

wherein R^7a, is selected from H, C_1-3-alkyl, —

(CH₂)_n—

C_3-6-cycloalkyl, —

(CH₂)_n-4-10-membered heterocyclyl and —

(CH₂)_n-phenyl;

wherein R^7b is selected from H, amino-C_1-3-alkyl, C_1-3-alkoxy, C_1-3-alkylamino, C_2-3-alkenyl, C_1-3-alkylthio-C_1-3-alkyl, C_1-3-alkylamino-C_1-3-alkyl, C_1-3-alkoxy-C_1-3-alkyl, H, C_1-3-alkyl, —

(CH₂)_n—

C_3-6-cycloalkyl, —

(CH₂)_n-4-10-membered heterocyclyl and —

(CH₂)_n-phenyl;

wherein R^9a is selected from H, C_1-6-alkyl, C_5-6-cycloalkyl-(CH₂)_n—

, 4-10-membered heterocyclyl-(CH₂)_n—

, and phenyl-(CH₂)_n—

;

wherein R^9b is selected from H, C_1-6-alkyl, C_5-6-cycloalkyl-(CH₂)_n—

, 4-10-membered heterocyclyl-(CH₂)_n—

, phenyl-(CH₂)_n—

, amino-C_1-3-alkyl, C_1-3-alkylcarbonylamino-C-_1-3-alkyl, C_5-6-cycloalkylamino-C_1-3-alkyl, C_5-6-cycloalkyl-C_1-3-alkylamino-C_1-3-alkyl, 5-6-membered 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, 5-6-membered heteroaryl-C_1-3-alkyloxy-C_1-3-alkyl, phenyl-C_1-3-alkyloxy-C_1-3-alkyl, phenyloxy-C_1-3-alkyl, C_1-3-alkylthio-C_1-3-alkyl, C_1-3-alkylamino-C_1-3-alkyl, C_1-3-hydroxyalkyl and C_1-3-alkoxy-C_1-3-alkyl;

wherein k is 1;

wherein m is 2;

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

wherein p is 1 or 2;

and a pharmaceutically-acceptable salt thereof.

4. A compound of claim 1 wherein R is

wherein R^1a, R^1b, R^1c, R^1d, R^1e, and R^1f are H;

wherein R² is selected from

wherein R³ is independently selected from H, chloro, bromo, iodo, fluoro, amino, methyl, trifluoromethyl, trifluoromethoxy and methoxy;

wherein R^4a is selected from —

C_1-2-alkyl-NR^9aSO₂R^7a, —

NR^9aSO₂R^7a, 4-5-membered heterocyclyl —

NR^9aR^9b, —

C(O)NR^9aR^9b, —

C_1-2-alkyl-NR^9aC(O)R^7b, —

NR^9bC(O)R^7a and —

C_1-2-alkyl-NR^9aR^9b;

wherein R^4b is selected from H, C_1-2-alkyl, —

(CH₂)_n—

C_5-6-cycloalkyl, —

(CH₂)_n-phenyl, —

(CH₂)_n-4-10-membered heterocyclyl, fluoro, chloro, —

OR⁷, —

NR⁷SO₂R⁷, —

N(R⁷)₂, cyano, —

(CH₂)—

C(O)R⁷, —

C(O)OR⁷, —

(CH₂)_n—

C(S)R⁷, —

[C(R⁷)₂]_pN(R⁷)₂, —

SO₂N(R⁷)₂, —

S(O)_mR⁷, —

C(R⁷)₂SO₂CF₃, C_1-2-haloalkyl and C_1-2-haloalkoxy;

wherein R⁵ is selected from chloro, fluoro, hydroxyl, —

NR^7aR^7b and —

SO₂N(R^7a)₂;

wherein R⁶ is phenyl optionally substituted with one or two R³;

wherein R^7a is selected from H, C_1-3-alkyl, —

(CH₂)_n—

C_3-6-cycloalkyl, —

(CH₂)_n-4-10-membered heterocyclyl and —

(CH₂)_n-phenyl;

wherein R^7b is selected from H, amino-C_1-3-alkyl, C_1-3-alkoxy, C_1-3-alkylamino, C_2-3-alkenyl, C_1-3-alkylthio-C_1-3-alkyl, C_1-3-alkylamino-C_1-3-alkyl, C_1-3-alkoxy-C_1-3-alkyl, H, C_1-3-alkyl, —

