Modulation of CCR4 function

A pharmaceutical composition for the treatment of a CCR4-mediated disease or condition, said composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound which inhibits the binding of MDC or TARC to CCR4, said compound having the formula:

• Ar1-X-Ar2 (I)
• Ar1 and Ar2 are each members independently selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted fused aryl-heteocyclic ring systems and substituted or unsubstituted heteroaryl;
• and
• X is a linking group selected from the group consisting of —N(R)—, —C(O)S—, —CH═CHSO2— and —SO2N(R)— wherein R is a member selected from the group consisting of H and substituted or unsubstituted (C1-C8)alkyl.

A compound of formula (I):

• 38
• or a pharmaceutically acceptable salt thereof, wherein
• W is selected from aryl, heteroaryl, (C1-C8)alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl;
• X is selected from N(R5), S, O, C(R3)═C(R4), N═C(R4) and, optionally, when Z is N, X can be C(R6)(R7);
• Y is selected from a bond, N(R5), N(R5)—(C1-C8)alkylene, O, S and S(O)n, wherein the integer n is 1 or 2;
• Z is selected from N and C(R8);
• R1 and R2 are independently selected from H, halogen, CN, CO2R′, CONR′R″, (C1-C8)alkyl, heteroalkyl, aryl, heteroaryl, N(R6)(R7), OR9 and optionally, R1 and R2 combine to form a 5- to 8-membered ring containing from 0 to 3 heteroatoms selected from N, O and S, wherein R′ and R″ are independently selected from H, (C1-C8)alkyl and aryl, and when R′ and R″ are attached to nitrogen atom, they may be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring;
• R3, R4 and R8are independently selected from H, halogen, CN, OH, (C1-C8)alkyl, heteroalkyl, aryl, heteroaryl, O(C1-C8)alkyl, N(R6)(R7) and OR9;
• R5 is selected from H, (C1-C8)alkyl, heteroalkyl, aryl and heteroaryl;
• R6 and R7 are independently selected from H, (C1-C8)alkyl, heteroalkyl, aryl and heteroaryl;
• and
• R9 is selected from (C1-C8)alkyl, heteroalkyl and haloalkyl;
• with the provisos that R2 is other than H when W is unsubstituted phenyl, X is S, Y is NH, Z is N and R1 is (C1-C8)alkyl;
• and R1 is other than phenyl, when W is phenyl or unsubstituted naphthyl, X is S, Y is NH, and Z is N.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I):

• 41
• or a pharmaceutically acceptable salt thereof, wherein
• W is selected from aryl, heteroaryl, (C1-C8)alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl;
• X is selected from N(R5), S, O, C(R3)═C(R4), N═C(R4) and, optionally, when Z is N, X can be C(R6)(R7);
• Y is selected from a bond, N(R5), N(R5)—(C1-C8)alkylene, O, S and S(O)n, wherein the integer n is 1 or 2;
• Z is selected from N and C(R8);
• R1 and R2 are independently selected from H, halogen, CN, CO2R′, CONR′R″, (C1-C8)alkyl, heteroalkyl, aryl, heteroaryl, N(R6)(R7), OR9 and optionally, R1 and R2 combine to form a 5- to 8-membered ring containing from 0 to 3 heteroatoms selected from N, O and S, wherein R′ and R″ are independently selected from H, (C1-C8)alkyl and aryl, and when R′ and R″ are attached to nitrogen atom, they may be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring;
• R3, R4 and R8are independently selected from H, halogen, CN, OH, (C1-C8)alkyl, heteroalkyl, aryl, heteroaryl, O(C1-C8)alkyl, N(R6)(R7) and OR9;
• R5 is selected from H, (C1-C8)alkyl, heteroalkyl, aryl and heteroaryl;
• R6 and R7 are independently selected from H, (C1-C8)alkyl, heteroalkyl, aryl and heteroaryl;
• and
• R9 is selected from (C1-C8)alkyl, heteroalkyl and haloalkyl.

A method for treating a CCR4-mediated condition in a subject, said method comprising administering to a subject in need of such treatment an effective amount of a compound of of formula (I):

• 42
• or a pharmaceutically acceptable salt thereof, wherein
• W is selected from aryl, heteroaryl, (C1-C8)alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl;
• X is selected from N(R5), S, O, C(R3)═C(R4), N═C(R4) and, optionally, when Z is N, X can be C(R6)(R7);
• Y is selected from a bond, N(R5), N(R5)—(C1-C8)alkylene, O, S and S(O)n, wherein the integer n is 1 or 2;
• Z is selected from N and C(R8);
• R1 and R2 are independently selected from H, halogen, CN, CO2R′, CONR′R″, (C1-C8)alkyl, heteroalkyl, aryl, heteroaryl, N(R6)(R7), OR9 and optionally, R1 and R2 combine to form a 5- to 8-membered ring containing from 0 to 3 heteroatoms selected from N, O and S, wherein R′ and R″ are independently selected from H, (C1-C8)alkyl and aryl, and when R′ and R″ are attached to nitrogen atom, they may be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring;
• R3, R4 and R8are independently selected from H, halogen, CN, OH, (C1-C8)alkyl, heteroalkyl, aryl, heteroaryl, O(C1-C8)alkyl, N(R6)(R7) and OR9;
• R5 is selected from H, (C1-C8)alkyl, heteroalkyl, aryl and heteroaryl;
• R6 and R7 are independently selected from H, (C1-C8)alkyl, heteroalkyl, aryl and heteroaryl;
• and
• R9 is selected from (C1-C8)alkyl, heteroalkyl and haloalkyl.