US 7491735 B2 - Chemokine Receptor Binding Compounds - The Lens

Chemokine Receptor Binding Compounds

Published: Feb 17, 2009
Earliest Priority: Dec 11 2003
Family: 7
Cited Works: 84
Cited by: 3
Cites: 17
Additional Info: Cited Works Full text Published

Abstract

The present invention relates to chemokine receptor binding compounds, pharmaceutical compositions and their use. More specifically, the present invention relates to modulators of chemokine receptor activity, preferably modulators of CCR5. These compounds demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).

Claims

A compound or a pharmaceutically acceptable salt thereof, having the formula:
where

n is 0 or 1;

R¹is pyridinyl or pyrimidinyl, each optionally substituted by one or more halogen, alkyl, amine or heteroaryl;

R²is phenyl, pyridinyl, thiazolyl, furanyl, or thiophenyl, each of which is optionally linked to one or more C1-C6 alkyl, alkoxy, trifluoromethyl, carboxylalkyl, cyano, or halogen;

R³is phenyl, pyridinyl, thiazolyl, oxazolyl, pyrimidinyl, indolyl, indolinyl, isoindolinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, benzofuranyl, 2,3-dihydroxybenzofuranyl or phthalanyl, each of which is optionally linked to one or more C1-C6 alkyl, trifluoromethyl, oxotrifluoromethyl, carboxylalkyl, cyano, halogen, sulfanyl, SO₂R⁹, where R⁹is alkyl, amine or amino alkyl, C(O)R¹⁰, where R¹⁰is alkyl, amine, morpholine, NMe₂, N(OMe)Me, NHPh, piperidine, NHMe, piperazine, NHCH₂C(O)OMe or PhC(O)OH, OR¹¹, where R¹¹is H, alkyl, (CH₂)₂OMe, CH₂C(O)NH₂, CH₂C(O)NHNH₂, CH₂C(O)OCMe₃, CH₂C(O)OMe, CH₂C(O)OH, PhC(O)OH, PhC(O)NH₂, SO₂Me, C(O)Me, C(O)OMe, C(O)NEt₂, C(O)NMe₂or
NHR¹², where R¹²is H, C(O)Me, C(O)CF₃, SO₂Me, C(O)NH₂, C(O)NMe₂or NO₂, CH₂PhC(O)OH, SOMe, CH₂NHC(O)Me, morpholine, CH═CHC(O)OMe, CH═CHC(O)OH, and
R⁴is hydrogen or alkyl.
The compound of claim 1, where R⁴is hydrogen.
A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of
N-(3-{4-[(4-Bromo-phenyl)-(3-chloro-benzyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (62);

N-(3-{4-[Benzyl-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (63);

3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(3-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (64);

3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (65);

3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(3-methyl-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (66);

N-(3-{4-[Benzyl-(4-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (67);

3,5-Dichloro-N-(3-{4-[(3-fluoro-benzyl)-(4-trifluoro-methyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (68);

3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (69);

N-(3-{4-[Benzyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (70);

3,5-Dichloro-N-(3-{4-[(3-methyl-benzyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (71);

3,5-Dichloro-N-(3-{4-[(3-fluoro-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (72);

3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (73);

3,5-Dichloro-N-(3-{4-[(3-methyl-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (74);

3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-methanesulfonyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (75);

3,5-Dichloro-N-(3-{4-[(4-methanesulfonyl-phenyl)-(3-methyl-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (76);

3,5-Dichloro-N-(3-{4-[(3-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (77);

3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (78);

N-(3-{4-Benzyl-(4-methylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (79);

Methanesulfonic acid 4-[benzyl-(1-{3-[(3,5-dichloro-pyridine-4-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (80);

N-(3-{4-[Benzyl-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (81);

3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (82);

N-(3-{4-[Benzyl-(4-sulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (83);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-fluoro-benzyl)-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (84);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-cyano-phenyl)-(3-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (95);

4-{4-[Benzyl-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxyl}-benzoic acid (96);

4-{4-[Benzyl-(1-{1-methyl-3-[(4-methyl-pyridine-3-carbonyl)-amino]-propyl}-piperidin-4-yl)-amino]-phenoxyl}-benzoic acid (99);

4-{4-[Benzyl-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzyl}-benzoic acid (102);

N-(3-{4-[(4-Bromo-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (103);

3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-trifluoro-methyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (104);

3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (105);

3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (106);

4-[(3-Cyano-benzyl)-(1-{3-[(3,5-dichloro-pyridine-4-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid methyl ester (107);

3,5-Dichloro-N-(3-{4-[(4-chloro-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (108);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetylamino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (111);

4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (114);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-hydrazinocarbonylmethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (116);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methanesulfonylamino-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (118);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (119);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (123);

3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-methanesulfinyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (125);

3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-methanesulfonyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (126);

3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (127);

3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (128);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (129);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (133);

4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(piperazine-1-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (135);

4,6-Dimethyl-pyrimidine-5-carboxylic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (136);

Acetic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (138);

Carbonic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester methyl ester (140);

{4-[(Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid tert-butyl ester (144);

Dimethyl-carbamic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (146);

{4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxyl-acetic acid methyl ester (148);

{4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxyl-acetic acid (150);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (152);

4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(cyclopropanecarbonyl-amino)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (154);

4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (157);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-ureido-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (159);

4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (161);

4-{4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxyl{-benzoic acid (162);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (164);

4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(morpholine-4-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (167);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl}-(4-sulfamoyl-phenyl)-amino]-piperidine-1-yl}-butyl)-amide (168);

Methanesulfonic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (169);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[[4-(acetylamino-methyl)-phenyl]-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (171);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (173);

{4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoylamino}-acetic acid methyl ester (175);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-amide (178);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzo[1,3]dioxol-5-yl-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (179);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(2,3-dihydro-benzofuran-5-yl)-amino]-piperidin-1-yl}-butyl)-amide (181);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzofuran-5-yl-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (184);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(3,4-dimethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (186);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-amide (188);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(6-methoxy-pyridin-3-yl)-amino]-piperidin-1-yl}-butyl)-amide (191);

3,5-Dichloro-N-(3-{4-[(5-chloro-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (195);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (197);

3,5-Dichloro-N-(3-{4-[(5-chloro-2-fluoro-benzyl)-(4-chloro-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (198);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (199);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (201);

4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(5-chloro-2-fluoro-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (203);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetylamino-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (205);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (207);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-sulfamoyl-phenyl)-amino]-piperidine-1-yl}-butyl)-amide (209);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetyl-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (211);

3-[(5-Chloro-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid methyl ester (2{3);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(3-methylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (214);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-amide (215);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzo[1,3]dioxol-5-yl-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (218);

3,5-Dichloro-N-(3-{4-[(5-cyano-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (219);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-cyano-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (221);

4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(5-cyano-2-fluoro-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (223);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetylamino-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (225);

(E)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl 1-acrylic acid methyl ester (227);

4-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-benzoic acid (228);

N-((R)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-isonicotinamide (230);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-acetyl-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (231);

N-((R)-3-{4-[(4-Acetyl-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (232);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(5-cyano-2-fluoro-benzyl)-(4-hydroxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (233);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-cyano-2-fluoro-benzyl)-(4-ureido-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (234);

{4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid tert-butyl ester (235);

{4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid methyl ester (237);

{4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid (238); 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-carbamoylmethoxy-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (239);

(E)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl}-acrylic acid (240);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzo[1,3]dioxol-5-yl-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (242);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-cyano-2-fluoro-benzyl)-(1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-amide (245);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(6-acetylamino-pyridin-3-yl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (246);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (290);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (291);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-chloro-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (292);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-acetyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (293);

4,6-Dimethyl-pyrimidine-5-carboxylic acid [(R)-3-(4-{[4-(1-methoxyimino-ethyl)-phenyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide (294);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[thiophen-3-ylmethyl-(4-trifluoromethyl-phenyl)-amino-piperidin-1-yl}-butyl)-amide (295);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-hydroxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (296);

{4-[(1-{(R)-3-[(4,6-Dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-acetic acid (297);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-carbamoylmethoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (298);

4-[(1-{(R)-3-[(4,6-Dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-benzoic acid methyl ester (299);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (300);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-bromo-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (301);

4-{4-[(1-{(R)-3-[(4,6-Dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-benzoic acid (302);

4,6-Dimethyl-pyrimidine-5-carboxylic acid [(R)-3-(4-{[4-(4-carbamoyl-phenoxy)-phenyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide (303);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-fluoro-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (304);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-ethoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (305);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-cyano-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (306);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methylsulfanyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (307);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methanesulfonyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (308);

3,5-Dimethyl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (309);

2,4-Dimethyl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (316);

N-((R)-3-{4-[(4-Methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (321);

3,5-Dichloro-N-((R)-3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-isonicotinamide (323);

N-((R)-3-{4-[(4-Methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-isonicotinamide (325);

4,6-Dimethyl-pyrimidine-5-carboxylic acid {3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide (327);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(6-acetylamino-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (328);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(6-chloro-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (329);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(6-bromo-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (330);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(6-ethoxy-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (331);

2,4-Dimethyl-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-nicotinamide (334);

3,5-Dichloro-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-isonicotinamide (336);

3,5-Dimethyl-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-isonicotinamide (337);

4,6-Dimethyl-pyrimidine-5-carboxylic acid {3-[4-(pyrimidin-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide (339);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (342);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-bromo-thiophen-3-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (343);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-(4-methoxy-thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (344);

4,6-Dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(benzo[1,3]dioxol-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide (345);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(2,3-dihydro-benzo[1,4]dioxin-6-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (346);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-thiophen-2-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (347);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-(3-methyl-thiophen-2-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (348);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-thiophen-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (349);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[furan-2-ylmethyl-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (350);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (351);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-bromo-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (352);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methyl-pyridin-3-ylmethyl)-p-tolyl-amino]-piperidin-1-yl}-butyl)-amide (353);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (354);

4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (355);

4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (356);

N-(3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-isonicotinamide (357);

N-((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (359);

3,5-Dichloro-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (362);

N-(3-{4-[(4-Carbamoyl-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (366);

N-((R)-3 {4-[(4-Carbamoylmethoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (367);

Methanesulfonic acid 4-[(1-{(R)-3-[(2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-(4-methyl-pyridin-3-ylmethyl)-amino]-phenyl ester (368); and

2,4-Dimethyl-N-(3-{4-[(4-methyl-pyridin-3-ylmethyl)-(4-morpholin-4-yl-phenyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (369).
A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable carrier.
The compound of claim 1, wherein R³is indolyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, or benzofuranyl.