Chemokine receptor antagonists and methods of use therefor

A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

• 35
• and physiologically acceptable salts thereof, wherein:
• n is an integer from one to about four;
• M is >NR2, >CR1R2, —O—CR1R2—O— or —CH2—CR1R2—O—;
• The ring containing M is substituted or unsubstituted;
• R1 is —H, —OH, —N3 , a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR3R41—NR3R4 or R1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;
• R2 is —H, —OH, an acyl group, a substituted acyl group, —NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);
• R3, R4, R5 and R6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group;
• or
• R1 and R2, R3 and R4, or R5 and R6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
• Z is represented by:
• 36
• wherein:
• X1 is —S—, —CH2—, —CH2—CH2—, —CH2—S—, —S—CH2—, —O—CH2—, —CH2—O—, —NRc—CH2—, —CH2—NRc—, —SO—CH2—, —CH2—SO—, —S(O)2—CH2—, —CH2—S(O)2—, —CH═CH—, —NRc—CO—, a bond, —O—, or —CO—NRc—;
• Rc is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group;
• and
• Ring A and Ring B are independently substituted or unsubstituted.

A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

• 39
• and physiologically acceptable salts thereof, wherein:
• n is an integer from one to about four;
• R50 and R51 are each, independently, —H,R50 and R51 are each independently —H, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —NR3R4, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, or a covalent bond between the nitrogen atom an adjacent carbon atom;
• R3 and R4are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group;
• Z is represented by:
• 40
• wherein:
• X1 is —S—, —CH2—, —CH2—CH2—, —CH2—S—, —S—CH2—, —O—CH2—, —CH2—O—, —NRc—CH2—, —CH2—NRc—, —SO—CH2—, —CH2—SO—, —S(O)2—CH2—, —CH2—S(O)2—, —CH=CH—, —Nrc—CO—, a bond, —O—, or —CO—NRc—;
• Rc is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group;
• and
• Ring A and Ring B are independently substituted or unsubstituted.

A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

• 43
• or a physiologically acceptable salt thereof, wherein:
• M is CR1R2;
• R1 is —OH;
• R is 4-chlorophenyl;
• n is two;
• Z is represented by:
• 44
• X1 is —CH2—O—;
• and
• R40 is
• 45

A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

• 46
• or a physiologically acceptable salt thereof, wherein:
• M is CR1R2;
• R1 is —OH;
• R2 is 4-chlorophenyl;
• n is two;
• Z is represented by:
• 47
• X1 is —CH2—O—;
• and
• R40 is —COOH.

A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

• 48
• or a physiologically acceptable salt thereof, wherein:
• M is CR1R2;
• R1 is —OH;
• R2 is 4-chlorophenyl;
• n is two;
• Z is represented by:
• 49
• X1 is —CH2—O—;
• and
• R40 is
• 50

A compound represented by the following structural formula:

• 51
• and physiologically acceptable salts thereof, wherein:
• n is an integer from one to about four;
• M is >NR2, >CR1R2, —O—CR1R2—O— or —CH2—CR1R2—O—;
• The ring containing M is substituted or unsubstituted;
• R1 is —H, —OH, —N3, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR3R4, —NR3R4 or R1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;
• R2 is —H, —OH, an acyl group, a substituted acyl group, —NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);
• R3, R4, R5 and R6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group;
• or
• R1 and R2, R3 and R4, or R5 and R6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
• Z is represented by:
• 52
• wherein:
• X1 is —S—, —CH2—, —CH2—CH2—, —CH2—S—, —S—CH2—, —O—CH2—, —CH2—O—, —NRc—CH2—, —CH2—NRc—, —SO—CH2—, —CH2—SO—, —S(O)2—CH2—, —CH2—S(O)2—, —CH═CH—, —NRc—CO—, a bond, —O—, or —CO—NRc—;
• Rc is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group;
• and
• Ring A and Ring B are independently substituted or unsubstituted.

A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

• 59
• and physiologically acceptable salts thereof, wherein:
• n is an integer from one to about four;
• M is >NR2, >CR1R2, —O—CR1R2—O— or —CH2—CR1R2—O—;
• The ring containing M is substituted or unsubstituted;
• R1 is —H, —OH, —N3, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR3R4, —NR3R4 or R1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;
• R2 is —H, —OH, an acyl group, a substituted acyl group, —NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);
• R3, R4, R5 and R6 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group;
• or
• R1 and R2, R3 and R4, or R5 and R6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;
• Z is represented by:
• 60
• wherein:
• X1 is —S—, —CH2—, —CH2—CH2—, —CH2—S—, —S—CH2—, —O—CH2—, —CH2—O—, —NRc—CH2—, —CH2—NRc—, —SO—CH2—, —CH2—SO—, —S(O)2—CH2—, —CH2—S(O)2—, —CH═CH—, —Nrc—CO—, a bond, —O—, or —CO—NRc—;
• Rc is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group;
• and
• Ring A and Ring B are independently substituted or unsubstituted.

A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

• 63
• and physiologically acceptable salts thereof, wherein:
• n is an integer from one to about four;
• R50 and R51 are each, independently, —H, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —NR 3R4, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, or a covalent bond between the nitrogen atom an adjacent carbon atom;
• R3 and R4 are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group;
• Z is represented by:
• 64
• wherein:
• X1 is —S—, —CH2—, —CH2—CH2—, —CH2—S—, —S—CH2—, —O—CH2—, —CH2—O—, —NRc—CH2—, —CH2—NRc—, —SO—CH2—, —CH2—SO—, —S(O)2—CH2—, —CH2—S(O)2—, —CH═CH—, —Nrc—CO—, a bond, —O—, or —CO—NRc—;
• Rc is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group;
• and
• Ring A and Ring B are independently substituted or unsubstituted.

A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

• 67
• or a physiologically acceptable salt thereof, wherein:
• M is CR1R2;
• R1 is —OH;
• R2 is 4-chlorophenyl;
• n is two;
• Z is represented by:
• 68
• X1 is —CH2—O—;
• and
• R40 is
• 69

A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

• 70
• or a physiologically acceptable salt thereof, wherein:
• M is CR1R2;
• R1 is —OH;
• R2 is 4-chlorophenyl;
• n is two;
• Z is represented by:
• 71
• X1 is —CH2—O—;
• and
• R40 is —COOH.

A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

• 72
• or a physiologically acceptable salt thereof, wherein:
• M is CR1R2;
• R1 is —OH;
• R2 is 4-chlorophenyl;
• n is two;
• Z is represented by:
• 73
• X1 is —CH2—;
• and
• R40 is
• 74