Piperazine derivatives

• US 7,098,212 B2
• Filed: 10/18/2002
• Issued: 08/29/2006
• Est. Priority Date: 10/22/2001
• Status: Expired due to Fees

• Current Assignee: Andrei Shavnya, Christopher S. Poss, Gregory D. Lundquist, Laura C. Blumberg, Matthew F. Brown, Matthew M. Hayward
• Original Assignee: Andrei Shavnya, Christopher S. Poss, Gregory D. Lundquist, Laura C. Blumberg, Matthew F. Brown, Matthew M. Hayward
• Inventors: Lundquist, Gregory D., Brown, Matthew F., Shavnya, Andrei, Blumberg, Laura C., Hayward, Matthew M., Poss, Christopher S.
• Primary Examiner(s): BERNHARDT, EMILY B
• Application Number:
  US10/273,658
• Publication Number:
  US 20040034034A1
• Time in Patent Office: 1,411 Days
• Field of Search: 544/391, 544/295, 544/365, 544/369, 544/372, 544/366, 514/255.01, 514/252.14, 514/253.13, 514/254.01, 514/254.02, 514/254.05
• US Class Current: 514/252.14
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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: C07D 207/16 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 213/63 One oxygen atom
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/76 to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 213/79 Acids; Esters
• CPC Class Codes: C07D 213/80 in position 3
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 239/34 One oxygen atom
• CPC Class Codes: C07D 239/60 Three or more oxygen or sulfur atoms
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 295/185 : from aliphatic carboxylic acids
• CPC Class Codes: C07D 307/33 : in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The present invention relates to compounds of the formula I

and the pharmaceutically acceptable forms thereof; wherein X, Y, a, b, c, d, R¹, R², R³, R⁴ and R⁵ are as defined herein. Moreover, the present invention is also directed at pharmaceutical compositions comprising a compound of the formula I and a pharmaceutically acceptable carrier. Furthermore, the present invention is directed at methods of using the herein described compounds and compositions for treating or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal.

Claims

1. A compound of the formula I

2. A compound according to claim 1, wherein R⁴ is [HO—

(C═

O)—

(C₁–

C₈)alkyl][C₁–

C₈)alkyl]N—

(C₁–

C₈)alkyl-, HO—

(C═

O)—

(C₁–

C₈)alkyl-O—

N═

(C₁–

C₈)alkyl-, HO—

(C═

O)—

(C₁–

C₈)alkyl-SO₂—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-SO₂—

(C₁–

C₈)alkyl-, HO—

(C═

O)—

(C₁–

C₈)alkyl-SO₂—

NH—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-SO₂—

NH—

(C₁–

C₈)alkyl-, HO—

(C═

O)—

(C₁–

C₈)alkyl-NH—

SO₂—

, HO—

(C═

O)—

(C═

O)—

NH—

SO₂—

, HO—

(C═

O)—

(C═

O)—

NH—

SO₂—

(C₁–

C₈)alkyl-, HO—

(C═

O)—

(C₁–

C₈)alkyl-NH—

(C═

O)—

NH—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-O—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-O—

(C₁–

C₈)alkyl-, HO—

(C═

O)—

(C₂–

C₈)alkenyl-, HO—

(C═

O)—

(C₁–

C₈)alkyl-S—

, HO—

(C═

O)—

(C═

O)—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-(C═

O)—

, NC—

NH—

(C═

O)—

(C₁–

C₈)alkyl, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-, (C₆–

C₁₀)aryl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-, H₂N—

SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-O—

, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-O—

(C₁–

C₈)alkyl-, H₂N—

SO₂—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-(C═

O)—

NH—

SO₂—

(C₁–

C₈)alkyl-, HO—

(C₁–

C₈)alkyl-(C═

O)—

NH—

SO₂—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-NH—

(C═

O)—

NH—

SO₂—

(C₁–

C₈)alkyl-, (C₆–

C₁₀)aryl-NH—

(C═

O)—

NH—

SO₂—

, (C₁–

C₈)alkyl-O—

(C═

O)—

NH—

SO₂—

, (C₁–

C₈)alkyl-O—

(C═

O)—

NH—

SO₂—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

O—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

NH—

(C₁–

C₈)alkyl-, (C₆–

C₁₀)aryl-SO₂—

NH—

(C═

O)—

O—

(C₁–

C₈)alkyl-, (C₆–

C₁₀)aryl-SO₂—

NH—

(C═

O)—

NH—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-(C═

O)—

NH—

SO₂—

NH—

(C₁–

C₈)alkyl, (C₆–

C₁₀)aryl-(C═

O)—

NH—

SO₂—

NH—

(C₁–

C₈)alkyl.

