IP Library › Patent Application 14105750

Patent Application

App. No. 14/105,750

CHEMOKINE RECEPTOR ANTAGONISTS AND METHODS OF USE THEREOF

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Patent No.: US None
App. No.: 14/105,750

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Abstract

Disclosed are novel compounds and a method of treating a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to a subject in need an effective amount of a compound represented by: or physiologically acceptable salt thereof.

Claims (184)

1 . A compound having the formula:

or physiologically acceptable salt thereof, wherein:

n is one to four;

M is >NR 2 or >CR 1 R 2 ;

R 1 is —H, —OH, —N 3 , 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—NR 3 R 4 , —NR 3 R 4 or R 1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M;

R 2 is —OH, a halogen, an acyl group, a substituted acyl group, —NR 5 R 6 , 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), —O-(substituted or unsubstituted aliphatic group), —C(O)-(substituted or unsubstituted aromatic group) or —C(O)-(substituted or unsubstituted aliphatic group);

R 3 , R 4 , R 5 and R 6 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

R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;

R 70 and R 71 are independently —H, —OH, —N 3 , 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—NR 3 R 4 , —NR 3 R 4 , an acyl group, a substituted acyl 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);

R 72 and R 73 are independently —OH, —N 3 , 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), —O—C(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR 3 R 4 , —NR 3 R 4 , an acyl group, a substituted acyl 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);

Z is

X 1 is —CH 2 —O—, —O—CH 2 —, —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO—, a bond, —O—, or —CO—NR c —;

R c 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 unsubstituted or substituted;

said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl;

said aliphatic group is a C 1 -C 6 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, —CONR 24 R 25 , —NR 24 R 25 , OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , —NR 60 , —(O) u —(CH 2 ) t —C(O)OR 20 ,

—(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 , —(O) u —(CH 2 ) t —NHC(O)O—R 20 , -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH 2 ) p -(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH 2 ) 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, —CONR 24 R 25 , —NR 24 R 25 , —OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , —NR 60 ,

—(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 , —(O) u —(CH 2 ) t —NHC(O)O—R 20 , -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH 2 ) p -(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH 2 ) 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, CONR 24 R 25 , —NR 24 R 25 , —OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , ═NR 60 ,

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) 2 NH—, —NHS(O) 2 —, —C(NR 23 )NHNH—, —NHNHC(NR 23 )—, —NR 24 C(O)— or

—NR 24 S(O) 2 —;

R 20 , R 21 and R 22 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 R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring;

R 23 is —H, an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group;

R 24 and R 25 are independently —H, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic group or R 24 and R 25 taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring.

R 60 is a —H, —OH, —NH 2 , an aromatic group or a substituted aromatic group.

t is zero to three;

u is zero or one;

p is one to five.

2 . The compound of claim 1 wherein Ring A is unsubstituted and B is substituted para to the carbon atom of ring B that is bonded to X 1 in ring C, and Z is represented by the structural formula:

wherein R 40 is —OH, —COOH, —NO 2 , halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR 24 R 25 , —CONR 24 R 25 , —NR 24 C(O)-(aliphatic group), C(O)-(substituted aliphatic group), —NR 24 S(O) 2 -(aliphatic group), —NR 24 S(O) 2 -(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —C(O)-(aliphatic group), —C(O)-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O), —(CH 2 ) t —C(O)OR 20 ,

—(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 or

—(O) u —(CH 2 ) t —NHC(O)O—R 20 ;

R 20 , R 21 or R 22 are independently-H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or

R 21 and R 22 , taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring;

R 24 and R 25 are independently —H, an aliphatic group or a substituted aliphatic group;

u is zero or one; and

t is an integer from zero to 3.

3 . The compound of claim 2 wherein

M is >CR 1 R 2 ;

R 1 is —H or —OH; and

R 2 is a substituted aromatic group, wherein said substituted aromatic group is 4-halophenyl.

4 . The compound of claim 3 wherein said 4-halophenyl is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl and 4-fluorophenyl.

5 . The compound of claim 4 wherein said 4-halophenyl is 4-chlorophenyl.

6 . The compound of claim 3 wherein X 1 is —CH 2 —O—.

7 . The compound of claim 2 wherein at least one of R 70 , R 71 , R 72 and R 73 is an aliphatic group or a substituted aliphatic group; wherein

said aliphatic group is a C 1 -C 6 alkyl and said substituted aliphatic group is a C 1 -C 6 alkyl substituted with a substitutent selected from the group consisting of —OH, —(O) u —(CH 2 ) t —C(O)OR 20 and —O-(aliphatic group);

t is zero to three;

u is zero or one; and

R 20 is C 1 -C 6 alkyl.

8 . The compound of claim 7 wherein

R 70 and R 71 are both —H;

R 72 and R 73 are independently selected from the group consisting of C 1 -C 6 alkyl and substituted C 1 -C 6 alkyl.

9 . The compound of claim 8 wherein R 72 is —CH 3 .

10 . A method for treating a disease associated with aberrant leukocyte recruitment, aberrant leukocyte activation or aberrant leukocyte recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 .

11 . A pharmaceutical composition comprising a compound according to claim 1 and a physiologically acceptable carrier.

12 . A compound having the formula:

or physiologically acceptable salt thereof, wherein:

n is one to four;

M is >CR 1 R 2 ;

R 1 is —OH;

R 2 is 4-halophenyl;

R 70 and R 71 are —H, and R 72 and R 73 are —CH 3 ; or

R 70 and R 71 are —CH 3 , and R 72 and R 73 are —H;

Z is

X 1 is —CH 2 —O—; and

R 40 is selected from the group consisting of:

13 . The compound of claim 12 wherein R 40 is

14 . The compound of claim 12 wherein said 4-halophenyl is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl and 4-fluorophenyl.

15 . The compound of claim 14 wherein said 4-halophenyl is 4-chlorophenyl.

16 . The compound of claim 15 wherein R 70 and R 71 are —H, R 72 and R 73 are —CH 3 , n is two, and the compound has the structure:

17 . A method for treating a disease associated with aberrant leukocyte recruitment, activation or recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound of claim 12 .

18 . A pharmaceutical composition comprising a compound of claim 12 and a physiologically acceptable carrier.

19 . A compound having the structure:

or a physiologically acceptable salt thereof, wherein

R 2 is 4-halophenyl; and

R 40 is selected from the group consisting of:

20 . The compound of claim 19 wherein R 40 is

21 . The compound of claim 19 wherein R 2 is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl and 4-fluorophenyl.

22 . The compound of claim 21 wherein R 2 is 4-chlorophenyl.

23 . A pharmaceutical composition comprising the compound of claim 18 and a physiologically acceptable carrier.

24 . A method for treating a disease associated with aberrant leukocyte recruitment, aberrant leukocyte activation or aberrant leukocyte recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound of claim 18 .

25 . The method of claim 24 wherein said disease is selected from the group consisting of arthritis, atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes mellitus, psoriasis, multiple sclerosis, inflammatory bowel diseases, rejection of a transplanted organ or tissue, graft versus host disease, allergy and asthma.

26 . The method of claim 25 wherein said disease is multiple sclerosis.

27 . The method of claim 25 wherein said disease is arthritis, and said arthritis is rheumatoid arthritis.

28 . A compound having the formula:

or physiologically acceptable salt thereof, wherein:

n is an integer from one to four;

M is >NR 2 , >CR 1 R 2 , —O—CR 1 R 2 —O— or —CH 2 —CR 1 R 2 —O—;

q 1 is an integer from zero to three;

q 2 is zero or one;

—OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group),

—O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);

R 1 and R 2 , R 3 and R 4 , or R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;

Z is:

X 1 is —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —NR c —CH 2 —, —CH 2 —NR c —, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO—, a bond, —O—, or —CO—NR c —;

R c 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 C 1 -C 6 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,

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, —CONR 24 R 25 , —NR 24 R 25 , —OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , —NR 60 , —(O) u —(CH 2 ) t —C(O)OR 20 ,

(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 , —(O) u —(CH 2 ) t —NHC(O)O—R 20 , -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH 2 ) p -(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH 2 ) p -(non-aromatic heterocyclic group);

—(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) t —(CH 2 ) t —C(O)—NR 21 R 22 , —(O) u —(CH 2 ) t NHC(O)O—R 20 , -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH 2 ) p -(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or Q-(CH 2 ) 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, —CONR 24 R 25 , —NR 24 R 25 , —OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , ═NR 60 , —(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u —(CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 , —(O) u —(CH 2 ) t —NHC(O)O—R 20 , -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH 2 ) p -(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH 2 ) 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) 2 NH—, —NHS(O) 2 —, —C(NR 23 )NHNH—, —NHNHC(NR 23 )—, —NR 24 C(O)— or

—NR 24 S(O) 2 —;

R 23 is —H, an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group;

R 24 and R 25 are independently —H, —OH, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic group or R 24 and R 25 taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring;

R 60 is a —H, —OH, —NH 2 , an aromatic group or a substituted aromatic group;

t is zero to three;

u is zero or one;

p is one to five; and

R 40 is selected from the group consisting of

29 . The compound of claim 28 wherein:

q 1 is one;

q 2 is one;

M is >CR 1 R 2 ;

R 1 is —H or —OH; and

R 2 is a substituted aromatic group.

30 . The compound of claim 29 wherein R 2 is phenyl substituted with a halogen.

31 . The compound of claim 30 wherein R 2 is 4-chloropheynl.

32 . The compound of claim 31 wherein n is 2, X 1 is —CH 2 —O—, and R 1 is —OH.

33 . A method for treating a disease associated with aberrant leukocyte recruitment, activation or recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound of claim 28 .

34 . A pharmaceutical composition comprising a compound of claim 28 and a physiologically acceptable carrier.

35 . A compound having the formula:

or physiologically acceptable salt thereof, wherein:

n is one to four;

—O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group);

R 5 and R 6 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

R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring;

Z is:

X 1 is —S—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —S—, —S—CH 2 —, —O—CH 2 —, —CH 2 —O—, —SO—CH 2 —, —CH 2 —SO—, —S(O) 2 —CH 2 —, —CH 2 —S(O) 2 —, —CH═CH—, —NR c —CO—, a bond, —O—, or —CO—NR c —;

R c 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 C 1 -C 6 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,

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, —CONR 24 R 25 , —NR 24 R 25 , —OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , ═NR 60 , —(O) u —(CH 2 ) t —C(O)OR 20 ,

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, —CONR 24 R 25 , —NR 24 R 25 , —OS(O) 2 NR 24 R 25 , —S(O) 2 NR 24 R 25 , —SO 3 H, guanidino, oxalo, —C(═NR 60 )NR 21 R 22 , ═NR 60 ,

—(O) u —(CH 2 ) t —C(O)OR 20 , —(O) u (CH 2 ) t —OC(O)R 20 , —(O) u —(CH 2 ) t —C(O)—NR 21 R 22 , —(O) u —(CH 2 ) t —NHC(O)O—R 20 , -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH 2 ) p -(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH 2 ) p -(non-aromatic heterocyclic group);

—NR 24 S(O) 2 —;

R 23 is —H, an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group;

R 60 is a —H, —OH, —NH 2 , an aromatic group or a substituted aromatic group;

t is zero to three;

u is zero or one;

p is one to five.

36 . The compound according to claim 35 wherein R 2 is —NR 5 R 6 .

37 . The compound of claim 36 wherein:

R 5 is aliphatic group or substituted aliphatic group; and

R 6 is benzyl or substituted benzyl; or

R 5 and R 6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.

38 . The compound of claim 37 wherein R 5 is ethyl, and R 6 is substituted benzyl, wherein said substituted benzyl is substituted with a halogen.

39 . A method for treating a disease associated with aberrant leukocyte recruitment, activation or recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound according to claim 35 .

40 . A pharmaceutical composition comprising a compound according to claim 35 and a physiologically acceptable carrier.

41 . A prodrug of the compound of claim 12 .

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 13, 2013

From: LULY, JAY R.; HARRIMAN, GERALDINE C.B.; CARSON, KENNETH G.; GHOSH, SHOMIR; ELDER, AMY M.; MATTIA, KAREN M.

To: MILLENNIUM PHARMACEUTICALS, INC.

Reel/Frame 031780/0448 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 13, 2013

From: NAKASATO, YOSHISUKE; OHSHIMA, ETSUO

To: KYOWA HAKKO KOGYO CO., LTD

Reel/Frame 031780/0573 →

CHANGE OF NAME Recorded Dec 13, 2013

From: KYOWA HAKKO KOGYO CO., LTD

To: KYOWA HAKKO KIRIN CO., LTD

Reel/Frame 031816/0110 →