3-aminocyclopentanecarboxamides as modulators of chemokine receptors
The present invention is directed to compounds of Formula I: which are modulators of chemokine receptors. The compounds of the invention, and compositions thereof, are useful in the treatment of diseases related to chemokine receptor expression and/or activity.
1. A method of modulating activity of a chemokine receptor comprising contacting said chemokine receptor with a compound of Formula I:
or pharmaceutically acceptable salt or prodrug thereof, wherein:
a dashed line indicates an optional bond;
W is:
V is N, NO or CR 5 ;
X is N, NO or CR 2 ;
Y is N, NO or CR 3 ;
Z is N, NO, or CR 4 ; wherein no more than one of V, X, Y and Z is NO;
R A , R A1 , R B and R B1 are each, independently, H, OH, halo, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, heterocyclyl, carbocyclyl, NR 10 R 12 , NR 10 CO 2 R 11 ; NR 10 CONR 10 R 12 , NR 10 SO 2 NR 10 R 12 , NR 10 —SO 2 —R 11 , CN, CONR 10 R 12 , CO 2 R 10 , NO 2 , SR 10 , SOR 10 , SO 2 R 10 , or SO 2 —NR 10 R 12 ;
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —(C 0-6 alkyl)-O—(C 1-6 alkyl), —(C 0-6 alkyl)-S—(C 1-6 alkyl), —(C 0-6 alkyl)-(C 3-7 cycloalkyl)-(C 0-6 alkyl), OH, OR 10 , SR 10 , COR 11 , CO 2 R 10 , CONR 10 R 12 , CR 10 R 11 CO 2 R 10 or CR 10 R 11 OCOR 10 ;
R 2 , R 3 , R 4 , R 5 and R 6 are each, independently H, OH, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 thioalkoxy, NR 10 R 12 , NR 10 CO 2 R 11 ; NR 10 CONR 10 R 12 , NR 10 SO 2 NR 10 R 12 , NR 10 —SO 2 —R 11 , heterocyclyl, carbocyclyl, carbocyclyloxy, heterocyclyloxy, CN, NO 2 , COR 11 , CONR 10 R 12 , CO 2 R 10 , NO 2 , SR 10 , SOR 10 , SO 2 R 10 ; or SO 2 —NR 10 R 12 ;
R 7 is H or C 1-6 alkyl optionally substituted by 1-3 substituents selected from halo, OH, CO 2 H, CO 2 —(C 1-6 alkyl), or C 1-3 alkoxy;
R 8 is C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyloxy or OH;
R 8′ is H;
R 9 and R 9′ are each, independently, H, C 1-6 alkyl, halo, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, OH, CO 2 R 10 , OCOR 10 , wherein said C 1-6 alkyl is optionally substituted with one or more substituents selected from F, C 1-3 alkoxy, OH or CO 2 R 10 ;
or R 9 and R 9′ together with the carbon atom to which they are attached form a 3-7 membered spirocyclyl group;
R 10 is H, C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl, wherein said C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl is optionally substituted with 1-3 selected from halo, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, CO 2 H, and CO 2 —(C 1-6 alkyl);
R 11 is H, OH, C 1-6 alkyl, C 1-6 alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, C 3-6 cycloalkyl or C 3-6 cycloalkyloxy, wherein said C 1-6 alkyl, C 1-6 alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, C 3-6 cycloalkyl or C 3-6 cycloalkyloxy, is optionally substituted with 1-3 substituents selected from halo, OH, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, CO 2 -(C 1-6 alkyl) and CF 3 ;
R 12 is H, C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl, wherein said C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl is optionally substituted with 1-3 selected from halo, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, CO 2 H, and CO 2 —(C 1-6 alkyl); and
p is 0 or 1.
