Chemokine receptor antagonists and methods of use thereof

A compound having the formula:

• or physiologically acceptable salt thereof, wherein:
• n is one to four;
• M is >CR1R2;
• R1 is —OH;
• R2 is 4-halophenyl;
• R70 and R71 are —H, and R72 and R73 are —CH3;
• or
• R70 and R71 are —CH3, and R72 and R73 are —H;
• Z is
• X1 is —CH2—O—;
• and
• R40 is selected from the group consisting of:

A compound having the structure:

• or a physiologically acceptable salt thereof, wherein
• R2 is 4-halophenyl;
• and
• R40 is selected from the group consisting of:

A compound having the formula:

• or physiologically acceptable salt thereof, wherein:
• n is an integer from one to four;
• M is >NR2, >CR1R2, —O—CR1R2—O— or —CH2—CR1R2—O—;
• q1 is an integer from zero to three;
• q2 is zero or one;
• 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 —OH, a halogen, 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:
• 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;
• said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl
• said aliphatic group is a C1-C6 alkyl, alkenyl or alkynyl;
• said aromatic group is selected from the group consisting of phenyl,
• 1-naphthyl, 2-naphthyl, 1-anthracyl, 2-anthracyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl,
• 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, tetrahydronaphthyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl, 2-benzimidazolyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, acridinyl, 3-benzisoxazolyl, benzocyclopentyl, benzocyclohexyl;
• said non-aromatic heterocyclic group is a five to eight-membered non-aromatic ring which contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur;
• said substituted aliphatic group is substituted with one or more substitutents selected from the group consisting of oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group, substituted benzyl group, aromatic group or substituted aromatic group electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, —NR60, —(O)u—(CH2)t—C(O)OR20,
• (O)u—(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group);
• said substituted non-aromatic heterocyclic ring is substituted with one or more substitutents selected from the group consisting of ═O, ═S, electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60,
• —(O)u—(CH2)t—C(O)OR20, —(O)u—(CH2)t—OC(O)R20, —(O)t—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)tNHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or Q-(CH2)p-(non-aromatic heterocyclic group);
• said substituted aromatic group and substituted benzyl group are substituted with one or more substitutents selected from the group consisting of electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60, —(O)u—(CH2)t—C(O)OR20, —(O)u—(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group);
• Q is —O—, —S—, —S(O)—, —S(O)2—, —OS(O)2—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)C(O)—C—, —O—C(O)C(O)—, —NHC(O)—, —OC(O)NH—, —NH—C(O)—NH—, —S(O)2NH—, —NHS(O)2—, —C(NR23)NHNH—, —NHNHC(NR23)—, —NR24C(O)— or
• —NR24S(O)2—;
• R20, R21 and R22 are independently —H, an aliphatic group, an aromatic group, a non-aromatic heterocyclic group, —NHC(O)—O-(aliphatic group), —NHC(O)—O-(aromatic group) or —NHC(O)—O-(non-aromatic heterocyclic group) or R21 and R22, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring;
• R23 is —H, an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group;
• R24 and R25 are independently —H, —OH, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic group or R24 and R25 taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring;
• R60 is a —H, —OH, —NH2, an aromatic group or a substituted aromatic group;
• t is zero to three;
• u is zero or one;
• p is one to five;
• and
• R40 is selected from the group consisting of

A compound having the formula:

• or physiologically acceptable salt thereof, wherein:
• n is one to four;
• R2 is —OH, a halogen, 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);
• 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
• 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:
• X1 is —S—, —CH2—, —CH2—CH2—, —CH2—S—, —S—CH2—, —O—CH2—, —CH2—O—, —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;
• Rings A and B are independently unsubstited or substituted;
• said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;
• said aliphatic group is a C1-C6 alkyl, alkenyl or alkynyl;
• said aromatic group is selected from the group consisting of phenyl,
• 1-naphthyl, 2-naphthyl, 1-anthracyl, 2-anthracyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl,
• 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, tetrahydronaphthyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl, 2-benzimidazolyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, acridinyl, 3-benzisoxazolyl, benzocyclopentyl, benzocyclohexyl;
• said non-aromatic heterocyclic group is a five to eight-membered non-aromatic ring which contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur;
• said substituted aliphatic group is substituted with one or more substitutents selected from the group consisting of oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group, substituted benzyl group, aromatic group or substituted aromatic group electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60, —(O)u—(CH2)t—C(O)OR20,
• —(O)u—(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group);
• said substituted non-aromatic heterocyclic ring is substituted with one or more substitutents selected from the group consisting of ═O, ═S, electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60,
• —(O)u—(CH2)t—C(O)OR20, —(O)u—(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group);
• said substituted aromatic group, substituted benzyl group, Ring A when substituted and Ring B when substituted, are substituted with one or more substitutents selected from the group consisting of electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60,
• —(O)u—(CH2)t—C(O)OR20, —(O)u(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group);
• Q is —O—, —S—, —S(O)—, —S(O)2—, —OS(O)2—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)C(O)—O—, —O—C(O)C(O)—, —NHC(O)—, —OC(O)NH—, —NH—C(O)—NH—, —S(O)2NH—, —NHS(O)2—, —C(NR23)NHNH—, —NHNHC(NR23)—, —NR24C(O)— or
• —NR24S(O)2—;
• R20, R21 and R22 are independently —H, an aliphatic group, an aromatic group, a non-aromatic heterocyclic group, —NHC(O)—O-(aliphatic group), —NHC(O)—O-(aromatic group) or —NHC(O)—O-(non-aromatic heterocyclic group) or R21 and R22, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring;
• R23 is —H, an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group;
• R24 and R25 are independently —H, —OH, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic group or R24 and R25 taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring;
• R60 is a —H, —OH, —NH2, an aromatic group or a substituted aromatic group;
• t is zero to three;
• u is zero or one;
• p is one to five.