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 - 57 . (canceled)
58 . A composition comprising a compound of Formula I:
or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, 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;
L is C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, C(O), C(O)NR 9 , S(O)NR 9 , S(O) 2 , or S(O) 2 NR 9 ,
R A , R A1 , R B and R B1 are each, Independently, HOH, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 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 S0 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-(C1 — 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 , carbocyclyl, heterocyclyl, CN, NR 10 R 12 , NR 10 —SO 2 R 10 , NR10COR 10 , NR 10 CO 2 R 10 , NR 10 CONR 12 , CR 10 R 11 CO 2 R 10 or CR 10 R 11 0COR 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 1O , SOR 1O SO 2 R 10 ; or SO 2 —NR 10 R 12 ;
R 7 is H or C 1-8 alkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from halo, C 1-10 haloalkyl, Cy, CN, NO 2 , OR a , C(O)R b , C(O)NR C R d , C(O)OR a , OC(O)R b , OC(O)NR C R d , NR c R d , NR C C(O)R b , NR C C(O)NR C R d , NR C C(O)OR a , S(O)R b , S(O)NR C R d , S(O) 2 R b , NR C S(O) 2 R b , and S(O) 2 NR c R d ; or R 7 is H, C 1-8 alkyl which is unsubstituted or substituted with 1-6 substituents selected from: hydroxy, —O—C 1-6 alkyl, —NR 12a R 12a , —NR 12a COR 13a , —NR 12a SO 2 R 14a , COR 11a , —CONR 12a R 12a , phenyl and heterocycle, where the alkyl, phenyl, and heterocycle are unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, trifluoromethyl, and —SO 2 C 1-6 alkyl which is unsubstituted or substituted with 1-6 substituents selected from: hydroxy, halo, —O—C 1-6 alkyl, CN, —NR 12a R 12a , —NR 12a COR 13a , —NR 12a S0 2 R 14a , —COR 11a , —CONR 12a R 12a , phenyl and heterocycle, where the alkyl, phenyl, and heterocycle are unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —C0 2 H, —C0 2 —C 1-6 alkyl, and trifluoromethyl; or R 7 is H, C 1-6 alkyl unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, —C0 2 H, —C0 2 C 1-6 alkyl, and —O—C 1-3 alkyl;
R 8 is C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from oxo, hydroxy, halo, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, Cy′, —(C 1-4 alkyl)-Cy′, CN, NO 2 , —(CH 2 ) q —ORa′, —(CH 2 ) q —SR a′ , —(CH 2 ) q —C(O) b′ , —(CH 2 ) q —C(O)NR C′ R d ′, —(CH 2 ) q —C(O)OR a′ , —(CH 2 ) q —S(O)R b′ , —(CH 2 ) q —S(O) 2 R b′ , and —(CH 2 ) q —S(O) 2 NR c′ R d′ ; or R 8 is selected from C 1-10 alkyl, —SO 2 C 1-10 alkyl, pyridyl or phenyl, unsubstituted or substituted with 1-5 substituents selected from: hydroxy, halo, —O—C 1-6 alkyl, —S—C 1-6 alkyl, CN, —NR 12a R 12a , —NR 12a COR 13a , —NR 12a S0 2 R 14a , —COR 12a , S0 2 R 14a , heterocycle, ═O (where the oxygen is connected via a double bond), phenoxy and phenyl, where the alkyl, phenyl, phenoxy and heterocycle are unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —COR 11a , —CN, —NR 12a R 12a , —S0 2 R 14a , —NR 12a COR 13a , —NR 12a S0 2 R 14a , and —CONR 12a R 12a , where the alkyl and alkoxy are optionally substituted with 1-5 fluoro; or R 8 is a group of formula:
Y and Z are independently selected from —O—, —NR 12b , —S—, —SO—, SO 2 —, —CR 12b R 12b —, NSO 2 R 14b —, —NCOR 13b —, —CR 12b COR 11b —, —CR 12b OCOR 13b —, —C— and —CO—;
R 8a is selected from: hydrogen, C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b , fluoro, —O—C 1-3 alkyl unsubstituted or substituted with 1-3 fluoro, C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, hydroxy, —COR 11b , —OCOR 13b ; or R 7 and R 8a together are C 2-4 alkyl or C 0-2 alkyl-O—C 1-3 alkyl, forming a 5-7 membered ring;
R 9a is selected from: hydrogen, C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b , COR 11b , hydroxy and —O—C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b ;
or R 8a and R 9a together are C 1-4 alkyl or C 0-3 alkyl-O—C 0-3 alkyl, forming a 3-6 membered ring;
R 10a is selected from: hydrogen, hydroxy, C 1-6 alkyl unsubstituted or substituted with 1-6 fluoro, fluoro, —O—C 3-6 cycloalkyl and —O—C 1-3 alkyl unsubstituted or substituted with 1-6 fluoro;
