Aminopyridinecarboxamides as CXCR2 modulators

Abstract

There is disclosed aminopyridine- and aminopyrimidinecarboxamide aminopyridinecarboxamide compounds useful as pharmaceutical agents, synthesis processes, and pharmaceutical compositions which include aminopyridine- and aminopyrimidinecarboxamides aminopyridinecarboxamide 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 (2 1): 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, unsaturated alkyl, alkyl substituted with 1-4 substituents, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl heterocycloalkylalkyl; 
         wherein R 2  is selected from the group consisting of 2- or 3- or 4-halo-phenyl, heteroalkyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, unsaturated alkyl, alkyl substituted with 1-4 substituents selected from the group consisting of hydroxy, alkylamino, boronyl, carboxy, nitro, and cyano, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl comprising a monocyclic or multicyclic ring system comprising 3 to 5 or 7 to 10 carbon atoms, heterocyclyl, and heterocyclylalkyl heterocycloalkylalkyl, wherein aryl is and heteroaryl are independently unsubstituted or substituted 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, —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  is selected from the group consisting of hydrogen, heteroalkyl, methyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, unsaturated alkyl, alkyl substituted with 1-4 substituents, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, wherein the heteroaryl of the heteroarylalkyl is selected from pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, and benzothiazolyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl heterocycloalkylalkyl, —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 ), —N(R 8 R 9 ), carboxylates, amines, phosphonates, and phosphates; 
         wherein R 4  is selected from the group consisting of heteroalkyl, methyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, unsaturated alkyl, alkyl substituted with 1-4 substituents, aminoalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, substituted cycloalkyl, unsubstituted cycloalkyl of 5 to 7 ring carbons, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl heterocycloalkylalkyl, wherein the heterocyclic ring of the heterocycloalkylalkyl is selected from piperidyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl, —B(R 5 R 6 ), —BF 3   − M + , —R 7 —B(R 5 R 6 ), —R 7 —BF 3   − M + , —C(O)—R 7  —C(O)R 10 , —O—R 7 , —S(O) y —R 7  (wherein y=0, 1, or 2), —P(O)—(R 5 R 6 ), —N(R 8 R 9 ), carboxylates, amines, phosphonates, and phosphates, aryl substituted with one or more substituents selected from the group consisting of —C(O)R, —OCF 3 , —O-ethyl, —O-propyl, —O-butyl, —O-pentyl, —O-hexyl, —O-heptyl, —O-octyl, —O-nonyl, —O-decyl, —O-undecyl, —O-dodecyl, —CF, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, aryl, —N(H)R, —N(R)R, —S—R, —NH 2 , —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 selected from the group consisting of F, Cl or Br, and wherein R is alkyl having less than twelve carbons, and heteroaryl, wherein the heteroaryl is selected from the group consisting of pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo(1,2-a)pyridinyl, imidazo(2,1-b)thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, and benzothiazolyl, and wherein the heteroaryl is unsubstituted or substituted by one or more substituents selected from acyl, alkoxy, aryl, aminoalkyl, 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 7  is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl , heteroarylalkyl, heterocyclyl and heterocyclylalkyl heterocycloalkylalkyl; 
         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 is selected from hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, hetercyclyl heterocyclyl and heterocyclylalkyl heterocycloalkylalkyl; and wherein R 9  is selected from haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl and heterocycloalkylalkyl; 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 R 10  is selected from the group consisting of aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocycloalkylalkyl; and 
         wherein n is 1; and or 
       
       a pharmaceutically acceptable solvated or unsolvated form thereof; a pharmaceutically acceptable salt thereof; or a pharmaceutical compositions composition thereof. 
     
     
       2. The compound of  claim 1  wherein R 2  is 4-fluoro-phenyl. 
     
     
       3. The compound of  claim 1  wherein R 4  is 4-phenylboronic acid. 
     
     
       4. A pharmaceutical composition comprising a compound of formula (2): 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, unsaturated alkyl, alkyl substituted with 1-4 substituents, 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, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, unsaturated alkyl, alkyl substituted with 1-4 substituents, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein aryl is substituted 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, —NO 2 , cyano, halo, haloalkyl, haloalkoxy, heterocyclyl, heteroalkyl, —OH, —OC(O)R, —C(O)R and —C(O)CH aXb , 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  is selected from the group consisting of hydrogen, heteroalkyl, methyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, unsaturated alkyl, alkyl substituted with 1-4 substituents, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, —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 ), —N(R 8 R 9 ), carboxylates, amines, phosphonates, and phosphates; 
         wherein R 4  is selected from the group consisting of heteroalkyl, methyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, unsaturated alkyl, alkyl substituted with 1-4 substituents, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, —B(R 5 R 6 ), —BF 3   − M + , —R 7 —B(R 5 R 6 ), —R 7 —BF 3   − M + , —(CO)—R 7 , —O—R 7 , —S(O) y —R 7  (wherein y=0, 1, or 2), —P(O)—(R 5 R 6 ), —N(R 8 R 9 ), carboxylates, amines, phosphonates, and phosphates; 
         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 X 1  is carbon; 
         wherein n is 1, and pharmaceutical compositions thereof. 
       
     
     
       5. The pharmaceutical composition of  claim 4 , wherein R 2  is 4-fluoro-phenyl. 
     
     
       6. The pharmaceutical composition of  claim 4 , wherein R 4  is 4-phenylboronic acid. 
     
     
       7. The compound of claim 1, wherein R 1  is hydrogen. 
     
     
       8. The compound of claim 1, wherein R 3  is hydrogen. 
     
     
       9. The compound of claim 1, wherein R 3  is methyl. 
     
     
       10. The compound of claim 1, wherein R 4  is —B(R 5 R 6 ), —BF 3   − M + , —R 7 —B(R 5 R 6 ), or —R 7 —BF 3   − M + . 
     
     
       11. The compound of claim 10, wherein R 7  is aryl. 
     
     
       12. The compound of claim 1, wherein R 4  is an heteroaryl, wherein the heteroaryl is substituted with a halide, —OH, or —B(R 5 R 6 ). 
     
     
       13. The compound of claim 12, wherein heteroaryl is substituted with —B(R 5 R 6 ). 
     
     
       14. The compound of claim 13, wherein heteroaryl is pyridine and —B(R 5 R 6 ) is —R 7 —B(OH) 2 . 
     
     
       15. The compound of claim 13, wherein heteroaryl is pyridine and —B(R 5 R 6 ) is 
       
         
           
           
               
               
           
         
        
       
     
     
       16. A compound comprising a compound from formula (1): 
       
         
           
           
               
               
           
         
         wherein R 2  is 2-, 3-, or 4-halophenyl; 
         wherein R 3  is hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkylalkyl, carboxylate, amine, phosphonate, phosphate, —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 ), or —N(R 8 R 9 ), 
         wherein R 4  is heteroalkyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, unsaturated alkyl, alkyl substituted with 1-4 substituents, aminoalkyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl, fluorenyl, substituted aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, substituted cycloalkyl, unsubstituted cycloalkyl of 5 to 7 ring carbons, cycloalkylalkyl, heterocyclyl, heterocycloalkylalkyl, carboxylate, amine, phosphonate, phosphate, —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 ), or —N(R 8 R 9 ); 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 7  is alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocycloalkylalkyl; 
         wherein R 8  and R 9  are independently hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl or heterocycloalkylalkyl; 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 is 1; 
         a pharmaceutically acceptable solvated or unsolvated form thereof; a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof. 
       
     
     
       17. A compound comprising a compound from formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, methyl, ethyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkylalkyl; 
         wherein R 2  is 2- or 3- or 4-halo-phenyl, methyl, ethyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkylalkyl; 
         wherein R 3  is hydrogen, heteroalkyl, alkyl, aminoalkyl, aryl, arylalkyl, carboxyalkyl, heteroaryl, heteroarylalkyl, wherein the heteroaryl of the heteroarylalkyl is selected from pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, and benzothiazolyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkylalkyl, carboxylate, amine, phosphonate, or phosphate; 
         wherein R 4  is —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 ), —N(R 8 R 9 ), cycloalkyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, heterocycloalkylalkyl, wherein the heterocyclic ring of the heterocycloalkylalkyl is selected from piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, or tetrahydrothiopyranyl, or an aryl substituted with a chloride, bromide, iodide, —OH, —OC(O)R, —OCF 3 , —C(O)R, —CF 3 , ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, —NO 2 , or —B(R 5 R 6 ), wherein R is methyl, ethyl, n-propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, or dodecyl, and 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 7  is alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocycloalkylalkyl; 
         wherein R 8  and R 9  are independently hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl or heterocycloalkylalkyl; 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 is 1; or 
       
       a pharmaceutically acceptable solvated or unsolvated form thereof; a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof. 
     
     
       18. The compound of claim 17, wherein the compound is of formula SX-626, SX-627, SX-628, SX-629, or SX-632, a pharmaceutically acceptable solvated or unsolvated form thereof; a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof 
       
         
           
           
               
               
           
         
        
       
     
     
       19. The compound of claim 17, wherein R 1  is hydrogen. 
     
     
       20. The compound of claim 17, wherein R 3  is hydrogen. 
     
     
       21. The compound of claim 17, wherein R 3  is methyl. 
     
     
       22. The compound of claim 17, wherein R 4  is an aryl substituted with a chloride, bromide, iodide, —OH, —OC(O)R, —OCF 3 , —C(O)R, —CF 3 , ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, —NO 2 , —B(R 5 R 6 ), —BF 3   − M + , —R 7 —B(R 5 R 6 ), or —R 7 —BF 3   − M + , wherein R is methyl, ethyl, n-propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, or dodecyl. 
     
     
       23. The compound of claim 22, wherein R 7  is an aryl substituted with a chloride, bromide, iodide, —OH, —OC(O)R, —OCF 3 , —C(O)R, —CF 3 , ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, —NO 2 , or —B(R 5 R 6 ), wherein R is methyl, ethyl, n-propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, or dodecyl. 
     
     
       24. The compound of claim 17, wherein R 4  is an aryl substituted with a chloride, bromide, iodide, —OH, or —B(R 5 R 6 ). 
     
     
       25. The compound of claim 24, wherein R 4  is an aryl substituted with —B(R 5 R 6 ). 
     
     
       26. The compound of claim 22, wherein R 4  is phenyl substituted with —R 7 —B(OH) 2 . 
     
     
       27. The compound of claim 25, wherein R 4  is phenyl substituted with