Thiadiazoles AS CXC- and CC- chemokine receptor ligands

• US 20060223864A1
• Filed: 12/16/2004
• Published: 10/05/2006
• Est. Priority Date: 12/19/2003
• Status: Active Grant

• Current Assignee: Pharmacopeia LLC (Ligand Pharmaceuticals, Inc.), Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation & Pharmacopeia Drug Discovery Incorporated
• Inventors: Baldwin, John J., Zheng, Junying, Biju, Purakkattle J., Chao, Jianhua, Lundell, Daniel, Yu, Younong, Taveras, Arthur G., Merritt, J. Robert, Aki, Cynthia J., Reggiani, Angelo, Priestley, Tony, Fine, Jay
• Granted Patent: US 7,338,968 B2
• Time in Patent Office: Days
• US Class Current: 514/341
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/14 : for baldness or alopecia
• CPC Class Codes: A61P 19/00 : Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 : Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 25/08 : Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 : without antiinflammatory effect
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 285/06 : 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 285/10 : 1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

Disclosed are novel compounds of the formula: and the pharmaceutically acceptable salts and solvates thereof. Examples of groups comprising Substituent A include heteroaryl, aryl, heterocycloalkyl, cycloalkyl, aryl, alkynyl, alkenyl, aminoalkyl, alkyl or amino. Examples of groups comprising Substituent B include aryl and heteroaryl. Also disclosed is a method of treating a chemokine mediated diseases, such as, cancer, angiogenisis, angiogenic ocular diseases, pulmonary diseases, multiple sclerosis, rheumatoid arthritis, osteoarthritis, stroke and ischemia reperfusion injury, pain (e.g., acute pain, acute and chronic inflammatory pain, and neuropathic pain) using a compound of formula IA.

Claims

1. A compound of the formula:

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

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

4. The compound of claim 1 wherein substituent A is:

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:

14. The compound of claim 1 wherein B is:

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:

21. The compound of claim 1 wherein B is:

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)NR¹³R¹⁴.

26. The compound of claim 24 wherein R³ is —

S(O)_tNR¹³R¹⁴.

27. The compound of claim 1 wherein B is:

28. The compound of claim 1 wherein B is:

29. The compound of claim 1 wherein:

(1) substituent A in formula IA is selected from the group consisting of;

wherein the above rings are unsubstituted, or the above rings are substituted with 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

wherein R⁷ is selected from the group consisting of;

H, —

CF₃, —

CF₂CH₃, methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and

R⁸ is H; and

R^8a 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 —

NHSO₂R¹³;

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:

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

33. A pharmaceutically acceptable salt of a compound of claim 1.

34. A sodium salt of a compound of claim 1.

35. A calcium salt of a compound of claim 1.

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, 110, 111, 112, 114-116, 118-132, 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, 111, 112, 114, 122, 120, 123, 124, 127, 128, 129, 130, 131, 139, 142, 144, 145, 300, 305, 306, 307, 313, 316, 317, 318, 323, 324, 327, 328, 329, 330, 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, 573, 587, 601, 616, 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, 110, 111, 112, 114, 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.

39. 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.

40. 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.

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

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

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

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

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

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

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

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

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

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

51. The compound of claim 1 in isolated and pure form.

52. A pharmaceutical composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

53. A pharmaceutical composition comprising at least one compound of claim 1, 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.

54. A method of treating a chemokine mediated diseases comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

55. A method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

56. A method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination 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.

57. A method of treating cancer in a patient in need of such treatment comprising administering to said patient at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with at least one antineoplastic agent selected from the group consisting of:

gemcitabine, paclitaxel, 5-Fluorourcil, cyclophosphamide, temozolomide, and Vincristine.

58. A method of treating cancer in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, concurrently or sequentially with a microtubule affecting agent.

59. A method of inhibiting angiogenesis, or a method of treating angiogenic ocular disease, in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

60. A method of 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 ehrlichiosis, 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 greata, 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 in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

61. A method of treating a chemokine mediated disease or condition in a patient in need of such treatment comprising comprising administering to said patient at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination 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.

62. A method of treating a disease selected from the group consisting of:

a pulmonary disease and multiple sclerosis in a patient in need of such treatment,

said treatment of a pulmonary disease comprising administering to said patient a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt or thereof, in combination 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-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones; and

said treatment of multiple sclerosis comprising administering to said patient a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the group consisting of glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, chemokine inhibitors, and CB2-selective agents.

63. A method of treating multiple sclerosis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the group consisting of:

methotrexate, cyclosporin, leflunimide, sulfasalazine, β

-methasone, β

-interferon, glatiramer acetate, and prednisone.

64. A method of treating rheumatoid arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

65. A method of treating rheumatoid arthritis in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination 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.

66. A method of treating stroke and cardiac reperfusion injury, or a method of treating psoriasis, in a patient in need of such treatment,

said treatment of stroke and cardiac reperfusion injury comprising administering to said patient a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination 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;

and

said treatment of psoriasis comprising administering to said patient a thereapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the group consisting of immunosuppressives, steroids, and anti-TNF-α

compounds.

67. A method of treating stroke and cardiac reperfusion injury in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the group consisting of tenecteplase, TPA, alteplase, abciximab, eftiifbatide, and heparin.

68. A method of treating COPD in a patient in need of such treatment, comprising administering to said patient a thereapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

69. A method of treating pain in a patient in need of such treatment, comprising administering to said patient a thereapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

70. The method of claim 69 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.

71. A method of treating pain in a patient in need of such treatment, comprising administering to said patient a thereapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, and administering to said patient a therapeutically effective amount of at least one medicament selected from the group consisting of:

NSAIDs, COXIB inhibitors, anti-depressants and anti-convulsants

72. The method of claim 71 wherein

said NSAID is selected from the group consisting of:

piroxicam, ketoprofen, naproxen, indomethacin, and ibuprofen;

said COXIB inhibitor is selected from the group consisting of;

rofecoxib and celecoxib;

said anti-depressant is selected from the group consisting of;

amitriptyline and nortriptyline;

and said ant-convulsant is selected from the group consisting of;

gabapentin, carbamazepine, pregabalin, and lamotragine.

73. A method of treating acute pain, acute inflammatory pain, chronic inflammatory pain, and neuropathic pain in a patient in need of such treatment, comprising administering to said patient a thereapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

74. A method of treating arthritis in a patient in need of such treatment, comprising administering to said patient a thereapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

75. A method of treating osteoarthritis in a patient in need of such treatment, comprising administering to said patient a thereapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

76. The method 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.

77. A method of 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 ehrlichiosis, 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 in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof;

or

a method of 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 greata, 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 in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof.

78. The method of claim 77 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.

79. A method of treating angina in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of claim 1.