(CH₂)_n—

C_3-6-cycloalkyl, —

(CH₂)_n-4-10-membered heterocyclyl and —

(CH₂)_n-phenyl;

wherein R⁸ is selected from

a) amino-C^1-4-alkylamino,

b) amino-C_1-4-alkyl,

c) C_1-4-alkylamino-C_1-4-alkylamino,

d) C_1-4-alkylamino-C_1-4-alkyl,

e) phenylamino-C_1-4-alkyl,

f) phenyl-C_1-2-alkylamino-C_1-4-alkyl,

g) 4-10-membered heterocyclyl-C_1-4-alkylamino-C_1-4-alkyl,

h) N-(4-10-membered heterocyclyl-C_1-4-alkyl)amino,

i) C_1-4-alkyl,

j) C_3-6-cycloalkyl-(CH₂)_n—

,

k) aryl-(CH₂)_n—

,

l) 4-10-membered heterocyclyl-(CH₂)_n—

,

m) amino-C_1-4-alkoxy,

n) phenyl-C_1-4-alkyl where the alkyl portion is substituted with amino, hydroxy or C_1-4-alkylamino, and

o) 4-10-membered heterocyclyl-C_1-4-alkylenyl where the alkylenyl portion is substituted with amino, hydroxy or —

C_1-4-alkylamino;

wherein the cycloalkyl and aryl groups are optionally substituted with 1 to 2 groups selected from R^4b; and

the heterocyclyl groups are optionally substituted with 1 to 2 groups selected from R^4b and oxo;

wherein R^9a is selected from H, C_1-6-alkyl, C_5-6-cycloalkyl-(CH₂)_n—

, 4-10-membered heterocyclyl-(CH₂)_n—

, and phenyl-(CH₂)_n—

;

wherein R^9b is selected from H, C_1-6-alkyl, C_5-6-cycloalkyl-(CH₂)_n—

, 4-10-membered heterocyclyl-(CH₂)_n—

, phenyl-(CH₂)_n—

, amino-C_1-3-alkyl, C_1-3-alkylcarbonylamino-C_1-3-alkyl, C_5-6-cycloalkylamino-C_1-3-alkyl, C_5-6-cycloalkyl-C_1-3-alkylamino-C_1-3-alkyl, 5-6-membered 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, 5-6-membered heteroaryl-C_1-3-alkyloxy-C_1-3-alkyl, phenyl-C_1-3-alkyloxy-C_1-3-alkyl, phenyloxy-C_1-3-alkyl, C_1-3-alkylthio-C_1-3-alkyl, C_1-3-alkylamino-C_1-3-alkyl, C_1-3-hydroxyalkyl and C_1-3-alkoxy-C_1-3-alkyl;

wherein R^a are H;

wherein k is 1;

wherein m is 2;

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

wherein p is 1 or 2;

and a pharmaceutically-acceptable salt thereof.

5. A compound of claim 4 wherein R⁸ is

or optionally substituted azetidinyl;

wherein A is selected from phenyl or 5-6-membered heteroaryl;

wherein R^c is H or methyl;

r is 0 or 1; and

q is 0 or 1.

6. Compound of claim 5 wherein R⁸ is

where R^b is selected from H, C_1-6-alkyl, C_5-6-cycloalkyl-(CH₂)—

, 4-10-membered heterocyclyl-(CH₂)_n- and phenyl-(CH₂)_n—

.

7. A compound of claim 1 and pharmaceutically acceptable salts thereof selected from

((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-{(1R)-2-[4-(2-methoxyphenyl)-piperidyl]-2-oxo-1-benzylethyl}carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

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

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((3S,1R)-3-aminocyclopentyl)carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((1S,3R)-3-aminocyclopentyl)carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl](5-oxopyrrolidin-2-yl)carboxamide;

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

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

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((2S,3R)-3-phenylpyrrolidin-2-yl)carboxamide;

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

((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperidyl)-2-oxoethyl]carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

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

N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(trifluoromethyl)phenyl]-piperidyl}ethyl)((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-[2-(hydroxyethyl)phenyl]piperidyl}-2-oxoethyl)((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