3. A compound according to claim 1, wherein the pharmaceutically acceptable form is a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1, wherein the stereochemistry is as depicted in formula Ia and b is 0 or 1 and c is 1:

5. A compound according to claim 4, wherein each R¹ is independently H—

, HO—

, halo, NC—

, (C₁–

C₈)alkyl, or (C₁–

C₈)alkyl-O—

; and

a is 1 or 2.

6. A compound according to claim 5, wherein R² is H—

or (C₁–

C₈)alkyl- and R³ is (C₁–

C₈)alkyl-.

7. A compound according to claim 6, wherein X is —

O—

or —

NR⁶— and

R⁶ is H—

.

8. A compound according to claim 7, wherein d is 1 or 2, and R⁵ is H—

, HO—

, NC—

, (C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-O—

, (C₁–

C₈)alkyl-(C═

O)—

, or halo.

9. A compound according to claim 8, wherein R⁴ is [HO—

(C═

O)—

(C₁–

C₈)alkyl][(C₁–

C₈)alkyl]N—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-, (C₁–

C₉)heterocyclyl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-, H₂N—

SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-O—

, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-O—

(C₁–

C₈)alkyl-, H₂N—

SO₂—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-(C═

O)—

NH—

SO₂—

(C₁–

C₈)alkyl-, HO—

(C₁–

C₈)alkyl-(C═

O)—

NH—

SO₂—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-NH—

(C═

O)—

NH—

SO₂-(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

NH—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-(C═

O)—

NH—

SO₂—

NH—

(C₁–

C₈)alkyl, HO—

(C═

O)—

(C₁–

C₈)alkyl-O—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-O—

(C₁–

C₈)alkyl-, (C₁–

C₉)heteroaryl-(C₁–

C₈)alkyl-O—

, (C₁–

C₉)heterocyclyl-O—

, (C₁–

C₉)heteroaryl-O—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-S—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-SO₂—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-SO₂—

(C₁–

C₈)alkyl-, HO—

(C═

O)—

(C₁–

C₈)alkyl-(C═

O)—

, or (C₁–

C₉)heteroaryl-(C₁–

C₈)alkyl-(C═

O)—

.

10. A compound according to claim 9, wherein Y is (C₆–

C₁₀)aryl.

11. A compound according to claim 4, wherein R⁴ is [HO—

(C═

O)—

(C₁–

C₈)alkyl][(C₁–

C₈)alkyl]N—

(C₁–

C₈)alkyl-, (C₁–

C₉)heteroaryl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-, H₂N—

SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-O—

, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-O—

(C₁–

C₈)alkyl-, H₂N—

SO₂—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-(C═

O)—

NH—

SO₂—

(C₁–

C₈)alkyl-, HO—

(C₁–

C₈)alkyl-(C═

O)—

NH—

SO₂—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-NH—

(C═

O)—

NH—

SO₂-(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

NH—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-(C═

O)—

NH—

SO₂—

NH—

(C₁–

C₈)alkyl, HO—

(C═

O)—

(C₁–

C₈)alkyl-O—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-O—

(C₁–

C₈)alkyl-, (C₁–

C₉)heteroaryl-(C₁–

C₈)alkyl-O—

, (C₁–

C₉)heterocyclyl-O—

, (C₁–

C₉)heteroaryl-O—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-S—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-SO₂—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-SO₂-(C₁–

C₈)alkyl-, HO—

(C═

O)—

(C₁–

C₈)alkyl-(C═

O)—

, or (C₁–

C₉)heteroaryl-(C₁–

C₈)alkyl-(C═

O).

12. A compound according to claim 11, wherein a is 1 or 2;

X is —

O—

or —

NR⁶—

;

each R¹ is independently H—

, HO—

, halo, NC—

, (C₁–

C₈)alkyl, or (C₁–

C₈)alkyl-O—

;

R² and R³ are each independently H—

, (C₁–

C₈)alkyl-, (C₃–

C₈)cycloalkyl-, (C₃–

C₈)cycloalkyl-(C₁–

C₈)alkyl-, (C₆–

C₁₀)aryl-, (C₆–

C₁₀)aryl-(C₁–

C₈)alkyl-, HO—

(C₁–

C₈)alkyl-, H₂N—

(C₁–

C₈)alkyl-, (C₁–

C₉)heterocyclyl-(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-O—

(C═

O)—

NH—

(C₁–

C₈)alkyl-, H₂N—

(C═

O)—

NH—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-SO₂—

NH—

(C₁–

C₈)alkyl-, (C₁–

C₉)heteroaryl-(C₁–

C₈)alkyl-, H₂N—

(C═

O)—

, or H₂N—

(C═

O)—

(C₁–

C₈)alkyl-; and

R⁵ is H—

, HO—

, NC—

, (C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-O—

, (C₁–

C₈)alkyl-(C═

O)—

, or halo.

