Aminopyrimidinecarboxamides as CXCR2 modulators

Abstract

There are disclosed aminopyrimidinecarboxamide compounds useful as pharmaceutical agents, synthesis processes, and pharmaceutical compositions which include aminopyrimidinecarboxamides 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  and R 2  are independently 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; 
         wherein R 3  is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, R 4  is selected from the group consisting of heteroalkyl, aminoalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, or R 3  or R 4  are independently an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates; 
         wherein R 3  and R 4  are also independently selected from the group consisting of —B(R 5 R 6 ), —BF 3   − M + , —R 7 —B(R 5 R 6 ), —R 7 —BF 3   − M + , R 7 ,—C(O)—R 7 , —O—R 7 , —S(O) y —R 7  (wherein y=0, 1, or 2), —P(O)—(R 5 R 6 ) and —N(R 8 R 9 ); 
         wherein R 7  is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; 
         wherein M +  is a Group I or a Group II metal; 
         wherein R 5  and R 6  are independently hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R 5  and R 6  together form a cyclic ester, or an acid anhydride (either mixed or symmetrical); 
         wherein R 8  and R 9  are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, hetercyclyl and heterocyclylalkyl; R 8  and R 9  are both oxygen to form a nitro group; or R 8  and R 9  together with the nitrogen to which they are attached, form a heterocyclyl; and 
         wherein n=1; 
       
       or pharmaceutical compositions thereof. 
     
     
       2. The compound of claim  1  3 wherein R 1  is hydrogen and R 2  is 4-fluoro-phenyl 4-fluorophenyl. 
     
     
       3. The A compound of  claim 1  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, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 2  is selected from the group consisting of 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 3  is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; or an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates; or selected from the group consisting of —B(R 5 R 6 ), —BR 3   − M + , —R 7 —B(R 5 R 6 ), —R 7 —BF 3   − M + , —C(O)—R 7 , —O—R 7 , —S(O) y —R 7  (wherein y=0, 1, or 2), —P(O)—(R 5 R 6 ), and —N(R 8 R 9 );  
         wherein R 4  is 4-phenylboronic acid; 
         wherein R 7  is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl; 
         wherein M +  is a Group I or a Group II metal; 
         wherein R 5  and R 6  are independently hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R 5  and R 6  together form a cyclic ester, or an acid anhydride (either mixed or symmetrical); 
         wherein R 8  and R 9  are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, and heterocyclylalkyl; R 8  and R 9  are both oxygen to form a nitro group; or R 8  and R 9  together with the nitrogen to which they are attached, form a heterocyclyl; and 
         wherein n=1; 
         or a pharmaceutical composition thereof. 
       
     
     
       4. A pharmaceutical composition comprising a compound of formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently 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; 
         wherein R 3  and R 4  are independently-selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, or R 3  and R 4  are independently an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates; 
         wherein R 3  and R 4  are also independently selected from the group consisting of —B(R 5 R 6 ), —BF 3   − M + , —R 7 —B(R 5 R 6 ), —R 7 —BF 3   − M + , R 7 ,—C(O)—R 7 , —O—R 7 , —S(O)—R 7 , —P(O)—(R 5 R 6 ) and —N(R 8 R 9 ); wherein y=0, 1, or 2; 
         wherein R 7  is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; 
         wherein M +  is a Group I or a Group II metal; 
         wherein R 5  and R 6  are independently selected from the group consisting of hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R 5  and R 6  together form a cyclic ester, or an acid anhydride; 
         wherein R 8  and R 9  are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, hetercyclyl and heterocyclylalkyl; R 8  and R 9  are both oxygen to form a nitro group; or R 8  and R 9  together with the nitrogen to which they are attached, form a heterocyclyl; and 
         wherein n=1. 
       
     
     
       5. The pharmaceutical composition of  claim 4 , wherein R 1  is hydrogen and R 2  is 4-fluoro-phenyl. 
     
     
       6. The pharmaceutical composition of  claim 4 , wherein R 4  is 4-phenylboronic acid. 
     
     
       7. 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, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; 
         wherein R 2  is heteroaryl, and wherein the heteroaryl is unsubstituted or substituted by one or more substituents selected from acyl, alkoxy, aryl, alkylamino, alkylthio, amino, azido, boronyl, carboxy, alkoxycarbonyl, aminocarbonyl, aminosulfonyl, alkylaminocarbonyl, cyano, halo, haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, hydroxyl, acyloxy, ketone, substituted halomethylketone, mercapto, and nitro; 
         wherein R 3  is selected from the group consisting of hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and R 4  is selected from the group consisting of aminoalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or 
         wherein R 3  and R 4  are independently an ionizing group selected from the group consisting of carboxylates, amines, phosphonates, and phosphates; or 
         wherein R 3  and R 4  are independently selected from the group consisting of —B(R 5 R 6 ), —BF 3   − M + , —R 7 —B(R 5 R 6 ), —R 7 —BF 3   − M + , —C(O)—R 7 , —O—R 7 , —S(O) y —R 7  (wherein y=0, 1, or 2), —P(O)—(R 5 R 6 ), and —N(R 8 R 9 ); 
         wherein R 7  is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl; 
         wherein M +  is a Group I or a Group II metal; 
         wherein R 5  and R 6  are independently hydrogen, hydroxyl, aryloxy, or alkoxy, or wherein R 5  and R 6  together form a cyclic ester, or an acid anhydride (either mixed or symmetrical); 
         wherein R 8  and R 9  are independently selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl, and heterocyclylalkyl; R 8  and R 9  are both oxygen to form a nitro group; or R 8  and R 9  together with the nitrogen to which they are attached, form a heterocyclyl; and 
         wherein n=1; 
         or a pharmaceutical composition thereof. 
       
