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1. (WO2005066147) UTILISATION DE THIADIAZOLES COMME LIGANDS DES RECEPTEURS AUX CHIMIOKINES CXC ET CC
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

WHAT IS CLAIMED IS:

A compound of the formula:



and the pharmaceutically acceptable salts thereof, wherein: A is selected from the group consisting of:
(1)












10

(2)










wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R9 groups;

(3)






wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of: R9 groups;

(4)



wherein the above phenyl rings of said A groups are substituted with 1 to 3
substituents each independently selected from the group consisting of: R9 groups; and (5)







is selected from the group consisting of



n is 0 to 6;
p is 1 to 5;
X is O, NR18, or S;
Z is 1 to 3;
R2 is selected from the group consisting of: hydrogen, OH, -C(O)OH, -SH, -SO2NR13R14, -NHC(O)R13, -NHSO2NR13R14, -NHSO2R13 , -NR13R14, -C(O)NR13R14, -C(O)NHOR13, -C(O)NR13OH, - S(O2)OH, -OC(O)R13, an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group; wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of: R9 groups;

each R3 and R4 is independently selected from the group consisting of:
hydrogen, cyano, halogen, alkyl, alkoxy, cycloalkyl substituted with 1 to 4 alkyl groups wherein each alkyl group is independently selected, unsubstituted cycloalkyl, cycloalkyl substituted with 1 to 4 alkyl groups, -OH, -CF3, -OCF3, -NO2, -C(O)R13, -C(O)OR13, -C(0)NHR17, -C(O)NR13R14, -SO(t)NR13R14, -SOrøR^. -C^NR^OR14, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,



wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R9 groups; or
R3 is and R4 taken together with the carbons atoms to which they are bonded to in the the phenyl B substituent



form a fused ring of the formula:



wherein Z1 or Z2 is an unsubstituted or substituted saturated heterocyclic ring
(preferably a 4 to 7 membered heterocyclic ring), said ring Z1 or Z2 optionally containing one additional heteroatom selected from the group consisting of: O, S and NR18; wherein there are 1 to 3 substituents on said ring Z1 or Z2, and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy,
hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, -C(O)OR15, -C(O)NR15R16, -SOtNR15R16, -C(O)R15, -SO2R15 provided that R15 is not H, -NHC(O)NR15R16, -NHC(O)OR15, halogen, and a heterocycloalkenyl group;
each R5 and R6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -CF3, -OCF3,
-N02, -C(O)R13, -C(O)OR13, -C(O)NR13R14, -SO(t)NR13R14, -C(O)NR13OR14, cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group; wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R9 groups; and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of: R9 groups;
each R7 and R8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, -CO2R13, -CONR13R14, alkynyl, alkenyl, and cycloalkenyl; and wherein there are one or more substituents on said substituted R7 and R8 groups, wherein each substitutent is independently selected from the group consisting of:
a) halogen,
b) -CF3,
c) -COR13,
d) -OR13,
e) -NR13R14,
f) -NO2,
g) -CN,
h) -SO2OR13,
i) -Si(alkyl)3, wherein each alkyl is independently selected,
j) -Si(aryl)3, wherein each alkyl is independently selected,
k) -(R13)2R14Si, wherein each R13 is independently selected,
I) -CO2R13,
m) -C(O)NR13R14,
n) -SO2NR13R14,
o) -SO2R13,
p) -OC(O)R13, q) -OC(O)NR13R14,
r) -NR13C(O)R14 , and
s) -NR13CO2R14;
(fluoroalkyl is one non-limiting example of an alkyl group that is substituted with halogen);
R8a is selected from the group consisting of: hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;
each R9 is independently selected from the group consisting of:
a) -R13,
b) halogen,
c) -CF3)
d) -COR13,
e) -OR13,
f) -NR13R14,
9) -NO2,
h) -CN,
i) -SO2R13,
j) -SO2NR13R14,
k) -NR13COR14,
I) -CONR13R14 ,
m) -NR13CO2R14
n) -CO2R13,
o)



p) alkyl substituted with one or more -OH groups,
q) alkyl substituted with one or more -NR13R14 group, and r) -N(R13)SO2R14;
each R10 and R11 is independently selected from the group consisting of R13, halogen, -CF3, -OCF3, -NR13R14, -NR13C(O)NR13R14, -OH, -C(O)OR13, -SH,
-SO(t)NR13R14, -SO2R13, -NHC(O)R13, -NHSO2NR13R14, -NHSO2R13, -C(O)NR13R14,