N-[(1R)-2-(4-{2-[(2-aminoethyl)(methylsulfonyl)amino]-phenyl}piperidyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-carboxamide;

((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-[2-(3-methyl-2-oxo(4-imidazolinyl))phenyl]piperidyl}-2-oxoethyl)carboxamide;

((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(2-oxo(4-imidazolinyl))phenyl]piperidyl)ethyl)carboxamide;

N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(2-oxo(4-imidazolinyl))phenyl]-piperidyl}ethyl)azetidin-3-ylcarboxamide;

tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl}(3S)-1,2,3,4-tetrahydroisoguinoline-2-carboxylate;

N-{(1R)-1-[(4-chlorophenyl)methyl]-2-[4-(2-{[(2-cyanophenyl)sulfonyl]amino}-phenyl)piperidyl]-2-oxoethyl}((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-[4-(2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}phenyl)piperidyl]ethyl}((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylamino)carbonylamino]-phenyl}piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-(2-(methoxycarbonylamino)phenyl]piperidyl}-2-oxoethyl)((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)amino]-phenyl}piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide; and

N-[(1R)-2-(4-{2-[(2-aminoethyl)amino]phenyl}piperidyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide.

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

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

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

8. A compound of Formula II

wherein R¹⁰ is selected from H, chloro or fluoro;

or wherein R¹⁰ is a C_1-4-alkylene bridge;

wherein R¹² is selected from optionally substituted phenyl-C_1-2-alkylenyl, optionally substituted 5-10 membered heteroaryl and

provided the optionally substituted heterocyclyl is not nitro substituted;

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

a) 4-6 membered saturated heterocyclyl,

b) 10 membered partially unsaturated heterocyclyl,

c) 5-10 membered heteroaryl,

d) C_1-4-aminoalkyl,

e) C_1-4-aminoalkylamino,

f) C_1-4-alkylamino-C_1-4-alkylamino,

g) C_1-4-alkylamino-C_1-4-alkyl,

h) arylamino-C_1-4-alkyl,

i) aryl-C_1-4-alkylamino-C_1-4alkyl,

j) heterocyclyl-C_1-4-alkylamino-C_1-4-alkyl,

k) aryl, provided if 2-substituted aryl, is 2-substituted with amino or chloro,

l) C_1-4-alkyl,

m) aralkyl,

n) heterocyclyl-C_1-4-alkyl, provided R¹⁶ is not 3-methylindol-1-ylethyl,

o) C_5-6-cycloalkyl,

p) C_1-4-aminoalkoxy,

q) heterocyclyl-C_1-4-alkoxy,

r) N-(heterocyclyl-C_1-4-alkyl)amino,

s) aryl-C_1-4-alkyl where the alkyl portion is substituted with amino, hydroxy or —

C_1-4-alkylamino, and

t) heterocyclyl-C_1-4-alkylenyl where the alkylenyl portion is substituted with amino, hydroxy or —

C_1-4-alkylamino;

wherein R¹⁷ is selected from H, C_1-4-alkyl, C_3-7-cycloalkyl-(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-alkyl, 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_1-6alkyl, 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 and cycloalkyl 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, —

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.

9. A compound of claim 8 wherein R¹⁰ is H;

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

wherein R^13b is H;

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

wherein R¹⁶ is selected from

a) 4-6 membered saturated heterocyclyl,

b) 10 membered partially unsaturated heterocyclyl,

c) 5-10 membered heteroaryl,

d) C_1-3-aminoalkyl,

e) C_1-3-aminoalkylamino,

f) C_1-3-alkylamino-C_1-3-alkylamino,

g) C_1-3-alkylamino-C_1-3-alkyl,

h) phenylamino-C_1-3-alkyl,

i) phenyl-C_1-4-alkylamino-C_1-3-alkyl,

j) heterocyclyl-C_1-3-alkylamino-C_1-3-alkyl,

k) phenyl, naphthyl or tetrahydronaphthyl, provided R¹⁶ is not 2-methoxyphenyl, 2-phenoxyphenyl or 2-phenylaminophenyl,

l) C_1-3-alkyl,

m) phenyl-C_1-2-alkyl,

n) 5-10-membered saturated or partially unsaturated heterocyclylmethyl,

o) 5-6 membered heteroaryl-C_1-4-alkyl,

p) optionally substituted C_5-6-cycloalkyl,

q) C_1-3-aminoalkoxy,

r) [5- or 6-membered heterocyclyl]—

C_1-3-alkoxy,

s) N-(5-10-membered heterocyclyl-C_1-3-alkyl)amino,

t) phenyl-C_1-2-alkyl where the alkyl portion is substituted with amino, hydroxy or C_1-3-alkylamino, and

u) 5- or 6-membered heterocyclyl-C_1-3-alkylenyl where the alkylenyl portion is substituted with amino, hydroxy or C_1-3-alkylamino;

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 4-7 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, cycloalkyl 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, —

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.

10. A compound of claim 9 wherein R^13a is selected from H, bromo, phenyl and chloro;

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, R²³SO₂—

, aminomethyl, aminoethyl, dimethylaminoethyl, diethylaminoethyl, dipropylaminoethyl, di-isobutylaminoethyl, di-(tert-butylmethyl)aminoethyl, di-(3-ethylbutyl)aminoethyl, di-(cyclohexylmethyl)aminoethyl, furylmethylaminoethyl, thienylmethylaminoethyl, benzylaminoethyl, di(furylmethyl)aminoethyl, di(cyclopropylmethyl)aminoethyl, di(thienylmethyl)aminoethyl, di(benzyl)aminoethyl, phenylmethoxyethyl, pyridyloxymethyl, methylthiopropyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, 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, cycloalkyl 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.

11. A compound of claim 10 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(3-ethylbutyl)aminoethyl)-N-methylsulfonylamino, N—

(N′

,N′

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

(N′

,N′

-di(cyclohexylmethyl)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-cyclohexylcarbonyl-N-cyclopropylmethylamino, N-thienylmethylcarbonyl-N-cyclopropylmethylamino, N-phenylethyl-N-cyclopropylmethylamino, N-(2-imidazolyl)-N-cyclopropylmethylamino, N-(4-methyl-5-imidazolyl)-N-cyclopropylmethylamino, N-(4-methyl-5-imidazolylmethyl)-N-cyclopropylmethylamino, N-(4-imidazolylmethyl)-N-cyclopropylmethylamino, N-(5-imidazolylmethyl)-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.

12. A compound of claim 10 wherein R¹² is selected from

and

wherein R¹⁶ is selected from

a) 4-6 membered saturated heterocyclyl,

b) 10 membered partially saturated heterocyclyl,

c) 5-10 membered heteroaryl,

d) C_1-3-aminoalkyl,

e) C_1-3-aminoalkylamino,

f) C_1-3-alkylamino-C_1-3-alkylamino,

g) C_1-3-alkylamino-C_1-3-alkyl,

h) phenylamino-C_1-3-alkyl,

i) phenyl-C_1-4-alkylamino-C_1-3-alkyl,

j) heterocyclyl-C_1-3-alkylamino-C_1-3-alkyl,

k) phenyl, naphthyl or tetrahydronaphthyl,

l) C_1-3-alkyl,

m) phenyl-C_1-2-alkyl,

n) 5-10-membered saturated or partially unsaturated heterocyclylmethyl,

o) 5-6 membered heteroaryl-C_1-4-alkyl,

p) optionally substituted C_5-6-cycloalkyl,

q) C_1-3-aminoalkoxy,

r) [5- or 6-membered heterocyclyl]—

C_1-3-alkoxy,

s) N-(5-10-membered heterocyclyl-C_1-3-alkyl)amino,

t) phenyl-C_1-2-alkyl where the alkyl portion is substituted with amino, hydroxy or C_1-3-alkylamino, and

u) 5- or 6-membered heterocyclyl-C_1-3-alkylenyl where the alkylenyl portion is substituted with amino, hydroxy or C_1-3-alkylamino;

wherein the heterocyclyl, aryl and cycloalkyl groups are optionally substituted;

and pharmaceutically-acceptable salts thereof.

13. A compound of claim 12 wherein R¹⁶ is selected from N-(piperidylmethyl)amino, aminopropylamino, aminomethyl, aminoethyl, aminopropyl, N-methylaminomethyl, N-(4-chlorophenyl)aminoethyl, N-methylaminoethyl, N,N-dimethylaminoethyl, 2-aminoethyl, aminopropoxy, pyrrolidinylmethoxy, N-methylaminoethylamino, 3-aminocyclopentyl, 4-aminocyclohexyl, 1-aminocyclohexyl, 2-indolyl, octahydro-indolyl, 1-methylindol-2-yl, 3-pyridyl, 2-pyridyl, N-methylbenzopyrrolyl, 5-benzopyrrolyl, 2-benzofuran, benzodioxolyl, 2-benzothienyl, 4-imidazolylmethyl, 3-azetidinyl optionally

N-substituted with a substituent selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclohexylmethyl and benzyl, 6-quinolyl, 2-quinolyl, 3-isoquinolyl, tetrahydroisoquinolyl, N-methylpyrrolidin-2-yl, pyrrolidin-2-yl, 5-oxopyrrolidin-2-yl, 3-phenylpyrrolidin-2-yl, (1-methyl-5-oxo-2-(pyridin-3-yl)-pyrrolidin-3-yl)methyl, thienyl, 4-piperidyl, 4-piperidylmethyl, N-methyl-4-piperidyl, N-methyl-2-piperidyl, N-ethyl-4-piperidyl, N-isobutyl-4-piperidyl, 3-piperidyl, 3-(aminomethyl)phenyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-aminophenyl, 3-aminophenyl, isopropyl, 4-chlorophenylmethyl, benzyl, phenyl-2-hydroxyethyl, 1-(amino)benzyl, 2-(1,2,3,4-tetrahydronaphthyl), naphthyl, (2-benzylamino)ethyl, imidazol-4-yl-(1-amino)ethyl, phenyl-1-(methylamino)ethyl and phenyl-1-(amino)ethyl;

and pharmaceutically-acceptable salts thereof.

14. A compound of claim 13 and pharmaceutically acceptable salts thereof selected from

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

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

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((3S,1R)-3-aminocyclopentyl)carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((1S,3R)-3-aminocyclopentyl)carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl](5-oxopyrrolidin-2-yl)carboxamide;

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

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

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]((2S,3R)-3-phenylpyrrolidin-2-yl)carboxamide;

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

((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}piperidyl)-2-oxoethyl]carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

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

N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(trifluoromethyl)phenyl]-piperidyl}ethyl)((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-[2-(hydroxyethyl)phenyl]piperidyl}-2-oxoethyl)((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

N-[(1R)-2-(4-{2-[(2-aminoethyl)(methylsulfonyl)amino]-phenyl}piperidyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-carboxamide;

((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-[2-(3-methyl-2-oxo(4-imidazolinyl))phenyl]piperidyl}-2-oxoethyl)carboxamide;

((3S)(3-1,2,3,4-tetrahydroisoquinolyl))-N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-(2-(2-oxo(4-imidazolinyl))phenyl]piperidyl}ethyl)carboxamide;

N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-{4-[2-(2-oxo(4-imidazolinyl))phenyl]-piperidyl}ethyl)azetidin-3-ylcarboxamide;

tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate;

N-{(1R)-1-[(4-chlorophenyl)methyl]-2-[4-(2-{([(2-cyanophenyl)sulfonyl]amino}-phenyl)piperidyl]-2-oxoethyl}((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

N-{(1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-[4-(2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}phenyl)piperidyl]ethyl}((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylamino)carbonylamino]-phenyl}piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

N-((1R)-1-[(4-chlorophenyl)methyl]-2-{4-[2-(methoxycarbonylamino)phenyl]piperidyl}-2-oxoethyl)((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide;

N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)amino]-phenyl}piperidyl)-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide; and

N-[(1R)-2-(4-{2-[(2-aminoethyl)amino]phenyl}piperidyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide.

15. A compound of claim 10 wherein R¹² is selected from optionally substituted benzyl, and optionally substituted 5-10-membered heteroaryl;

and wherein R^13a and R^13b are independently H or chloro.

16. A compound of claim 15 wherein R¹² is selected from oxazolo[5,4-b]pyridin-2-yl, oxazolo[4,5-b]pyridin-2-yl, 4-chlorobenzyl, benzoxazol-2-yl and benzyl.