2. The method of claim 1 wherein said chemokine receptor is CCR2 or CCR5.
3. The method of claim 1 wherein said modulating is inhibiting.
4. The method of claim 1 wherein said compound inhibits both CCR2 and CCR5.
5. A method of treating a disease associated with expression or activity of a chemokine receptor in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula I:
or pharmaceutically acceptable salt or prodrug thereof, wherein:
a dashed line indicates an optional bond;
W is:
V is N, NO or CR 5 ;
X is N, NO or CR 2 ;
Y is N, NO or CR 3 ;
Z is N, NO, or CR 4 ; wherein no more than one of V, X, Y and Z is NO;
R A , R A1 , R B and R B1 are each, independently, H, OH, halo, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, heterocyclyl, carbocyclyl, NR 10 R 12 , NR 10 CO 2 R 11 ; NR 10 CONR 10 R 12 , NR 10 SO 2 NR 10 R 12 , NR 10 —SO 2 —R 11 , CN, CONR 10 R 12 , CO 2 R 10 , NO 2 , SR 10 , SOR 10 , SO 2 R 10 , or SO 2 —NR 10 R 12 ;
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —(C 0-6 alkyl)-O—(C 1-6 alkyl), —(C 0-6 alkyl)-S—(C 1-6 alkyl), —(C 0-6 alkyl)-(C 3-7 cycloalkyl)-(C 0-6 alkyl), OH, OR 10 , SR 10 , COR 11 , CO 2 R 10 , CONR 10 R 12 , CR 10 R 11 CO 2 R 10 or CR 10 R 11 OCOR 10 ;
R 2 , R 3 , R 4 , R 5 and R 6 are each, independently H, OH, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 thioalkoxy, NR 10 R 12 , NR 10 CO 2 R 11 ; NR 10 CONR 10 R 12 , NR 10 SO 2 NR 10 R 12 , NR 10 —SO 2 —R 11 , heterocyclyl, carbocyclyl, carbocyclyloxy heterocyclyloxy, CN, NO 2 , COR 11 , CONR 10 R 12 , CO 2 R 10 , NO 2 , SR 10 , SOR 10 , SO 2 R 10 ; or SO 2 —NR 10 R 12 ;
R 7 is H or C 1-6 alkyl optionally substituted by 1-3 substituents selected from halo, OH, CO 2 H, CO 2 —(C 1-6 alkyl), or C 1-3 alkoxy;
R 8 is C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyloxy or OH;
R 8′ is H;
R 9 and R 9′ are each, independently, H, C 1-6 alkyl, halo, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, OH, CO 2 R 10 , OCOR 10 , wherein said C 1-6 alkyl is optionally substituted with one or more substituents selected from F, C 1-3 alkoxy, OH or CO 2 R 10 ;
or R 9 and R 9′ together with the carbon atom to which they are attached form a 3-7 membered spirocyclyl group;
R 10 is H, C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl, wherein said C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl is optionally substituted with 1-3 selected from halo, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, CO 2 H, and CO 2 —(C 1-6 alkyl);
R 11 is H, OH, C 1-6 alkyl, C 1-6 alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, C 3-6 cycloalkyl or C 3-6 cycloalkyloxy, wherein said C 1-6 alkyl, C 1-6 alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, C 3-6 cycloalkyl or C 3-6 cycloalkyloxy, is optionally substituted with 1-3 substituents selected from halo, OH, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, CO 2 —(C 1-6 alkyl) and CF 3 ;
R 12 is H, C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl, wherein said C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl is optionally substituted with 1-3 selected from halo, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, CO 2 H, and CO 2 —(C 1-6 alkyl); and
p is 0 or 1.
6. The method of claim 5 wherein said disease is an eye disorder.
7. The method of claim 6 wherein said eye disorder is characterized by dryness of the eye.
8. A method of treating dryness of the eye in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula I:
or pharmaceutically acceptable salt or prodrug thereof, wherein:
a dashed line indicates an optional bond;
W is:
V is N, NO or CR 5 ;
X is N, NO or CR 2 ;
Y is N, NO or CR 3 ;
Z is N, NO, or CR 4 ; wherein no more than one of V, X, Y and Z is NO;
R A , R A1 , R B and R B1 are each, independently, H, OH, halo, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, heterocyclyl, carbocyclyl, NR 10 R 12 , NR 10 CO 2 R 11 ; NR 10 CONR 10 R 12 , NR 10 SO 2 NR 10 R 12 , NR 10 —SO 2 —R 11 , CN, CONR 10 R 12 , CO 2 R 10 , NO 2 , SR 10 , SOR 10 , SO 2 R 10 , or SO 2 —NR 10 R 12 ;
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, —(C 0-6 alkyl)-O—(C 1-6 alkyl), —(C 0-6 alkyl)-S—(C 1-6 alkyl), —(C 0-6 alkyl)-(C 3-7 cycloalkyl)-(C 0-6 alkyl), OH, OR 10 , SR 10 , COR 11 , CO 2 R 10 , CONR 10 R 12 , CR 10 R 11 CO 2 R 10 or CR 10 R 11 OCOR 10 ;
R 2 , R 3 , R 4 , R 5 and R 6 are each, independently H, OH, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 thioalkoxy, NR 10 R 12 , NR 10 CO 2 R 11 ; NR 10 CONR 10 R 12 , NR 10 SO 2 NR 10 R 12 , NR 10 —SO 2 —R 11 , heterocyclyl, carbocyclyl, carbocyclyloxy, heterocyclyloxy, CN, NO 2 , COR 11 , CONR 10 R 12 , CO 2 R 10 , NO 2 , SR 10 , SOR 10 , SO 2 R 10 ; or SO 2 —NR 10 R 12 ;
R 7 is H or C 1-6 alkyl optionally substituted by 1-3 substituents selected from halo, OH, CO 2 H, CO 2 —(C 1-6 alkyl), or C 1-3 alkoxy;
R 8 is C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyloxy or OH;
R 8′ is H;
R 9 and R 9′ are each, independently, H, C 1-6 alkyl, halo, C 1-3 alkoxy, C 1-3 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, OH, CO 2 R 10 , OCOR 10 , wherein said C 1-6 alkyl is optionally substituted with one or more substituents selected from F, C 1-3 alkoxy, OH or CO 2 R 10 ;
or R 9 and R 9′ together with the carbon atom to which they are attached form a 3-7 membered spirocyclyl group;
R 10 is H, C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl, wherein said C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl is optionally substituted with 1-3 selected from halo, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, CO 2 H, and CO 2 —(C 1-6 alkyl);
R 11 is H, OH, C 1-6 alkyl, C 1-6 alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, C 3-6 cycloalkyl or C 3-6 cycloalkyloxy, wherein said C 1-6 alkyl, C 1-6 alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, C 3-6 cycloalkyl or C 3-6 cycloalkyloxy, is optionally substituted with 1-3 substituents selected from halo, OH, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, CO 2 —(C 1-6 alkyl) and CF 3 ;
R 12 is H, C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl, wherein said C 1-6 alkyl, benzyl, phenyl, or C 3-6 cycloalkyl is optionally substituted with 1-3 selected from halo, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, CO 2 H, and CO 2 —(C 1-6 alkyl); and
p is 0 or 1.