CCR5 modulators

• US 7,217,714 B1
• Filed: 11/30/1999
• Issued: 05/15/2007
• Est. Priority Date: 12/23/1998
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc.
• Original Assignee: Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Stammen, Blanda Luzia Christa, Wood, Anthony, Price, David Anthony, Perros, Manoussos, Edwards, Martin Paul, Armour, Duncan Robert
• Primary Examiner(s): McKenzie; Thomas
• Assistant Examiner(s): Covington; Raymond
• Application Number:
  US09/451,826
• Time in Patent Office: 2,723 Days
• Field of Search: 546/192, 546/193, 546/194, 546/206, 546/209, 546/210, 546/216, 546/211, 546/218, 546/152, 546/156, 546/161, 546/139, 546/146, 546/147, 546/148, 546/266.4, 546/268.7, 546/269.1, 514/318, 514/326, 514/885, 514/336, 514/236.2, 514/252, 514/255, 514/256, 514/363, 514/359, 514/361, 514/364, 514/307, 514/314, 514/231.5, 544/111, 544/112, 544/113, 544/114, 544/115, 544/224, 544/238, 544/242, 544/333, 544/336, 544/359, 544/366, 544/367, 548/127, 548/131, 548/134, 548/136, 548/262.2, 548/266.2, 548/250
• US Class Current: 514/236.2
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• 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: C07D 451/04 with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system

Abstract

Compounds of Formula 1
[R_egion α]−[R_egion β]−[R_egion γ]−[R_egion δ]   (I)
which are useful as modulators of chemokine activity. The invention also provides pharmaceutical formulations and methods of treatment using these compounds.

Claims

1. A compound of the formula

[Region α

]−

[Region β

]−

[Region γ

]−

[Region δ

]

or a pharmaceutically acceptable salt thereof, wherein [Region α

] is a moiety of the formula

2. A compound according to claim 1, wherein R⁶ is H.

3. A compound according to claim 1, wherein A is phenyl.

4. A compound according to claim 1, wherein R²⁷ is methyl, ethyl, isopropyl, tert-butyl or alkyl, each optionally substituted by one substituent selected from fluoro, chloro, —

OH, —

CF₃, methyl, methoxy, —

CN, —

NH₂, —

NH(CH₃), —

N(CH₃)₂, —

NHCOCH₃, and —

N(CH₃)COCH₃.

5. A compound according to claim 1, wherein R²⁷ is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylethyl, cyclopentylpropylmethyl or cyclopentylmethyl.

6. A compound according to claim 1, wherein R²⁷ is tetrahydropyranyl, oxetanyl, azetidinyl or tetrahydrofuranyl, each optionally substituted by up to three substituents R²⁸.

7. A compound according to claim 1, wherein [Region β

] is unsubstituted ethylene.

8. A compound according to claim 1, wherein R⁴⁶ is absent.

9. A compound according to claim 1, wherein the heterocycle constituting [Region γ

] is unsubstituted on any ring carbon atom.

10. A compound according to claim 1, wherein [Region δ

] is selected from;

11. A compound according to claim 1, wherein [Region δ

] is selected from;

12. A compound according to claim 1, which is selected from:

N-{(1S)-3-[4-(3-Benzyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-{1-Phenyl-3-[4-(4H-1,2,4-triazol-4-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-{3-[4-(1-Methyl-1H-1,2,4-triazol-5-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-{3-[4-(1-Methyl-1H-1,2,4-triazol-3-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-{3-[4-(3,5-Dimethyl-4H-1,2,4-triazol-4-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-{1-Phenyl-3-[4-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl]propyl}cyclobutanecarboxamide;

N-{1-Phenyl-3-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl]propyl}cyclobutanecarboxamide;

N-{3-[4-(3-Benzyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-(3-{4-[3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)cyclobutanecarboxamide;

N-{3-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide,

N-{1-Phenyl-3-[4-(5-phenyl-1,2,4-oxadiazol-3-yl)-1-piperidinyl]propyl}cyclobutanecarboxamide;

N-{3-[4-(5-Benzyl-1,2,4-oxadiazol-3-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-{3-[4-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-{1-Phenyl-3-[4-(5-phenyl-1,3,4-oxadiazol-2-yl)-1-piperidinyl]propyl}cyclobutanecarboxamide;

N-{3-[4-(5-Benzyl-1,3,4-oxadiazol-2-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-[(1S)-3-[4-(3-Benzyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-(3-fluorophenyl)propyl]-2-cyclopropylacetamide;

N-((1S)-3-{4-[3-(4-Methylbenzyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)cyclobutanecarboxamide;