C(O)NR13OR14, -OC(O)R13 and cyano;

R12 is selected from the group consisting of: hydrogen, -C(O)OR13,
unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group; wherein there are 1 to 6 substituents on the substituted R12 groups and each substituent is independently selected from the group consisting of: R9 groups;
each R13 and R14 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted cyanoalkyl,
unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cyanocycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl (wherein "heterocyloalkyl" means heterocyclic); wherein there are 1 to 6 substituents on said substituted R13 and R14 groups and each substituent is independently selected from the group consisting of: alkyl, -CF3, -OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, -N(R40)2, -C(O)OR15, -C(O)NR15R16, -S(O)tNR15R16, -C(0)R15, halogen, -NHC(O)NR 5R16 and -SO2R15 provided that R15 is not H; and provided that for the substituted cyanoalkyl and the substituted
cyanocycloalkyl moieties the carbon atom to which the cyano group is bound to does not also have bound to said carbon atom a substituent selected from the group consisting of: -OH, alkoxy, -N(R40)2, halogen and -NHC(O)NR15R16 ; or
R13 and R14 taken together with the nitrogen they are attached to in the groups -C(O)NR13R14 and -SO2NR13R14 form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR18; wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups and each substituent is independently selected from the group consisting of: CN, alkyl, cyanoalkyl, aryl, hydroxy,
hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, -C(O)OR15, -C(O)NR15R16,
-SOtNR15R16, -C(0)R15, -SO2R15 (provided that R15 is not H), -NHC(O)NR15R16, -NHC(O)OR15, halogen, and a heterocycloalkenyl group; and provided that the carbon atom to which the cyano group is bound to does not also have bound to said carbon atom a substituent selected from the group consisting of: hydroxy, alkoxy, amino, halogen, -NHC(O)NR15R16 and -NHC(O)OR15;
each R15 and R16 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;
R17 is selected from the group consisting of: -SO2alkyl, -SO2aryl,
-SO2cycloalkyl, and -SO2heteroaryl;
R18 is selected from the group consisting of: H, alkyl, aryl, heteroaryl, -C(O)R19, -SO2R19 and -C(O)NR19R20;
each R19 and R20 is independently selected from the group consisting of: alkyl, aryl and heteroaryl;
R30 is selected from the group consisting of: alkyl, cycloalkyl, -CN, -NO2, or -SO2R15 provided that R15 is not H;
each R31 is independently selected from the group consisting of: unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl and unsubstituted or substituted cycloalkyl; wherein there are 1 to 6 substituents on said substituted R31 groups and each substituent is independently selected from the group consisting of: alkyl, halogen and -CF3;
each R40 is independently selected from the group consisting of: H, alkyl and cycloalkyl; and
t is O, 1 or 2.

2. The compound of claim 1 wherein A is selected from the group consisting of:
(1) unsubstituted or substituted:


(2)


3. The compound of Claim 1 wherein substituent A is:



wherein the furan ring is unsubstituted or substituted with 1 or 2 alkyl groups wherein each alkyl group is independently selected, R7 is selected from the group consisting of: -CF3, alkyl and cycloalkyl, and R8 is H.

The compound of Claim 1 wherein substituent A is:



wherein the furan ring is substituted with 1 or 2 alkyl groups independently selected from the group consisting of methyl, ethyl and isopropyl, R7 is selected from the group consisting of: ethyl, isopropyl and t-butyl, and R8 is H.

5. The compound of Claim 1 wherein A is selected from the group consisting of:


6. The compound of claim 1 wherein A is selected from the group consisting of:


7. The compound of Claim 1 wherein substituent A is selected from the group consisting of:


8. The compound of Claim 1 wherein B is selected from the group consisting of:

9. The compound of Claim 1 wherein B is selected from the group consisting of:


10. The compound of Claim 1 wherein B is selected from the group consisting of:


11. The compound of Claim 1 wherein B is selected from the group consisting of:


12. The compound of Claim 1 wherein B is


13. The compound of Claim 1 wherein B is:



wherein R is -OH.

14. The compound of Claim 1 wherein B is:



wherein R2 is-OH, and R13 and R14 are independently selected from the group consisting of H and alkyl.

15. The compound of Claim 1 wherein B is


16. The compound of Claim 15 wherein R11 is H.

17. The compound of Claim 16 wherein R2 is -OH.

18. The compound of Claim 17 wherein R3 is -C(O)NR13R14.

19. The compound of Claim 17 wherein R3 is -S(O)tNR13R14.

20. The compound of Claim 1 wherein B is:



wherein R2 is -OH, R3 is -C(0)NR13R14, R11 is H or methyl, and R13 and R14 are independently selected from the group consisting of: H, alkyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heteroaryl and substituted heteroaryl.

21. The compound of Claim 1 wherein B is:



wherein R2 is -OH, R3 is -S(0)tNR13R14, R11 is H or methyl, and R13 and R14 are independently selected from the group consisting of H, alkyl, unsubstituted cycloalkyl and substituted cycloalkyl.

22. The compound of Claim 1 wherein B is:


23. The compound of Claim 22 in R11 is H.

24. The compound of Claim 23 wherein R2 is -OH.

25. The compound of Claim 24 wherein R3 is -C(O)NR13R1'

26. The compound of Claim 24 wherein R3 is -S(O)tNR13R1

27. The compound of Claim 1 wherein B is:



wherein R2 is -OH, R3 is -C(O)NR13R14, R11 is H, and R13 and R14 are independently selected from the group consisting of: H, alkyl, unsubstituted heteroaryl and substituted heteroaryl.

28. The compound of Claim 1 wherein B is:



wherein R2 is -OH, R3 is -S(O)tNR13R14, R11 is H, and R 3 and R14 are independently selected from the group consisting of H and alkyl.

29. The compound of Claim 1 wherein:
(1 ) substituent A in formula IA is selected from the group consisting of:
(a)




wherein the above rings are unsubstituted, or the above rings are substituted 1 to 3 substituents independently selected from the group consisting of: F, Cl, Br, alkyl, cycloalkyl, and -CF3; R7 is selected from the group consisting of: H, -CF3, -CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and
(b)
R7 R8
.X.R8a
wherein R7 is selected from the group consisting of: H, -CF3, -CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R8 is H; and R8a is as defined in Claim 1 ;
(2) substituent B in formula IA is selected from the group consisting of:



wherein:
R2 is selected from the group consisting of: H, OH, -NHC(O)R13 and


R3 is selected from the group consisting of: -C(O)NR13R14 -SO2NR13R14, -NO2, cyano, and -SO2R13;

R4 is selected from the group consisting of: H, -NO2, cyano, alkyl, halogen and

-CF3
R5 is selected from the group consisting of: H, -CF3, -NO2, halogen and cyano; R6 is selected from the group consisting of: H, alkyl and -CF3;
R11 is selected from the group consisting of: H, halogen and alkyl; and
each R13 and R14 is independently selected from the group consisting of: H, unsubstituted alkyl.

30. The compound of Claim 1 wherein:
(1 ) substituent A in formula IA is selected from the group consisting of:


(2) substituent B in formula IA is selected from the group consisting of:



wherein:
R2 is -OH;
R3 is selected from the group consisting of: -SO2NR13R14 and -CONR13R14;

R4 is selected form the group consisting of: H, Br, -CH3, ethyl and -CF3;
R5 is selected from the group consisting of: H and cyano;
R6 is selected from the group consisting of: H, -CH3 and -CF3;
R11 is H; and
R13 and R14 are independently selected from the group consisting of H and methyl.

31. The compound of Claim 1 wherein substituent A is selected from the group consisting of:


and substituent B is selected from the group consisting of:


32. The compound of Claim 1 wherein substituent A is selected from the group consisting of:



and substituent B is selected from the group consisting of:


33. A pharmaceutically acceptable salt of a compound of any of Claims 1 to

32.

34. A sodium salt of a compound of any of Claims 1 to 32.

35. A calcium salt of a compound of any of Claims 1 to 32.

36. The compound of Claim 1 selected from the group consisting of the final compounds of Examples 1 , 2-4, 6-35, 100-105, 107, 108, 1 10, 111 , 1 12, 1 14-1 16,

1 18-132, 134-145, 148, 180, 182, 183, 185, 186, 188, 300-389, 500-639, 700-787, and 900-987, and the pharmaceutically acceptable salts thereof.

37. The compound of Claim 1 selected from the group consisting of the final compounds of Examples 1 , 6, 8, 110, 1 1 1 , 1 12, 1 14, 122, 120, 123, 124, 129, 130, 131 , 142, 144, 145, 300, 305, 306, 307, 313, 316, 317, 318, 323, 324, 327, 328, 329, 334, 335, 338, 339, 340, 349, 350, 351 , 359, 360, 361 , 362, 364, 370, 372, 373, 374, 381 , 544, 545, 546, 548, 558, 559, 560, 561 , 562, 572, 708,718, 719, 721 , 732, 754, 774, 784, 928, 930, 931 , 939, 942, 941 , 950, 952, and the pharmaceutically
acceptable salts thereof.

38. The compound of Claim 1 selected from the group consisting of the final compounds of Examples 1 , 6, 8, 114, 120, 123, 129, 131 , 300, 305, 306, 307, 316, 317, 318, 323, 327, 328, 329, 334, 359, 360, 361 , 370, 372, 373, 374, 544, 545, 546, 548, 558, 559, 560, 561 , 562, 928, 930, 931 , 939, 942, 941 , 950, 952, and the pharmaceutically acceptable salts thereof.

39. The compound of Claim 1 wherein said compound is the final compound of Example 1 , or a pharmaceutically acceptable salt thereof.

40. The compound of Claim 1 wherein said compound is the final compound of Example 6, or a pharmaceutically acceptable salt thereof.

41. The compound of Claim 1 wherein said compound is the final compound of Example 8, or a pharmaceutically acceptable salt thereof.

42. The compound of Claim 1 wherein said compound is the final compound of Example 120, or a pharmaceutically acceptable salt thereof.

43. The compound of Claim 1 wherein said compound is the final compound of Example 131 , or a pharmaceutically acceptable salt thereof.

44. The compound of Claim 1 wherein said compound is the final compound of Example 545, or a pharmaceutically acceptable salt thereof.

45. The compound of Claim 1 wherein said compound is the final compound of Example 561 , or a pharmaceutically acceptable salt thereof.

46. The compound of Claim 1 wherein said compound is the final compound of Example 928, or a pharmaceutically acceptable salt thereof.

47. The compound of Claim 1 wherein said compound is the final compound of Example 930, or a pharmaceutically acceptable salt thereof.

48. The compound of Claim 1 wherein said compound is the final compound of Example 931 , or a pharmaceutically acceptable salt or thereof.

49. The compound of any of Claims 1 to 48 in isolated and pure form.

50. A pharmaceutical composition comprising at least one compound of any of Claims 1 to 49, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

51. A pharmaceutical composition comprising at least one compound of any of Claims 1 to 49, or a pharmaceutically acceptable salt thereof, and at least one other agent, medicament, antibody and/or inhibitor for treating a chemokine mediated disease, in combination with a pharmaceutically acceptable carrier.

52. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a chemokine mediated disease.

53. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer.

54. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one anticancer agent selected from the group consisting of: (a)
microtubule affecting agents, (b) antineoplastic agents, (c) anti-angiogenesis agents, or (d) VEGF receptor kinase inhibitors, (e) antibodies against the VEGF receptor, (f) interferon and g) radiation, for treating cancer

55. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one antineoplastic agent selected from the group consisting of: gemcitabine, paclitaxel, 5-Fluorourcil, cyclophosphamide, temozolomide and
Vincristine, for treating cancer.

56. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use concurrently or sequentially with a microtubule affecting agent, for treating cancer.

57. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use concurrently or sequentially with (b) at least one agent selected from the group consisting of: (1) antineoplastic agents, (2) microtubule affecting agents, and (3) anti-angiogenesis agents, for treating cancer.

58. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting angiogenesis.

59. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating angiogenic ocular disease.

60. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or condition selected from the group consisting of: pain, acute inflammation, chronic inflammation, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, ischemia reperfusion injury, renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. host reaction, allograft rejections, malaria, acute respiratory distress syndrome, delayed type hypersensitivity reaction, atherosclerosis, cerebral ischemia, cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus, meningitis, cystic fibrosis, pre-term labor, cough, pruritis, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes,
encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease, ocular
inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred, corneal neovascularization, polymyositis, vasculitis, acne, gastric ulcers, duodenal ulcers, celiac disease, esophagitis, glossitis, airflow
obstruction, airway hyperresponsiveness, bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), granulocytic ehriichiosis, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burn therapy, periodontitis, cancer, transplant reperfusion injury, early transplantation rejection, airway hyperreactivity, allergic contact dermatitis, allergic rhinitis, alopecia areata, antiphospholipid syndromes, aplastic anemia, autoimmune deafness, autoimmune hemolytic syndromes, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, bullous pemphigoid, chronic allograft vasculopathy, chronic inflammatory
demyelinating polyneuropathy, cirrhosis, cor pneumoniae, cryoglobulinemia, dermatomyositis, diabetes, drug-induced autoimmunity, epidermolysis bullosa acquisita, endometriosis, fibrotic diseases, gastritis, Goodpasture's syndrome, Graves' disease, Gullain-Barre disease, Hashimoto's thyroiditis, hepatitis-associated
autoimmunity, HIV-related autoimmune syndromes and hematologic disorders, hypophytis, idiopathic thrombocytic pupura, interstitial cystitis, juvenile arthritis, Langerhans' cell histiocytitis, lichen planus, metal-induced autoimmunity, myasthenia gravis, myelodysplastic syndromes, myocarditis, myositis, Neuropathies, nephritic syndrome, optic neuritis, pancreatitis, paroxysmal nocturnal hemoglobulinemia, pemphigus, polymyalgia, post-infectious autoimmunity, primary biliary cirrhosis, reactive arthritis, ankylosing spondylitis, Raynaud's phenomenon, Reiter's syndrome, reperfusion injury, scleritis, scleroderma, secondary hematologic manifestation of autoimmune diseases, silicone implant associated autoimmune disease, Sjogren's syndrome, systemic lupus erythematosus, thrombocytopenia, transverse myelitis, tubulointerstitial nephritis, uveitis, vasculitis syndromes, and Vitiligo.

61. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament, for treating a chemokine mediated disease or condition, for use with at least one other medicament useful for the treatment of chemokine mediated diseases.

62. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one other medicament selected from the group consisting of:
a) disease modifying antirheumatic drugs;
b) nonsteroidal anitinflammatory drugs;
c) COX-2 selective inhibitors;
d) COX-1 inhibitors;
e) immunosuppressives;
f) steroids;
g) biological response modifiers; and
h) other anti-inflammatory agents or therapeutics useful for the
treatment of chemokine mediated diseases,
for treating a chemokine mediated disease or condition.

63. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament foruse with at least one compound selected from the group consisting of: glucocorticoids, 5-lipoxygenase inhibitors, β-2 adrenoceptor agonists, muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors,
phospholipase D inhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-b agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IL-8 anti-bodies, anti-IL-5 antibodies, anti-lgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors and growth hormones, for treating a pulmonary disease.

64. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one compound selected from the group consisting of glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, chemokine inhibitors and CB2-selective agents, for treating multiple sclerosis.

65. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one compound selected from the group consisting of: methotrexate, cyclosporin, leflunimide, sulfasalazine, β-methasone, β-interferon, glatiramer acetate and prednisone, for treating multiple sclerosis.

66. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating rheumatoid arthritis.

67. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one compound selected from the group consisting of COX-2 inhibitors, COX inhibitors, immunosuppressives, steroids, PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, CB2-selective inhibitors, and other classes of compounds indicated for the treatment of rheumatoid arthritis, for treating rheumatoid arthritis.

68. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one compound selected from the group consisting of thrombolitics, antiplatelet agents, antagonists, anticoagulants, and other compounds indicated for the treatment of rheumatoid arthritis, for treating rheumatoid arthritis.

69. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one compound selected from the group consisting of tenecteplase, TPA, alteplase, abciximab, eftiifbatide, and heparin, for treating stroke and cardiac reperfusion injury.

70. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one compound selected from the group consisting of
immunosuppressives, steroids, and anti-TNF-α compounds, for treating psoriasis.

71. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating COPD.

72. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating pain.

73. The use of Claim 72 wherein said pain is associated with: allodynia, ankylosing spondylitis, appendicitis, autoimmune disorders, bacterial infections, Behcet's syndrome, broken bones, bronchitis, burns, bursitis, cancer including metastatic cancer, candidiasis, cardiovascular conditions, casualgia, chemical injury, childbirth, chronic regional neuropathies, Crohn's disease, colorectal cancer, connective tissue injuries, conjunctivitis, COPD, decreased intracranial pressure, dental procedures, dermatitis, diabetes, diabetic neuropathy, dysesthesia,
dysmenorrhea, eczema, emphysema, fever, fibromyalgia, gastric ulcer, gastritis, giant cell arteritis, gingivitis, gout, gouty arthritis, headache, headache pain resulting from lumbar puncture, headaches including migraine headache, herpes simplex virus infections, HIV, Hodgkin's disease, hyperalgesia, hypersensitivity, inflammatory bowel disease, increased intracranial pressure, irritable bowel syndrome, ischemia, juvenile arthritis, kidney stones, lumbar spondylanhrosis, lower back, upper back and lumbrosacral conditions, lumbar spondylarthrosis, menstrual cramps, migraines, minor injuries, multiple sclerosis, myasthenia gravis, myocarditis, muscle strains,
musculoskeletal conditions, myocardial ischemia, nephritic syndrome, nerve root avulsion, neuritis, nutritional deficiency, ocular and corneal conditions, ocular photophobia, ophthalmic diseases, osteoarthritis, otic surgery, otitis externa, otitis media, periarteritis nodosa, peripheral neuropathies, phantom limb pain, polymyositis, post-herpetic neuralgia, post-operative/surgical recovery, post-thoracotomy, psoriatic arthritis, pulmonary fibrosis, pulmonary edema, radiculopathy, reactive arthritis, reflex sympathetic dystrophy, retinitis, retinopathies, rheumatic fever, rheumatoid arthritis, sarcoidosis, sciatica, scleroderma, sickle cell anemia, sinus headaches, sinusitis, spinal cord injury, spondyloarthropathies, sprains, stroke, swimmer's ear, tendonitis, tension headaches, thalamic syndrome, thrombosis, thyroiditis, toxins, traumatic injury, trigeminal neuralgia, ulcerative colitis, urogenital conditions, uveitis, vaginitis, vascular diseases, vasculitis, viral infections and/or wound healing.

74. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one medicament selected from the group consisting of: NSAIDs, COXIB inhibitors, anti-depressants and anti-convulsants, for treating pain.

75. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one NSAID, for treating pain.

76. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one COXIB inhibitor, for treating pain.

77. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one anti-depressant, for treating pain.

78. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use with at least one anti-convulsant, for treating pain.

79. The use of Claim 75 wherein said NSAID is selected from the group consisting of: piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen.

80. The use of Claim 76 wherein said COXIB inhibitor is selected from the group consisting of: rofecoxib and celecoxib.

81. The use of Claim 77 wherein said anti-depressant is selected from the group consisting of: amitriptyline and nortriptyline.

82. The method of Claim 78 wherein said ant-convulsant is selected from the group consisting of: gabapentin, carbamazepine, pregabalin, and lamotragine.

83. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating acute pain.

84. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating acute inflammatory pain.

85. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating chronic inflammatory pain.

86. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating neuropathic pain.

87. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating arthritis.

88. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating osteoarthritis.

89. The use of Claim 60 wherein said
(a) Allograft rejections are selected from the group consisting of
acute allograft rejections and chronic allograft rejections,
(b) Early transplantation rejection is an acute allograft rejection,
(c) Autoimmune deafness is Meniere's disease,
(d) Myocarditis is viral myocarditis,
(e) Neuropathies are selected from the group consisting of IgA
neuropathy, membranous neuropathy and idiopathic neuropathy,
(f) Autoimmune diseases are anemias,
(g) Vasculitis syndromes are selected from the group consisting of giant cell arteritis, Behcet's disease and Wegener's granulomatosis, and
(h) pain is selected from the group consisting of: acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain.

90. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a CXCR1 and/or a CXCR2 mediated disease or condition selected from the group consisting of: pain, acute inflammation, chronic inflammation, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, ischemia reperfusion injury, renal reperfusion injury, glomerulonephritis, thrombosis,
Alzheimer's disease, graft vs. host reaction, allograft rejections, malaria, acute respiratory distress syndrome, delayed type hypersensitivity reaction, atherosclerosis, cerebral ischemia, cardiac ischemia, osteoarthritis, multiple sclerosis, restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus, meningitis, cystic fibrosis, pre-term labor, cough, pruritis, multi-organ dysfunction, trauma, strains, sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitial pneumonitis, hypersensitivity, crystal induced arthritis, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease, ocular inflammation, retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred, corneal neovascularization, polymyositis, vasculitis, acne, gastric ulcers, duodenal ulcers, celiac disease, esophagitis, glossitis, airflow obstruction, airway hyperresponsiveness, bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), granulocytic ehriichiosis, sarcoidosis, small airway disease, ventilation-perfusion mismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burn therapy, periodontitis, cancer, transplant reperfusion injury, and early
transplantation rejection.

91. Use of at least one compound of any of Claims 1 to 49, or a
pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a CCR7 mediated disease or condition selected from the group consisting of: pain, acute inflammation, chronic inflammation, acute allograft rejection, acute respiratory distress syndrome, adult respiratory disease, airway hyperreactivity, allergic contact dermatitis, allergic rhinitis, alopecia areata, alzheimer's disease, angiogenic ocular disease, antiphospholipid syndromes, aplastic anemia, asthma, atherosclerosis, atopic dermatitis, autoimmune deafness, autoimmune hemolytic syndromes, autoimmune hepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmune orchitis, autoimmune thrombocytopenia, bronchiolitis, bronchiolitis obliterans syndrome, bullous pemphigoid, burn therapy, cancer, cerebral ischemia, cardiac ischemia, chronic allograft rejection, chronic allograft vasculopathy, chronic bronchitis, chronic inflammatory demyelinating polyneuropathy, chronic sinusitis, cirrhosis, CNS vasculitis, COPD, Cor pneumoniae, Crohn's disease, cryoglobulinemia, crystal-induced arthritis, delayed-type hypersensitivity reactions, dermatomyositis, diabetes, diabetic retinopathy, drug-induced autoimmunity, dyspnea, emphysema, epidermolysis bullosa acquisita, endometriosis, fibrotic diseases, gastritis,
glomerulonephritis, Goodpasture's syndrome, graft vs host disease, Graves' disease, Gullain-Barre disease, Hashimoto's thyroiditis, hepatitis-associated autoimmunity, HIV-related autoimmune syndromes and hematologic disorders, hyperoxia-induced inflammation, hypercapnea, hyperinflation, hypophytis, hypoxia, idiopathic
thrombocytic pupura, inflammatory bowel diseases, interstitial cystitis, interstitial pneumonitis, juvenile arthritis, Langerhans' cell histiocytitis, lichen planus, metal-induced autoimmunity, multiple sclerosis, myasthenia gravis, myelodysplastic syndromes, myocarditis including viral myocarditis, myositis, neuropathies, nephritic syndrome, ocular inflammation, optic neuritis, osteoarthritis, pancreatitis, paroxysmal nocturnal hemoglobulinemia, pemphigus, polymyalgia, polymyositis, post-infectious autoimmunity, pulmonary fibrosis, primary biliary cirrhosis, psoriasis, pruritis, rheumatoid arthritis, reactive arthritis, ankylosing spondylitis, psoriatic arthritis,
Raynaud's phenomenon, Reiter's syndrome, reperfusion injury, restenosis,
sarcoidosis, scleritis, scleroderma, secondary hematologic manifestation of
autoimmune diseases, silicone implant associated autoimmune disease, Sjogren's syndrome, systemic lupus erythematosus, thrombocytopenia, thrombosis, transverse myelitis, tubulointerstitial nephritis, ulcerative colitis, uveitis, vasculitis and vasculitis syndromes, and vitiligo.

92. The use of Claim 90 wherein said:
(a) Allograft rejections are selected from the group consisting of
acute allograft rejections and chronic allograft rejections,
(b) Early transplantation rejection is an acute allograft rejection,
(c) Autoimmune deafness is Meniere's disease,
(d) Myocarditis is viral myocarditis,
(e) Neuropathies are selected from the group consisting of IgA
neuropathy, membranous neuropathy and idiopathic neuropathy,
(f) Autoimmune diseases are anemias, (g) Vasculitis syndromes are selected from the group consisting of giant cell arteritis, Behcet's disease and Wegener's granulomatosis, and
(h) pain is selected from the group consisting of: acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain.

93. The use of Claim 91 wherein said
(a) Allograft rejections are selected from the group consisting of acute allograft rejections and chronic allograft rejections,
(b) Early transplantation rejection is an acute allograft rejection,
(c) Autoimmune deafness is Meniere's disease,
(d) Myocarditis is viral myocarditis,
(e) Neuropathies are selected from the group consisting of IgA neuropathy, membranous neuropathy and idiopathic neuropathy,
(f) Autoimmune diseases are anemias,
(g) Vasculitis syndromes are selected from the group consisting of giant cell arteritis, Behcet's disease and Wegener's granulomatosis, and
(h) pain is selected from the group consisting of: acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain.

94. Use of at least one compound of any of Claims 1 to 49, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating angina.