or R 8a and R ma together are C 2-3 alkyl, forming a 5-6 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, COR 11b , C 1-3 alkyl and C 1-3 alkoxy;
or R 8a and R 10a together are O—C 1-2 alkyl-O—C 1-2 alkyl, forming a 6-8 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, —COR 11b , C 1-3 alkyl and C 1-3 alkoxy;
or R 8a and R 10a together are —O—C 1-2 alkyl-O—, forming a 6-7 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, —COR 11b , C 1-3 alkyl and C 1-3 alkoxy;
R 11a and R 11b are independently selected from: hydroxy, hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl and C 3-6 cycloalkyl, where said alkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
R 12a and R 12b are independently selected from: hydrogen, hydroxy, C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl; or R 12a and R 12b are selected from: C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and COR 11b , fluoro, —O—C 1-3 alkyl unsubstituted or substituted with 1-6 fluoro, C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, hydroxy, —O—C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b ;
R 13a and R 13b are independently selected from: hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
R 14a and R 14b independently selected from: hydroxy, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
Cy and Cy′ are, independently, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from oxo, hydroxy, halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, CN, NO 2 , OR a″ , SR a″ , C(O)R b″ , C(O)NR C″ R d″ , C(O)OR a″ , OC(O)R b″ , OC(O)NR C″ R d″ , NR c″ R d″ , NR C″ C(O)R b″ , NR C″ C(O)OR a″ , S(O)R b″ , S(O)NR C″ R b″ , and S(O) 2 NR C″ R d″ , aryl, or heteroaryl, cycloalkyl, or heterocycloalkyl;
R 9 is H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
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, 2, or 3 substituents independently 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, 2 or 3 substituents independently 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, 2, or 3 substituents independently 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 a , R a′ and R a″ are, independently, H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R b , R b′ and R b″ are, independently, H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R C and R d are, independently, H, C 1-10 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or R C and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R c ′ and R d′ are, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or R C′ and R d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R C″ and R d″ are, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or R C″ and R d″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
m is 0, 1, or 2;
n is 0 or 1;
p is 0 or 1; and
q is 0, 1, 2, or 3.
59 . A method of modulating activity of a chemokine receptor comprising contacting said chemokine receptor with a compound of Formula I:
or a 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;
L is C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, C(O), C(O)NR 9 , S(O)NR 9 , S(O) 2 , or S(O) 2 NR 9 ,
R A , R A1 , R B and R 81 are each, Independently, HOH, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 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)-0-(C1 — 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 , carbocyclyl, heterocyclyl, CN, NR 10 R 12 , NR 10 —SO 2 R 10 , NR10COR 10 , NR 10 CO 2 R 10 , NR 10 CONR 12 , CR 10 R 11 CO 2 R 10 or CR 10 R 11 0COR 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 1O , SOR 1O SO 2 R 10 ; or SO 2 —NR 10 R 12 ;
R 7 is H or C 1-8 alkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from halo, C 1-10 haloalkyl, Cy, CN, NO 2 , OR a , C(O)R b , C(O)NR C R d , C(O)OR a , OC(O)R b , OC(O)NR C R d , NR c R d , NR C C(O)R b , NR C C(O)NR C R d , NR C C(O)OR a , S(O)R b , S(O)NR C R d , S(O) 2 R b , NR C S(O) 2 R b , and S(O) 2 NR c R d ; or R 7 is H, C 1-8 alkyl which is unsubstituted or substituted with 1-6 substituents selected from: hydroxy, —O—C 1-6 alkyl, —NR 12a R 12a , —NR 12a COR 13a , —NR 12a SO 2 R 14a , COR 11a , —CONR 12a R 12a , phenyl and heterocycle, where the alkyl, phenyl, and heterocycle are unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, trifluoromethyl, and —SO 2 C 1-6 alkyl which is unsubstituted or substituted with 1-6 substituents selected from: hydroxy, halo, —O—C 1-6 alkyl, CN, —NR 12a R 12a , —NR 12a COR 13a , —NR 12a S0 2 R 14a , —COR 11a , —CONR 12a R 12a , phenyl and heterocycle, where the alkyl, phenyl, and heterocycle are unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —C0 2 H, —C0 2 —C 1-6 alkyl, and trifluoromethyl; or R 7 is H, C 1-6 alkyl unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, —C0 2 H, —C0 2 C 1-6 alkyl, and —O—C 1-3 alkyl;
R 8 is C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from oxo, hydroxy, halo, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, Cy′, —(C 1-4 alkyl)-Cy′, CN, NO 2 , —(CH 2 ) q —ORa′, —(CH 2 ) q —SR a′ , —(CH 2 ) q —C(O) b′ , —(CH 2 ) q —C(O)NR C′ R d ′, —(CH 2 ) q —C(O)OR a′ , —(CH 2 ) q —S(O)R b′ , —(CH 2 ) q —S(O) 2 R b′ , and —(CH 2 ) q —S(O) 2 NR c′ R d′ ; or R 8 is selected from C 1-10 alkyl, —SO 2 C 1-10 alkyl, pyridyl or phenyl, unsubstituted or substituted with 1-5 substituents selected from: hydroxy, halo, —O—C 1-6 alkyl, —S—C 1-6 alkyl, CN, —NR 12a R 12a , —NR 12a COR 13a , —NR 12a S0 2 R 14a , —COR 12a , S0 2 R 14a , heterocycle, ═O (where the oxygen is connected via a double bond), phenoxy and phenyl, where the alkyl, phenyl, phenoxy and heterocycle are unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —COR 11a , —CN, —NR 12a R 12a , —S0 2 R 14a , —NR 12a COR 13a , —NR 12a S0 2 R 14a , and —CONR 12a R 12a , where the alkyl and alkoxy are optionally substituted with 1-5 fluoro; or R 8 is a group of formula:
Y and Z are independently selected from —O—, —NR 12b , —S—, —SO—, SO 2 —, —CR 12b R 12b —, NSO 2 R 14b —, —NCOR 13b —, —CR 12b COR 11b —, —CR 12b OCOR 13b —, —C— and —CO—;
R 8a is selected from: hydrogen, C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b , fluoro, —O—C 1-3 alkyl unsubstituted or substituted with 1-3 fluoro, C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, hydroxy, —COR 11b , —OCOR 13b ; or R 7 and R 8a together are C 2-4 alkyl or C 0-2 alkyl-O—C 1-3 alkyl, forming a 5-7 membered ring;
R 9a is selected from: hydrogen, C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b , COR 11b , hydroxy and —O—C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b ;
or R 8a and R 9a together are C 1-4 alkyl or C 0-3 alkyl-O—C 0-3 alkyl, forming a 3-6 membered ring;
R 10a is selected from: hydrogen, hydroxy, C 1-6 alkyl unsubstituted or substituted with 1-6 fluoro, fluoro, —O—C 3-6 cycloalkyl and —O—C 1-3 alkyl unsubstituted or substituted with 1-6 fluoro;
or R 8a and R ma together are C 2-3 alkyl, forming a 5-6 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, COR 11b , C 1-3 alkyl and C 1-3 alkoxy;
or R 8a and R 10a together are O—C 1-2 alkyl-O—C 1-2 alkyl, forming a 6-8 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, —COR 11b , C 1-3 alkyl and C 1-3 alkoxy;
or R 8a and R 10a together are —O—C 1-2 alkyl-O—, forming a 6-7 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, —COR 11b , C 1-3 alkyl and C 1-3 alkoxy;
R 11a and R 11b are independently selected from: hydroxy, hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl and C 3-6 cycloalkyl, where said alkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
R 12a and R 12b are independently selected from: hydrogen, hydroxy, C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl; or R 12a and R 12b are selected from: C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and COR 11b , fluoro, —O—C 1-3 alkyl unsubstituted or substituted with 1-6 fluoro, C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, hydroxy, —O—C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b ;
R 13a and R 13b are independently selected from: hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
R 14a and R 14b independently selected from: hydroxy, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
Cy and Cy′ are, independently, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from oxo, hydroxy, halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, CN, NO 2 , OR a″ , SR a″ , C(O)R b″ , C(O)NR C″ R d″ , C(O)OR a″ , OC(O)R b″ , OC(O)NR C″ R d″ , NR c″ R d″ , NR C″ C(O)R b″ , NR C″ C(O)OR a″ , S(O)R b″ , S(O)NR C″ R b″ , and S(O) 2 NR C″ R d″ , aryl, or heteroaryl, cycloalkyl, or heterocycloalkyl;
R 9 is H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
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, 2, or 3 substituents independently 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, 2 or 3 substituents independently 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, 2, or 3 substituents independently 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 a , R a′ and R a″ are, independently, H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R b , R b′ and R b″ are, independently, H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R C and R d are, independently, H, C 1-10 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or R C and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R c ′ and R d′ are, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or R C′ and R d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R C″ and R d″ are, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or R C″ and R d″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
m is 0, 1, or 2;
n is 0 or 1;
p is 0 or 1; and
q is 0, 1, 2, or 3.
60 . The method of claim 59 wherein said chemokine receptor is CCR2 or CCR5.
61 . The method of claim 59 wherein said modulating is inhibiting.
62 . 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 a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, 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;
L is C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, C(O), C(O)NR 9 , S(O)NR 9 , S(O) 2 , or S(O) 2 NR 9 ,
R A , R A1 , R B and R B1 are each, Independently, HOH, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 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 S0 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-(C1 — 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 , carbocyclyl, heterocyclyl, CN, NR 10 R 12 , NR 10 —SO 2 R 10 , NR10COR 10 , NR 10 CO 2 R 10 , NR 10 CONR 12 , CR 10 R 11 CO 2 R 10 or CR 10 R 11 0COR 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 1O , SOR 1O SO 2 R 10 ; or SO 2 —NR 10 R 12 ;
R 7 is H or C 1-8 alkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from halo, C 1-10 haloalkyl, Cy, CN, NO 2 , OR a , C(O)R b , C(O)NR C R d , C(O)OR a , OC(O)R b , OC(O)NR C R d , NR c R d , NR C C(O)R b , NR C C(O)NR C R d , NR C C(O)OR a , S(O)R b , S(O)NR C R d , S(O) 2 R b , NR C S(O) 2 R b , and S(O) 2 NR c R d ; or R 7 is H, C 1-8 alkyl which is unsubstituted or substituted with 1-6 substituents selected from: hydroxy, —O—C 1-6 alkyl, —NR 12a R 12a , —NR 12a COR 13a , —NR 12a SO 2 R 14a , COR 11a , —CONR 12a R 12a , phenyl and heterocycle, where the alkyl, phenyl, and heterocycle are unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, trifluoromethyl, and —SO 2 C 1-6 alkyl which is unsubstituted or substituted with 1-6 substituents selected from: hydroxy, halo, —O—C 1-6 alkyl, CN, —NR 12a R 12a , —NR 12a COR 13a , —NR 12a S0 2 R 14a , —COR 11a , —CONR 12a R 12a , phenyl and heterocycle, where the alkyl, phenyl, and heterocycle are unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —C0 2 H, —C0 2 —C 1-6 alkyl, and trifluoromethyl; or R 7 is H, C 1-6 alkyl unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, —C0 2 H, —C0 2 C 1-6 alkyl, and —O—C 1-3 alkyl;
R 8 is C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from oxo, hydroxy, halo, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, Cy′, —(C 1-4 alkyl)-Cy′, CN, NO 2 , —(CH 2 ) q —ORa′, —(CH 2 ) q —SR a′ , —(CH 2 ) q —C(O) b′ , —(CH 2 ) q —C(O)NR C′ R d ′, —(CH 2 ) q —C(O)OR a′ , —(CH 2 ) q —S(O)R b′ , —(CH 2 ) q —S(O) 2 R b′ , and —(CH 2 ) q —S(O) 2 NR c′ R d′ ; or R 8 is selected from C 1-10 alkyl, —SO 2 C 1-10 alkyl, pyridyl or phenyl, unsubstituted or substituted with 1-5 substituents selected from: hydroxy, halo, —O—C 1-6 alkyl, —S—C 1-6 alkyl, CN, —NR 12a R 12a , —NR 12a COR 13a , —NR 12a S0 2 R 14a , —COR 12a , S0 2 R 14a , heterocycle, ═O (where the oxygen is connected via a double bond), phenoxy and phenyl, where the alkyl, phenyl, phenoxy and heterocycle are unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —COR 11a , —CN, —NR 12a R 12a , —S0 2 R 14a , —NR 12a COR 13a , —NR 12a S0 2 R 14a , and —CONR 12a R 12a , where the alkyl and alkoxy are optionally substituted with 1-5 fluoro; or R 8 is a group of formula:
Y and Z are independently selected from —O—, —NR 12b , —S—, —SO—, SO 2 —, —CR 12b R 12b —, NSO 2 R 14b —, —NCOR 13b —, —CR 12b COR 11b —, —CR 12b OCOR 13b —, —C— and —CO—;
R 8a is selected from: hydrogen, C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b , fluoro, —O—C 1-3 alkyl unsubstituted or substituted with 1-3 fluoro, C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, hydroxy, —COR 11b , —OCOR 13b ; or R 7 and R 8a together are C 2-4 alkyl or C 0-2 alkyl-O—C 1-3 alkyl, forming a 5-7 membered ring;
R 9a is selected from: hydrogen, C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b , COR 11b , hydroxy and —O—C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b ;
or R 8a and R 9a together are C 1-4 alkyl or C 0-3 alkyl-O—C 0-3 alkyl, forming a 3-6 membered ring;
R 10a is selected from: hydrogen, hydroxy, C 1-6 alkyl unsubstituted or substituted with 1-6 fluoro, fluoro, —O—C 3-6 cycloalkyl and —O—C 1-3 alkyl unsubstituted or substituted with 1-6 fluoro;
or R 8a and R ma together are C 2-3 alkyl, forming a 5-6 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, COR 11b , C 1-3 alkyl and C 1-3 alkoxy;
or R 8a and R 10a together are O—C 1-2 alkyl-O—C 1-2 alkyl, forming a 6-8 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, —COR 11b , C 1-3 alkyl and C 1-3 alkoxy;
or R 8a and R 10a together are —O—C 1-2 alkyl-O—, forming a 6-7 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, —COR 11b , C 1-3 alkyl and C 1-3 alkoxy;
R 11a and R 11b are independently selected from: hydroxy, hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl and C 3-6 cycloalkyl, where said alkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
R 12a and R 12b are independently selected from: hydrogen, hydroxy, C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl; or R 12a and R 12b are selected from: C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and COR 11b , fluoro, —O—C 1-3 alkyl unsubstituted or substituted with 1-6 fluoro, C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, hydroxy, —O—C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b ;
R 13a and R 13b are independently selected from: hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
R 14a and R 14b independently selected from: hydroxy, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
Cy and Cy′ are, independently, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from oxo, hydroxy, halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, CN, NO 2 , OR a″ , SR a″ , C(O)R b″ , C(O)NR C″ R d″ , C(O)OR a″ , OC(O)R b″ , OC(O)NR C″ R d″ , NR c″ R d″ , NR C″ C(O)R b″ , NR C″ C(O)OR a″ , S(O)R b″ , S(O)NR C″ R b″ , and S(O) 2 NR C″ R d″ , aryl, or heteroaryl, cycloalkyl, or heterocycloalkyl;
R 9 is H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
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, 2, or 3 substituents independently 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, 2 or 3 substituents independently 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, 2, or 3 substituents independently 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 a , R a′ and R a″ are, independently, H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R b , R b′ and R b″ are, independently, H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R C and R d are, independently, H, C 1-10 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or R C and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R c ′ and R d′ are, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or R C′ and R d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R C″ and R d″ are, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or R C″ and R d″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
m is 0, 1, or 2;
n is 0 or 1;
p is 0 or 1; and
q is 0, 1, 2, or 3.
63 . The method of claim 62 wherein said chemokine receptor is CCR2 or CCR5.
64 . The method of claim 62 wherein said disease is an inflammatory disease.
65 . The method of claim 64 further comprising administering an anti-inflammatory agent.
66 . The method of claim 65 wherein said anti-inflammatory agent is an antibody.
67 . The method of claim 62 wherein said disease is an immune disorder.
68 . The method of claim 62 wherein said disease is rheumatoid arthritis, atherosclerosis, lupus, multiple sclerosis, pain, neuropathic pain, transplant rejection, diabetes, or obesity.
69 . The method of claim 62 wherein said disease is cancer.
70 . The method of claim 69 wherein said cancer is characterized by tumor associated macrophages.
71 . The method of claim 69 wherein said cancer is breast cancer, ovarian cancer or multiple myeloma.
72 . The method of claim 62 wherein said disease or condition is a viral infection.
73 . The method of claim 72 wherein said viral infection is HIV infection.
74 . A method of treating HIV infection in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, 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;
L is C 1-4 alkylenyl, C 2-4 alkenylenyl, C 2-4 alkynylenyl, C(O), C(O)NR 9 , S(O)NR 9 , S(O) 2 , or S(O) 2 NR 9 ,
R A , R A1 , R B and R B1 are each, Independently, HOH, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 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 S0 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-(C1 — 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 , carbocyclyl, heterocyclyl, CN, NR 10 R 12 , NR 10 —SO 2 R 10 , NR10COR 10 , NR 10 CO 2 R 10 , NR 10 CONR 12 , CR 10 R 11 CO 2 R 10 or CR 10 R 11 0COR 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 1O , SOR 1O SO 2 R 10 ; or SO 2 —NR 10 R 12 ;
R 7 is H or C 1-8 alkyl optionally substituted by 1, 2, 3, 4, 5 or 6 substituents independently selected from halo, C 1-10 haloalkyl, Cy, CN, NO 2 , OR a , C(O)R b , C(O)NR C R d , C(O)OR a , OC(O)R b , OC(O)NR C R d , NR c R d , NR C C(O)R b , NR C C(O)NR C R d , NR C C(O)OR a , S(O)R b , S(O)NR C R d , S(O) 2 R b , NR C S(O) 2 R b , and S(O) 2 NR c R d ; or R 7 is H, C 1-8 alkyl which is unsubstituted or substituted with 1-6 substituents selected from: hydroxy, —O—C 1-6 alkyl, —NR 12a R 12a , —NR 12a COR 13a , —NR 12a SO 2 R 14a , COR 11a , —CONR 12a R 12a , phenyl and heterocycle, where the alkyl, phenyl, and heterocycle are unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, trifluoromethyl, and —SO 2 C 1-6 alkyl which is unsubstituted or substituted with 1-6 substituents selected from: hydroxy, halo, —O—C 1-6 alkyl, CN, —NR 12a R 12a , —NR 12a COR 13a , —NR 12a S0 2 R 14a , —COR 11a , —CONR 12a R 12a , phenyl and heterocycle, where the alkyl, phenyl, and heterocycle are unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —C0 2 H, —C0 2 —C 1-6 alkyl, and trifluoromethyl; or R 7 is H, C 1-6 alkyl unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, —C0 2 H, —C0 2 C 1-6 alkyl, and —O—C 1-3 alkyl;
R 8 is C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from oxo, hydroxy, halo, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, Cy′, —(C 1-4 alkyl)-Cy′, CN, NO 2 , —(CH 2 ) q —ORa′, —(CH 2 ) q —SR a′ , —(CH 2 ) q —C(O) b′ , —(CH 2 ) q —C(O)NR C′ R d ′, —(CH 2 ) q —C(O)OR a′ , —(CH 2 ) q —S(O)R b′ , —(CH 2 ) q —S(O) 2 R b′ , and —(CH 2 ) q —S(O) 2 NR c′ R d′ ; or R 8 is selected from C 1-10 alkyl, —SO 2 C 1-10 alkyl, pyridyl or phenyl, unsubstituted or substituted with 1-5 substituents selected from: hydroxy, halo, —O—C 1-6 alkyl, —S—C 1-6 alkyl, CN, —NR 12a R 12a , —NR 12a COR 13a , —NR 12a S0 2 R 14a , —COR 12a , S0 2 R 14a , heterocycle, ═O (where the oxygen is connected via a double bond), phenoxy and phenyl, where the alkyl, phenyl, phenoxy and heterocycle are unsubstituted or substituted with 1-3 substituents selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —COR 11a , —CN, —NR 12a R 12a , —S0 2 R 14a , —NR 12a COR 13a , —NR 12a S0 2 R 14a , and —CONR 12a R 12a , where the alkyl and alkoxy are optionally substituted with 1-5 fluoro; or R 8 is a group of formula:
Y and Z are independently selected from —O—, —NR 12b , —S—, —SO—, SO 2 —, —CR 12b R 12b —, NSO 2 R 14b —, —NCOR 13b —, —CR 12b COR 11b —, —CR 12b OCOR 13b —, —C— and —CO—;
R 8a is selected from: hydrogen, C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b , fluoro, —O—C 1-3 alkyl unsubstituted or substituted with 1-3 fluoro, C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, hydroxy, —COR 11b , —OCOR 13b ; or R 7 and R 8a together are C 2-4 alkyl or C 0-2 alkyl-O—C 1-3 alkyl, forming a 5-7 membered ring;
R 9a is selected from: hydrogen, C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b , COR 11b , hydroxy and —O—C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b ;
or R 8a and R 9a together are C 1-4 alkyl or C 0-3 alkyl-O—C 0-3 alkyl, forming a 3-6 membered ring;
R 10a is selected from: hydrogen, hydroxy, C 1-6 alkyl unsubstituted or substituted with 1-6 fluoro, fluoro, —O—C 3-6 cycloalkyl and —O—C 1-3 alkyl unsubstituted or substituted with 1-6 fluoro;
or R 8a and R ma together are C 2-3 alkyl, forming a 5-6 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, COR 11b , C 1-3 alkyl and C 1-3 alkoxy;
or R 8a and R 10a together are O—C 1-2 alkyl-O—C 1-2 alkyl, forming a 6-8 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, —COR 11b , C 1-3 alkyl and C 1-3 alkoxy;
or R 8a and R 10a together are —O—C 1-2 alkyl-O—, forming a 6-7 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, —COR 11b , C 1-3 alkyl and C 1-3 alkoxy;
R 11a and R 11b are independently selected from: hydroxy, hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl and C 3-6 cycloalkyl, where said alkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
R 12a and R 12b are independently selected from: hydrogen, hydroxy, C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl; or R 12a and R 12b are selected from: C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and COR 11b , fluoro, —O—C 1-3 alkyl unsubstituted or substituted with 1-6 fluoro, C 3-6 cycloalkyl, —O—C 3-6 cycloalkyl, hydroxy, —O—C 1-6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1-3 alkoxy, hydroxy and —COR 11b ;
R 13a and R 13b are independently selected from: hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
R 14a and R 14b independently selected from: hydroxy, C 1-6 alkyl, —O—C 1-6 alkyl, benzyl, phenyl, C 3-6 cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, CO 2 H, —CO 2 —C 1-6 alkyl, and trifluoromethyl;
Cy and Cy′ are, independently, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from oxo, hydroxy, halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, CN, NO 2 , OR a″ , SR a″ , C(O)R b″ , C(O)NR C″ R d″ , C(O)OR a″ , OC(O)R b″ , OC(O)NR C″ R d″ , NR c″ R d″ , NR C″ C(O)R b″ , NR C″ C(O)OR a″ , S(O)R b″ , S(O)NR C″ R b″ , and S(O) 2 NR C″ R d″ , aryl, or heteroaryl, cycloalkyl, or heterocycloalkyl;
R 9 is H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
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, 2, or 3 substituents independently 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, 2 or 3 substituents independently 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, 2, or 3 substituents independently 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 a , R a′ and R a″ are, independently, H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R b , R b′ and R b″ are, independently, H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R C and R d are, independently, H, C 1-10 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or R C and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R c ′ and R d′ are, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or R C′ and R d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
R C″ and R d″ are, independently, H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
or R C″ and R d″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, amino, halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
m is 0, 1, or 2;
n is 0 or 1;
p is 0 or 1; and
q is 0, 1, 2, or 3.
75 . The method of claim 74 further comprising simultaneously or sequentially administering at least one anti-viral agent.