13. A compound according to claim 12, wherein a is 1 or 2;

d is 1 or 2;

X is —

O—

;

Y is (C₆–

C₁₀)aryl;

R¹ is halo;

R² is H—

or (C₁–

C₈)alkyl-;

R³ is (C₁–

C₈)alkyl-; and

R⁵ is H—

, halo, (C₁–

C₈)alkyl-, or(C₁–

C₈)alkyl-O—

.

14. A compound according to claim 13, wherein R⁴ is (C₁–

C₉)heteroaryl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-, H₂N—

SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-O—

, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

(C₁–

C₈)alkyl-O—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-NH—

(C═

O)—

NH—

SO₂—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-SO₂—

NH—

(C═

O)—

NH—

(C₁–

C₈)alkyl-, (C₁–

C₈)alkyl-(C═

O)—

NH—

SO₂—

NH—

(C₁–

C₈)alkyl, HO—

(C═

O)—

(C₁–

C₈)alkyl-SO₂—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-SO₂—

(C₁–

C₈)alkyl-, HO—

(C═

O)—

(C₁–

C₈)alkyl-(C═

O)—

, HO—

(C═

O)—

(C₁–

C₈)alkyl-O—

N═

(C₁–

C₈)alkyl-, HO—

(C═

O)—

(C₁–

C₈)alkyl-SO₂—

NH—

, or HO—

(C═

O)—

(C₁–

C₈)alkyl-NH—

SO₂—

.

18. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to any of claims 1 to 15 to 17, or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier.

15. A compound selected from the group consisting of:

(2-{2-[4-(4-Fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-5-trifluoromethyl-phenyl)-methanesulfonamide;

(2-{3-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-3-oxo-propyl}-5-methyl-phenoxy)-acetic acid;

(5-Bromo-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide;

(5-Bromo-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}phenyl)methanesulfonamide;

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyloxy)-acetyl methanesulfonamide;

2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-4-methyl-thiazole-5-carboxylic acid;

3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acrylic acid;

4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4-oxo-butyric acid;

5-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-5-methyl-pyrimidine-2,4,6-trione;

6-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxymethyl)-nicotinic acid;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-N-(3-hydroxy-3-methyl-butyryl)-methanesulfonamide;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-N-hydroxyacetyl-methanesulfonamide;

N-[(2-{2-[4-(4-Fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-4-methoxy-phenyl)-acetyl]-methanesulfonamide; and

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]-4-fluoro-benzenesulfonamide;

or a pharmaceutically acceptable form thereof.

16. A compound selected from the group consisting of:

(2S)-2-Amino-4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-butyric acid;

(4S)-4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-pyrrolidine-(2S)-2-carboxylic acid;

(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylideneaminooxy)-acetic acid;

(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-acetic acid;

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylsulfamoyl)-acetic acid;

3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acrylic acid;

4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4-oxo-butyric acid;

5-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-5-oxo-pentanoic acid;

(5-Chloro-2{-2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylideneaminooxy)-acetic acid;

6-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-nicotinic acid;

C-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-N-hydroxyacetyl-methanesulfonamide;

N-[(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]-methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]-methanesulfonamide; and

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]-methanesulfonamide;

or a pharmaceutically acceptable form thereof.

17. A compound selected from the group consisting of:

(2R)-2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-propionic acid;

(4S)-4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-pyrrolidine-2-carboxylic acid;

(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenylsulfamoyl)-acetic acid;

4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-pyridine-2-carboxylic acid;

4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-but-3-enoic acid;

4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4-hydroxy-but-3-enoic acid;

N-[(5-Bromo-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]-methanesulfonamide;

N-[(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]-sulfamide;

N-Acetyl-C-(5-bromo-2-{2-[4-(4-chloro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide;

N-Acetyl-C-(5-chloro-2-{2-[(2R)-2-ethyl-4-(4-fluoro-benzyl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide;

N-Acetyl-C-(5-chloro-2-{2-[4-(4-chloro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-methanesulfonamide; and

Propane-1-sulfonic acid [(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetyl]-amide;

or a pharmaceutically acceptable form thereof.

19. A compound of 4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4-oxo-butyric acid or a pharmaceutically acceptable form thereof.

20. A compound of 4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethylpiperazin-1-yl]-2-oxo-ethoxy}-phenyl)-4-oxo-butyric acid or a pharmaceutically acceptable salt thereof.