N-((1S)-3-{4-[3-(4-Trifluoromethylbenzyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)cyclobutanecarboxamide;

N-((1S)-3-{4-[3-(1,3-Benzodioxol-5-ylmethyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)cyclobutanecarboxamide;

N-((1S)-3-{4-[3-(3,5-Difluorobenzyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)cyclobutanecarboxamide;

N-[(1S)-3-[4-(3-Benzyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-(3-fluorophenyl)propyl]cyclobutanecarboxamide;

N-{(1S)-3-[4-(3-{4-[(Methylsulfonyl)amino]benzyl}-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl)cyclobutanecarboxamide;

4-{[5-(1-{(3S)-3-[(Cyclobutylcarbonyl)amino]-3-phenylpropyl}-4-piperidinyl)-1,2,4-oxadiazol-3-yl]methyl}benzamide;

N-((1S)-3-{4-[3-(2,5-Difluorobenzyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)cyclobutanecarboxamide;

N-((1S)-3-{4-[3-(2,6-Difluorobenzyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)cyclobutanecarboxamide;

N-((1S)-1-Phenyl-3-{4-[3-(3-pyridinylmethyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl]propyl)cyclobutanecarboxamide;

N-((1S)-1-Phenyl-3-{4-[3-(4-pyridinylmethyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}propyl)cyclobutanecarboxamide;

N-{(1S)-3-[4-(3-{2-[(Methylsulfonyl)amino]benzyl}-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-((1S)-1-Phenyl-3-{4-[3-(2-pyridinylmethyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}propyl)cyclobutanecarboxamide;

N-(1S)-3-[4-(3-Isobutyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-((1S)-3-{4-[3-(3-Chlorobenzyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)cyclobutanecarboxamide;

N-((1S)-3-{4-[3-(1-Benzofuran-5-ylmethyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)cyclobutanecarboxamide;

N-[(1S)-1-Phenyl-3-(4-{3-[4-(trifluoromethoxy)benzyl]-1,2,4-oxadiazol-5-yl}-1-piperidinyl)propyl]cyclobutanecarboxamide;

N-{(1S)-3-[4-(3-{3-[(Methylsulfonyl)amino]benzyl}-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

3,3,3-Trifluoro-N-{(1S)-3-[4-(3-{4-[(methylsulfonyl)amino]benzyl}-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}propanamide;

2-Cyclopropyl-N-{(1S)-3-[4-(3-{4-[(methylsulfonyl)amino]benzyl}-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}acetamide;

N-{(1S)-3-[4-(3-{4-[(Methylsulfonyl)amino]benzyl}-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}tetrahydro-2H-pyran-4-carboxamide;

1-Acetyl-N-{(1S)-3-[4-(3-{4-[(methylsulfonyl)amino]benzyl}-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}-3-azetidinecarboxamide;

N-{(1S)-3-[4-(3-Benzyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}tetrahydro-2H-pyran-4-carboxamide;

1-Acetyl-N-{(1S)-3-[4-(3-benzyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}-3-azetidinecarboxamide;

1-(Acetylamino)-N-{(1S)-3-[4-(3-benzyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}cyclopentanecarboxamide;

N-{(1S)-3-[4-(3-Benzyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl]-1-phenylpropyl}-1-methoxycyclobutanecarboxamide;

3-{[5-(1-(3S)-3-[(Cyclobutylcarbonyl)amino]-3-phenylpropyl}4-piperidinyl)-1,2,4-oxadiazol-3-yl]methyl}benzamide;

Ethyl 4-(3-benzyl-1,2,4-oxadiazol-5-yl)-1-((3S)-3-[(cyclobutylcarbonyl)amino]-3-phenylpropyl}-4-piperidinecarboxylate;

N-{(1S)-3-[4-(3-Benzyl-1,2,4-oxadiazol-5-yl)₄-cyano-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-[(1S)-3-[4-3-[3-(Aminosulfonyl)benzyl]-1,2,4-oxadiazol-5-yl}-1-piperidinyl)-1-phenylpropyl]cyclobutanecarboxamide;

1-{(3S)-3-[(Cyclobutylcarbonyl)amino]-3-phenylpropyl}-4-[3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl]-N-methyl-4-piperidinecarboxamide;

N-((1S)-3-{4-[3-(4-Fluorobenzyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)tetrahydro-2H-pyran-4-carboxamide;

3,3,3-Trifluoro-N-((1S)-3-{4-[3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)propanamide;

N-((1S)-3-{4-[3-(4-Morpholinylmethyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)cyclobutanecarboxamide;

N-((1S)-3-{4-Cyano-4-[3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)tetrahydro-2H-pyran-4-carboxamide;

N-((1S)-3-{4-Cyano-4-[3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)-2-cyclopropylacetamide;

1-Acetyl-N-((1S)-3-{4-cyano-4-[3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)-3-azetidinecarboxamide;

N-((1S)-3-{4-Cyano-4-[3-(4-fluorobenzyl)-1,2,4-oxadiazol-5-yl]-1-piperidinyl}-1-phenylpropyl)-3,3,3-trifluoropropanamide;

N-[(1S)-3-(4-{3-[4-(Aminosulfonyl)benzyl]-1,2,4-oxadiazol-5-yl}I—

-piperidinyl)-1-phenylpropyl]cyclobutanecarboxamide;

N-{(1S)-3-[3-Benzyl-1,2,4-oxadiazol-5-yl)-1-azetidinyl]-1-phenylpropyl}tetrahydro-3-furancarboxamide;

N-[(1S)-3-(4-{3-[(4-Acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-5-yl}-1-piperidinyl)-1-phenylpropyl]cyclobutanecarboxamide;

N-{(1S)-3-[3-Benzyl-1,2,4-oxadiazol-5-yl)-1-azetidinyl]-1-phenylpropyl}tetrahydro-3-furancarboxamide;

N-{(1S)-3-[4-[3-(4-Fluorobenzyl)-1,2,4-oxadiazol-5-yl]4-(methoxymethyl)-1-piperidinyl]-1-phenylpropyl}acetamide;

N-{3-[4-(3-Methyl-5-phenyl-4H-1,2,4-triazol-4-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-{(1S)-3-[4-(3-Benzyl-5-methyl-4H-1,2,4-triazol-4-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-{(1S)-3-[4-(5-Benzyl-4-methyl-4H-1,2,4-triazol-3-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-{(1S)-3-[4-(3-Benzyl-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl)-cyclobutanecarboxamide;

N-{(1S)-3-[4-(5-Benzyl-1-methyl-1H-1,2,4-triazol-3-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-{3-[4-(5-Benzyl-1H-1,2,4-triazol-3-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

N-{(1S)-3-[4-(3-{4-[(methylsulfonyl)amino]benzyl}-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}tetrahydro-2H-pyran-4-carboxamide;

2-Cyclopropyl-N-{(1S)-3-[4-(3-{4-[(methylsulfonyl)amino]benzyl}-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}acetamide;

3,3,3-Trifluoro-N-{(1S)-3-[4-(3-{4-[(methylsulfonyl)amino]benzyl}-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}propanamide;

N-(1S)-{3-[4-(3-Benzyl-1-methyl-1H-1,2,4-triazol-5-yl)-1-piperidinyl]-1-phenylpropyl}cyclobutanecarboxamide;

4-{[1-(1-{(3S)-3-Phenyl-3-[(3,3,3-trifluoropropanoyl)amino]propyl}4-piperidinyl)-1H-1,2,4-triazol-3-yl]methyl}benzamide;

N-(1S)-3-[4-(3-Benzyl-5-methyl-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}tetrahydro-2H-pyran-4-carboxamide;

N-{(1S)-3-[4-(3-Benzyl-5-methyl-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}tetrahydro-3-furancarboxamide;

1-Amino-N-{(1S)-3-[4-(3-benzyl-5-methyl-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}cyclopentanecarboxamide;

N-{(1S)-3-[4-(3-Benzyl-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}tetrahydro-3-furancarboxamide;

N-{(1S)-3-[4-(3-Benzyl-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}tetrahydro-2H-pyran-4-carboxamide;

1-Amino-N-{(1S)-3-[4-(3-benzyl-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}cyclopentanecarboxamide;

1-Acetyl-N-{(1S)-3-[4-(3-benzyl-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}-3-azetidinecarboxamide;

N-{(1S)-3-[4-(3-Benzyl-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}-1-propionyl-3-azetidinecarboxamide;

1-Acetyl-N-{(1S)-3-[4-(3-benzyl-5-methyl-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}-3-azetidinecarboxamide;

N-{(1S)-3-[4-(3-(4-Fluorobenzyl)-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}-1-propionyl-3-azetidinecarboxamide;

1-Acetyl-N-{(1S)-3-[4-(3-(4-fluorobenzyl)-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}-3-azetidinecarboxamide;

2-Methoxy-N-{(1S)-3-[4-(3-(4-fluorobenzyl)-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}acetamide; and

3-Methoxy-N-{(1S)-3-[4-(3-(4-fluorobenzyl)-1H-1,2,4-triazol-1-yl)-1-piperidinyl]-1-phenylpropyl}propanamide;

and the pharmaceutically acceptable salts thereof.

13. A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically acceptable excipient, diluent or carrier.