     
     
       8. The compound of claim 3, wherein R 2  is arylalkyl, and wherein the alkyl group in arylalkyl comprises a straight hydrocarbon chain of 1-18 carbon atoms. 
     
     
       9. The compound of claim 3, wherein the compound is in a pharmaceutically acceptable solvated or unsolvated form or a pharmaceutically acceptable salt. 
     
     
       10. A pharmaceutical composition comprising the compound of claim 3. 
     
     
       11. The composition of claim 10, comprising a therapeutically effective amount of the compound for treating a CXC chemokine-mediated disease. 
     
     
       12. The composition of claim 11, wherein the CXC chemokine-mediated disease comprises overproduction of glutamic acid-leucine-arginine (ELR)-CXC chemokine. 
     
     
       13. The composition of claim 11, wherein the CXC chemokine-mediated disease is a tumor or cancer. 
     
     
       14. The composition of claim 11, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis. 
     
     
       15. The composition of claim 11, wherein the CXC chemokine-mediated disease is multiple sclerosis. 
     
     
       16. The composition of claim 11, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis. 
     
     
       17. The composition of claim 11, further comprising a therapeutically effective amount of a second medicament. 
     
     
       18. The composition of claim 17, wherein second medicament is an 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 another anti-inflammatory agent. 
     
     
       19. The composition of claim 17, wherein the second medicament is useful for treating cancer and is selected from the group consisting of gemcitabine, paclitaxel, 5-fluorouracil, cyclophosphamide, temozolomide, and vincristine, microtubule affecting agents, anti-angiogenesis agents, VEGF receptor kinase inhibitors, antibodies against the VEGF receptor, and interferon. 
     
     
       20. The composition of claim 17, wherein the second medicament is useful for treating COPD, asthma, or cystic fibrosis; and 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. 
     
     
       21. The composition of claim 17, wherein the second medicament is useful for treating multiple sclerosis and is selected from the group consisting of glatiramer acetate, glucocorticoids, methotrexate, azathioprine, mitoxantrone, CB2-selective inhibitors, cyclosporin, leflunomide, sulfasalazine, β-methasone, β-interferon, glatiramer acetate, prednisone, etanercept, and infliximab. 
     
     
       22. The composition of claim 17, wherein the second medicament is useful for treating rheumatoid arthritis or psoriasis and is 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. 
     
     
       23. The composition of claim of 10, wherein composition is suitable for oral administration. 
     
     
       24. The composition of claim 23, wherein the composition is a tablet. 
     
     
       25. The compound of claim 7, wherein the compound is in a pharmaceutically acceptable solvated or unsolvated form or a pharmaceutically acceptable salt. 
     
     
       26. A pharmaceutical composition comprising the compound of claim 7. 
     
     
       27. The composition of claim 26, comprising a therapeutically effective amount of the compound for treating a CXC chemokine-mediated disease. 
     
     
       28. The composition of claim 27, wherein the CXC chemokine-mediated disease comprises overproduction of glutamic acid-leucine-arginine (ELR)-CXC chemokine. 
     
     
       29. The composition of claim 27, wherein the CXC chemokine-mediated disease is a tumor or cancer. 
     
     
       30. The composition of claim 27, wherein the CXC chemokine-mediated disease is a pulmonary disease, wherein the pulmonary disease is COPD, asthma, or cystic fibrosis. 
     
     
       31. The composition of claim 27, wherein the CXC chemokine-mediated disease is multiple sclerosis. 
     
     
       32. The composition of claim 27, wherein the CXC chemokine-mediated disease is rheumatoid arthritis or psoriasis. 
     
     
       33. The composition of claim 27, further comprising a therapeutically effective amount of a second medicament. 
     
     
       34. The composition of claim 33, wherein second medicament is an 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 another anti-inflammatory agent. 
     
     
       35. The composition of claim 33, wherein the second medicament is useful for treating cancer and is selected from the group consisting of gemcitabine, paclitaxel, 5-fluorouracil, cyclophosphamide, temozolomide, and vincristine, microtubule affecting agents, anti-angiogenesis agents, VEGF receptor kinase inhibitors, antibodies against the VEGF receptor, and interferon. 
     
     
       36. The composition of claim 33, wherein the second medicament is useful for treating COPD, asthma, or cystic fibrosis; and 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. 
     
     
       37. The composition of claim 33, wherein the second medicament is useful for treating multiple sclerosis and is selected from the group consisting of glatiramer acetate, glucocorticoids, methotrexate, azathioprine, mitoxantrone, CB2-selective inhibitors, cyclosporin, leflunomide, sulfasalazine, β-methasone, β-interferon, glatiramer acetate, prednisone, etanercept, and infliximab. 
     
     
       38. The composition of claim 22, wherein the second medicament is useful for treating rheumatoid arthritis or psoriasis and is 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. 
     
     
       39. The composition of claim 26, wherein composition is suitable for oral administration. 
     
     
       40. The composition of claim 39, wherein the composition is a tablet.