US 7,678,798 B2Granted

Piperazinylpiperidine derivatives as chemokine receptor antagonists

AssigneeIncyte Corporation

InventorsChu-Biao Xue, Ganfeng Cao, Taisheng Huang, Lihua Chen, Ke Zhang, Anlai Wang, David Meloni, Rajan Anand, Joseph Glenn, Brian W. Metcalf

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Abstract

The present invention relates to compounds of Formula I: wherein variable substituents are defined herein, that modulate the activity of or bind to chemokine receptors such as CCR5. In some embodiments, the compounds of the invention are selective for CCR5. The compounds can be used, for example, to treat diseases associated with chemokine receptor expression or activity such as inflammatory diseases, immune diseases and viral infections.

Claims35

Dependent claims

A compound of Formula I:

or pharmaceutically acceptable salt thereof, wherein:
R1 is pyrimidinyl optionally substituted by one or more R6;
R2 is H, halo, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, SOR7, SO2R7, COR8, OR9, SR9, COOR9, NR10R11 or NR10COR8;
R3 is F, Cl, Br, I, C1-C4 haloalkyl, C1-C4 haloalkoxy or heteroaryl;
R4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;
R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;
R6 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino or di(C1-C6 alkyl)amino;
R7 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C3-C7 cycloalkyl)alkyl, heterocycloalkylalkyl, or NR12R13;
R8 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C3-C7 cycloalkyl)alkyl, heterocycloalkylalkyl, or NR12R13;
R9 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, cycloalkyloxyalkyl, heterocycloalkyloxyalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl;
(C3-C7 cycloalkyl)alkyl or heterocycloalkylalkyl;
R10 and R11 are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl;
(C3-C7 cycloalkyl)alkyl or heterocycloalkylalkyl;
or R10 and R11 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group;
R12 and R13 are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl;
(C3-C7 cycloalkyl)alkyl or heterocycloalkylalkyl;
or R12 and R13 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group;
r is 1, 2 or 3.

15 more elements

A compound of Formula I:

or pharmaceutically acceptable salt thereof, wherein:
R1 is pyrimidinyl optionally substituted by one or more R6;
R2 is H, halo, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, SOR7, SO2R7, COR8, OR9, SR9, COOR9, NR10R11 or NR10COR8;
R3 is F, Cl, Br, I or C1-C4 haloalkyl;
R4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;
R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C1-C6 haloalkyl;
R6 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, (C1-C6 alkyl)amino or di(C1-C6 alkyl)amino;
R7 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C3-C7 cycloalkyl)alkyl, heterocycloalkylalkyl,or NR12R13;
R8 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, (C3-C7 cycloalkyl)alkyl, heterocycloalkylalkyl, or NR12R13;
R9 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, cycloalkyloxyalkyl, heterocycloalkyloxyalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl;
(C3-C7 cycloalkyl)alkyl or heterocycloalkylalkyl;
R10 and R11 are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl;
(C3-C7 cycloalkyl)alkyl or heterocycloalkylalkyl;
or R10 and R11 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group;
R12 and R13 are each, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C7 cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl;
(C3-C7 cycloalkyl)alkyl or heterocycloalkylalkyl;
or R12 and R13 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group;
r is 1, 2 or 3.

15 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/104,041Filed 12 Apr 2005 · us provisional application
Priority: 13 Apr 2004
Published: US 2005/0261310 A124 Nov 2005
Granted: 16 Mar 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61K 31/496
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: non-condensed piperazines…
A61K 31/502
Pyridazines; Hydrogenated pyridazines: ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings