Pyridinecarboxamides as CXCR2 modulators

Abstract

There is disclosed pyridine-and pyrimidinecarboxamide compounds useful as pharmaceutical agents, synthesis processes, and pharmaceutical compositions which include pyridine-and pyrimidinecarboxamides compounds. More specifically, there is disclosed a genus of CXCR2 inhibitor compounds that are useful for treating a variety of inflammatory and neoplastic disorders.

We claim: 
     
       1. A compound comprising a compound from formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylaryl, arylheteroaryl, heteroarylheteroaryl, heterocyclylaryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl heterocycloalkylalkyl; 
         wherein R 2  is selected from the group consisting of 2- or 3- or 4-halo-phenyl, heteroalkyl, lower alkyl, C 7-25  alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylaryl, arylheteroaryl, heteroarylheteroaryl, heterocyclylaryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl heterocycloalkylalkyl, wherein, if substituted, the lower alkyl is selected from the group consisting of methyl, n-propyl, isopropyl, n-butyl, t-butyl, and n-pentyl, and wherein aryl in R 2  is unsubstituted or substituted with with one or more substituents selected from the group consisting of —C(O)R, —OR, alkyl, aryl, —N(H)R, -N(R)R, —S—R, —N 3 , —B(R)R, —B(OH) 2 , —B(OR) 2 , —C(O)OH, —C(O)OR, —C(O)NH 2 , —S(O) 2 NH 2 , —C(O)N(H)R, —C(O)N(R)R, —SH, —S—R —SR, —NO 2 , cyano, halo, haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, —OH, —OC(O)R, —C(O)R, and —C(O)CH a X b , wherein a+b=3 and X is selected from the group consisting of F, Cl or Br, and wherein R is alkyl having less than twelve carbons; 
         wherein R 3  R 3  is selected from the group consisting of —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), substituted aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl heterocycloalkylalkyl, —C(O)—R 6 , —O—R 6 , —S(O) y —R 6  heteroarylaryl, heterocyclylaryl, arylheteroaryl, heteroarylheteroaryl, —C(O)R 6 , —OR 6 , —S(O) y R 6  (wherein y =0, 1, or 2), —P(O)—(R 4 R 5 ) —P(O)(R 4 R 5 ), and —N(R 7 R 8 ), wherein a heterocyclyl in a bicyclic substituted aryl is a 5 or 6 membered ring; 
         wherein R 6  is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl heterocycloalkylalkyl, alkylaryl, arylheteroaryl, heteroarylaryl, and heterocyclylaryl; 
         wherein R 4  and R 5  are independently selected from the group consisting of hydrogen, hydroxyl, aryloxy, and alkoxy, or wherein R 4  and R 5  together form a cyclic ester, or an acid anhydride (either mixed or symmetrical); 
         wherein R 7  and R 8  are independently is selected from the group consisting of from hydrogen, C7-C18 alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, and heterocyclylalkyl heterocycloalkylalkyl; R 8  is selected from the group consisting of C7-C18 alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, and heterocycloalkylalkyl; R 7  and R 8  are both oxygen; or R 7  and R 8  form a heterocyclyl; and 
         wherein X 1  is —CH— or —CCl—, X 2  is —S(O) y-  —S(O) y — (wherein y=0, 1, or 2) or oxygen; and n is an integer between 1 and 8; or 
         a pharmaceutically acceptable solvated or unsolvated form thereof; a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof. 
       
     
     
       2. The compound of  claim 1  wherein R l  R 1  is hydrogen and R 2  is 4-fluorophenyl. 
     
     
       3. The compound of  claim 1  wherein y=0. 
     
     
       4. The compound of  claim 1  wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       5. A compound comprising a compound from formula (1): 
       
         
           
           
               
               
           
         
         wherein R l  R 1  is selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylaryl, arylheteroaryl, heteroarylheteroaryl, heterocyclylaryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl heterocycloalkylalkyl; 
         wherein R 2  is an unsubstituted or a substituted C 1-18  alkyl, wherein the alkyl substituents are substituent is selected from the group consisting of hydroxy, alkylamino, boronyl, carboxy, nitro, and cyano; 
         wherein R 3  R 3  is selected from the group consisting of —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), substituted aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl heterocycloalkylalkyl, heteroarylaryl, arylheteroaryl, heteroarylheteroaryl, heterocyclylaryl, —C(O)R 6 , —OR 6 , —S(O) y R 6  (wherein y=0, 1, or 2), —P(O)(R 4 R 5 ), and —N(R 7 R 8 ); 
         wherein R 4  and R 5  are independently selected from the group consisting of hydrogen, hydroxyl, aryloxy, and alkoxy; or wherein R 4  and R 5  form a mixed or symmetrical cyclic ester or acid anhydride; 
         wherein R 6  is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, heterocycloalkylalkyl, alkylaryl, arylheteroaryl, heteroarylaryl, and heterocyclylaryl; 
         wherein R 7  and R 8  are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, and heterocyclylalkyl heterocycloalkylalkyl; R 7  and R 8  are both oxygen; or R 7  and R 8  form a heterocyclyl; and 
         wherein X 1  is —CH— or —CCl—, X 2  is —S(O) y-  —S(O) y — (wherein y=0, 1, or 2) or oxygen; and n is an integer between 1 and 8; or 
         a pharmaceutically acceptable solvated or unsolvated form thereof; a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof. 
       
     
     
       6. A compound comprising a compound from formula (1): 
       
         
           
           
               
               
           
         
         wherein R l  R 1  is selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl heterocycloalkylalkyl, alkylaryl, arylheteroaryl, heteroarylaryl, and heterocyclylaryl; 
         wherein R 2  is a fluoro-substituted hydrocarbon wherein the hydrocarbon is selected from the group consisting of aryl, arylalkyl, fluoro-substituted heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl heterocycloalkylalkyl, arylheteroaryl, heteroarylaryl, and heterocyclylaryl; 
         wherein R 3  is selected from the group consisting of —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), aryl, substituted arylalkyl, substituted cycloalkyl, unsubstituted heteroaryl, heteroaryl substituted by one or more substituents selected from —C(O)R, —OR, alkyl, aryl, —N(H)R, —N(R)R, amino, azido, —B(R)R, —B(OH) 2 , —B(OR) 2 , —C(O)OR, aminocarbonyl, aminosulfonyl, —C(O)NHR, —C(O)N(R)R, cyano, halo, haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl, —OC(O)R, —C(O)R, substituted halomethylketone, —SH, —SR, and nitro, where R is an alkyl having less than 12 carbons, heteroarylalkyl, heterocyclyl selected from the group consisting of lactam, lactone, piperidyl, piperazinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl and tetrahydrothiopyranyl, heterocycloalkylalkyl, heteroarylaryl, arylheteroaryl, heteroarylheteroaryl, heterocyclylaryl, heterocyclylalkyl, —C(O)R 6 , —OR 6 , —S(O) y R 6  (wherein y=0, 1, or 2), —P(O)(R 4 R 5 ), and —N(R 7 R 8 ); 
         wherein R 4  and R 5  are independently selected from the group consisting of hydrogen, hydroxyl, aryloxy, and alkoxy, or wherein R 4  and R 5  together form a mixed or symmetrical cyclic ester or acid anhydride; 
         wherein R 6  is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl heterocycloalkylalkyl, alkylaryl, arylheteroaryl, heteroarylaryl, and heterocyclylaryl; 
         wherein R 7  and R 8  are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, and heterocyclylalkyl heterocycloalkylalkyl; R 7  and R 8  are both oxygen; or R 7  and R 8  form a heterocyclyl; and 
         wherein X 1  is —CH— or —CCl—, X 2  is —S(O) y-  —S(O) y — (wherein y=0, 1, or 2) or oxygen; and n is an integer between 0 and 8; 
         a pharmaceutically acceptable solvated or unsolvated form thereof, a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof. 
       
     
     
       7. The compound of  claim 6 , wherein R 3  is —R 6 —B(R 4 R 5 ). 
     
     
       8. The compound of  claim 7 , wherein R 3  is —R 6 —B(OH) 2 . 
     
     
       9. The compound of  claim 7 , wherein R 6  is an aryl substituted with an F, —OCF 3 , or —OCH 3 . 
     
     
       10. The compound of  claim 6 , wherein R 3  is a halo-substituted hydrocarbon selected from the group consisting of aryl, arylalkyl, halo-substituted cycloalkyl, halo-substituted heteroaryl, halo-substituted heteroarylalkyl, halo-substituted heterocyclyl and heterocyclylalkyl, or halo-substituted heterocycloalkylalkyl. 
     
     
       11. The compound of  claim 6 , wherein R 3  is —C(O)R 6 , wherein R 6  is a halo-substituted hydrocarbon selected from the group consisting of aryl, arylalkyl, halo-substituted cycloalkyl, halo-substituted heteroaryl, halo-substituted heteroarylalkyl, halo-substituted heterocyclyl, and heterocyclylalkyl or halo-substituted heterocycloalkylalkyl. 
     
     
       12. The compound of  claim 11 , wherein R 6  is a halo-substituted aryl. 
     
     
       13. The compound of  claim 6 , wherein y=0. 
     
     
       14. The compound of  claim 6  wherein R 3  R 3  is 
       
         
           
           
               
               
           
         
       
       wherein R′ is OH, O-alkyl, or O-aryl —OH, —O-alkyl, or —O-aryl. 
     
     
       15. The compound of  claim 6 , wherein R 3  is —R 6  or —C(O)R 6  wherein R 6  is a hydroxy-substituted hydrocarbon selected from the group consisting of aryl, hydroxy-substituted arylalkyl, hydroxy-substituted cycloalkyl, hydroxy-substituted heteroaryl, hydroxy-substituted heteroarylalkyl, hydroxy-substituted heterocyclyl, and  heterocyclylalkyl hydroxy-substituted heterocycloalkylalkyl. 
     
     
       16. The compound of  claim 6 , wherein, R l  R 1  is hydrogen. 
     
     
       17. A compound comprising a compound from formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkylalkyl, alkylaryl, arylheteroaryl, heteroarylaryl, and heterocyclylaryl; 
         wherein R 2  is a fluoro-substituted substituent compound selected from the group consisting of fluoro-substituted heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkylalkyl, arylheteroaryl, heteroarylaryl, and heterocyclylaryl; 
         wherein R 3  is selected from the group consisting of —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), substituted aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl selected from the group consisting of lactam, lactone, piperidyl, piperazinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl and tetrahydrothiopyranyl, heterocycloalkylalkyl, heteroarylaryl, arylheteroaryl, heteroarylheteroaryl, heterocyclylaryl, —C(O)R 6 , —OR 6 , —S(O) y R 6  (wherein y=0, 1, or 2), —P(O)(R 4 R 5 ), and —N(R 7 R 8 ); 
         wherein R 4  and R 5  are independently selected from the group consisting of hydrogen, hydroxyl, aryloxy, and alkoxy, or wherein R 4  and R 5  together form a mixed or symmetrical cyclic ester or acid anhydride; 
         wherein R 6  is selected from the group consisting of-alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkylalkyl, alkylaryl, arylheteroaryl, heteroarylaryl, and heterocyclylaryl; 
         wherein R 7  and R 8  are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, and heterocyclylalkyl; R 7  and R 8  are both oxygen; or R 7  and R 8  form a heterocyclyl; and 
         wherein X 1  is —CH— or —CCl—, X 2  is —S(O) y — (wherein y=0, 1, or 2) or oxygen; and n is an integer between 1 and 8; 
         a pharmaceutically acceptable solvated or unsolvated form thereof; a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof. 
       
     
     
       18. The compound of claim 1, wherein R 3  is —B(R 4 R 5 ), —R 6 B(R 4 R 5 ), or —P(O)(R 4 R 5 ). 
     
     
       19. The compound of claim 18, wherein y is 0. 
     
     
       20. The compound of claim 18, wherein R 6  is an aryl substituted with an F, —OCF 3 , or —OCH 3 . 
     
     
       21. The compound of claim 5, wherein R 3  is —B(R 4 R 5 ), —R 6 B(R 4 R 5 ), or —P(O)(R 4 R 5 ). 
     
     
       22. The compound of claim 21, wherein y is 0. 
     
     
       23. The compound of claim 21, wherein R 6  is an aryl substituted with one or more substituents selected from F, —OCF 3 , and —OCH 3 . 
     
     
       24. The compound of claim 3, wherein R 3  is an aryl substituted with one or more substituents selected from a halide, —OH, —OC(O)R, —OCF 3 , —OCH 3 , —C(O)R, —R, —NO 2 , and —B(R 4 R 5 ), wherein R is alkyl having less than 12 carbons, or hydroxy. 
     
     
       25. The compound of claim 5, wherein R 3  is an aryl substituted with one or more substituents selected from a halide, —OH, —OC(O)R, —OCF 3 , —OCH 3 , —C(O)R, —R, —NO 2 , and —B(R 4 R 5 ); and y is 0, wherein R is alkyl having less than 12 carbons, or hydroxy. 
     
     
       26. The compound of claim 13, wherein R 3  is a heteroaryl substituted with one or more substituents selected from a halide, —OH, —OC(O)R, —OCF 3 , —OCH 3 , —C(O)R, —NO 2 , and —B(R 4 R 5 ). 
     
     
       27. The compound of claim 3, wherein R 3  is an aryl or a heteroaryl substituted with one or more substituents selected from a halide, —OH, —OC(O)R, —OCF 3 , —OCH 3 , —C(O)R, —CF 3 , —NO 2 , —SO 2 -phenyl, —NH 2 , and —B(R 4 R 5 ), wherein R is alkyl having less than 12 carbons, or hydroxy. 
     
     
       28. The compound of claim 5, wherein R 3  is an aryl or a heteroaryl substituted with one or more substituents selected from a halide, —OH, —OC(O)R, —OCF 3 , —OCH 3 , —C(O)R, —CF 3 , —NO 2 , —SO 2 -phenyl, —NH 2 , and —B(R 4 R 5 ), wherein R is alkyl having less than 12 carbons, or hydroxy; and y is 0. 
     
     
       29. The compound of claim 13, wherein R 3  is a heteroaryl substituted with one or more substituents selected from a halo, —OH, —OC(O)R, —OCH 3 , —C(O)R, —CF 3 , —NO 2 , —NH 2 , and —B(R)R. 
     
     
       30. The compound of claim 3, wherein R 3  is —OR 6  or —C(O)R 6 . 
     
     
       31. The compound of claim 5, wherein R 3  is —OR 6  or —C(O)R 6 ; and y is 0. 
     
     
       32. The compound of claim 13, wherein R 3  is —OR 6  or —C(O)R 6 . 
     
     
       33. The compound of claim 3, wherein R 3  is arylalkyl, arylheteroaryl, heteroarylalkyl, heteroarylaryl, heteroarylheteroaryl, heterocyclylaryl, heterocyclyl, or heterocycloalkylalkyl. 
     
     
       34. The compound of claim 5, wherein R 3  is arylalkyl, arylheteroaryl, heteroarylalkyl, heteroarylaryl, heteroarylheteroaryl, heterocyclylaryl, heterocyclyl, or heterocycloalkylalkyl; and y is 0. 
     
     
       35. The compound of claim 13, wherein R 3  is arylalkyl, arylheteroaryl, heteroarylalkyl, heteroarylaryl, heteroarylheteroaryl, heterocyclylaryl, heterocyclyl, or heterocycloalkylalkyl. 
     
     
       36. The compound of claim 3, wherein R 3  is heterocyclyl or is selected from the group consisting of 
       
         
           
           
               
               
           
         
        
       
     
     
       37. The compound of claim 5, wherein y is 0, and R 3  is heterocyclyl or is selected from the group consisting of 
       
         
           
           
               
               
           
         
        
       
     
     
       38. The compound of claim 13, wherein R 3  is heterocyclyl or is selected from the group consisting of 
       
         
           
           
               
               
           
         
        
       
     
     
       39. The compound of claim 3, wherein R 3  is —C(O)R 6 , and wherein R 6  is selected from the group consisting of 
       
         
           
           
               
               
           
         
        
       
     
     
       40. The compound of claim 5, wherein y is 0, wherein R 3  is —C(O)R 6 , and wherein R 6  is selected from the group consisting of 
       
         
           
           
               
               
           
         
        
       
     
     
       41. The compound of claim 13, wherein R 3  is —C(O)R 6 , and wherein R 6  is selected from the group consisting of 
       
         
           
           
               
               
           
         
        
       
     
     
       42. A method of treating a patient with a CXC chemokine-mediated disease, comprising administering a therapeutically effective amount of the compound of claim 1 to the patient. 
     
     
       43. The of method claim 42, wherein the CXC chemokine-mediated disease comprises overproduction of glutamic acid-leucine-arginine (ELR)-CXC chemokine. 
     
     
       44. The method of claim 42, wherein the CXC chemokine-mediated disease is a tumor or cancer. 
     
     
       45. The method of claim 42, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis. 
     
     
       46. The method of claim 42, wherein the CXC chemokine-mediated disease is multiple sclerosis. 
     
     
       47. The method of claim 42, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis. 
     
     
       48. The method of claim 42, wherein the solvated or unsolvated form, the salt, or the composition is administered to the patient in combination with a second medicament useful for treating the CXC chemokine-mediated disease. 
     
     
       49. The method of claim 48, wherein second medicament is a anti-rheumatic drug, a nonsteroidal anti-inflammatory drug, a COX-2 selective inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, a biological response modifier, or other anti-inflammatory agent or therapeutics useful for the treatment of CXC chemokine mediated diseases. 
     
     
       50. The method of claim 48, wherein the CXC chemokine-mediated disease is cancer, and the second medicament is at least one antineoplastic agent selected from the group consisting of gemcitabine, paclitaxel, 5-fluorouracil, cyclophosphamide, temozolomide, and vincristine; or at least one agent selected from the group consisting of microtubule affecting agents, antineoplastic agents, anti-angiogenesis agents, VEGF receptor kinase inhibitors, antibodies against the VEGF receptor, interferon, and radiation. 
     
     
       51. The method of claim 48, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis; and wherein the second medicament is selected from the group consisting of glucocorticoids, 5-lipoxygenase inhibitors, beta-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-β agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IL-8 antibodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones. 
     
     
       52. The method of claim 48, wherein the CXC chemokine-mediated disease is multiple sclerosis, wherein the second medicament is at least one compound selected from the group consisting of glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, CB2-selective inhibitors, cyclosporin, leflunimide, sulfasalazine, β-methasone, β-interferon, glatiramer acetate, prednisone, etonercept, and infliximab. 
     
     
       53. The method of claim 45, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis, wherein the second medicament is at least one compound selected from the group consisting of COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, steroids, PDE 4 inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, and CB2-selective agents. 
     
     
       54. The method of claim 42, wherein pharmaceutical composition is administered orally. 
     
     
       55. The method of claim 42, wherein the pharmaceutical composition is a tablet. 
     
     
       56. A method of using the compound of claim 5 in a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound sufficient for treating a CXC chemokine-mediated disease, and wherein the pharmaceutical composition is administered to a patient in need thereof. 
     
     
       57. The method of claim 56, wherein the CXC chemokine-mediated disease is a tumor or cancer. 
     
     
       58. The method of claim 56, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis. 
     
     
       59. The method of claim 56, wherein the CXC chemokine-mediated disease is multiple sclerosis. 
     
     
       60. The method of claim 56, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis. 
     
     
       61. The method of claim 56, wherein the pharmaceutical composition is administered to the patient in combination with a second medicament useful for treating the CXC chemokine-mediated disease. 
     
     
       62. The method of claim 56, wherein pharmaceutical composition is administered orally. 
     
     
       63. The method of claim 62, wherein the pharmaceutical composition is a tablet. 
     
     
       64. A method of using the compound of claim 6 in a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound sufficient for treating a CXC chemokine-mediated disease, and wherein the pharmaceutical composition is administered to a patient in need thereof. 
     
     
       65. The method of claim 64, wherein the CXC chemokine-mediated disease is a tumor or cancer. 
     
     
       66. The method of claim 64, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis. 
     
     
       67. The method of claim 64, wherein the CXC chemokine-mediated disease is multiple sclerosis. 
     
     
       68. The method of claim 64, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis. 
     
     
       69. The method of claim 64, wherein the pharmaceutical composition is administered to the patient in combination with a second medicament useful for treating the CXC chemokine-mediated disease. 
     
     
       70. The method of claim 64, wherein the pharmaceutical composition is administered orally. 
     
     
       71. The method of claim 70, wherein the pharmaceutical composition is a tablet. 
     
     
       72. A method of using the compound of claim 16 in a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of the compound sufficient for treating a CXC chemokine-mediated disease, and wherein the pharmaceutical composition is administered to a patient in need thereof. 
     
     
       73. The method of claim 72, wherein the CXC chemokine-mediated disease is a tumor or cancer. 
     
     
       74. The method of claim 72, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis. 
     
     
       75. The method of claim 72, wherein the CXC chemokine-mediated disease is multiple sclerosis. 
     
     
       76. The method of claim 72, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis. 
     
     
       77. The method of claim 72, wherein the pharmaceutical composition is administered to the patient in combination with a second medicament useful for treating the CXC chemokine-mediated disease. 
     
     
       78. The method of claim 72, wherein the pharmaceutical composition is administered orally. 
     
     
       79. The method of claim 78, wherein the pharmaceutical composition is a tablet. 
     
     
       80. A compound comprising a compound from formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylaryl, arylheteroaryl, heteroarylheteroaryl, heterocyclylaryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocycloalkylalkyl; 
         wherein R 2  is selected from the group consisting of heteroalkyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, C 7-25  alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarylaryl, arylheteroaryl, heteroarylheteroaryl, heterocyclylaryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocycloalkylalkyl, wherein aryl in R 2  is unsubstituted or substituted with one or more substituents selected from —C(O)R, —OR, alkyl, aryl, —N(H)R, —N(R)R, —S—R, —N 3 , —B(R)R, —B(OH) 2 , —B(OR) 2 , —C(O)OH, —C(O)OR, —C(O)NH 2 , —S(O) 2 NH 2 , —C(O)N(H)R, —C(O)N(R)R, —SH, —S—R, —NO 2 , cyano, halo, haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, —OH, —OC(O)R, —C(O)R, and —C(O)CH a X b , wherein a+b=3 and X is F, Cl or Br, and wherein R is alkyl having less than twelve carbons; 
         wherein R 3  is —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), substituted aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocycloalkylalkyl where the heterocyclyl is selected from the group consisting of lactam, lactone, thiazolidinyl, 1,3-tetrahydrothiophenyl and tetrahydrothiopyranyl, heteroarylaryl, arylheteroaryl, heteroarylheteroaryl, heterocyclylaryl, —C(O)—R 6 , —O—R 6 , —S(O) y —R 6  (wherein y=0, 1, or 2), —P(O)—(R 4 R 5 ), and —N(R 7 R 8 ); 
         wherein R 6  is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkylalkyl, alkylaryl, arylheteroaryl, heteroarylaryl, heterocyclylaryl; 
         wherein R 4  and R 5  are independently selected from the group consisting of hydrogen, hydroxyl, aryloxy, and alkoxy, or wherein R 4  and R 5  together form a cyclic ester, or an acid anhydride (either mixed or symmetrical); 
         wherein R 7  and R 8  are independently selected from the group consisting of from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, and heterocycloalkylalkyl; R 7  and R 8  are both oxygen; or R 7  and R 8  form a heterocyclyl; and 
         wherein X 1  is —CH— or —CCl—, X 2  is oxygen; and n is an integer between 1 and 8; 
         a pharmaceutically acceptable solvated or unsolvated form thereof; a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof.