Pyrimidinecarboxamides as CXCR2 modulators
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.
1. A compound comprising a compound from formula (1):
wherein R 1 and R 2 are independently selected from hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl;
wherein R 3 is selected from —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, R 6 , —O—R 6 , —S(O) y —R 6 (wherein y=0, 1, or 2), —P(O)—(R 4 R 5 ), —N(R 7 R 8 ), or C(O)—R 9 ;
wherein R 6 is selected from alkyl, aryl, arylalkyl, cycloalkyl with 5 to 7 ring atoms, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
wherein R 4 and R 5 are independently selected from hydrogen, hydroxyl, aryloxy, or 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 hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl or heterocyclylalkyl; R 7 and R 8 are both oxygen to form a nitro group; or R 7 and R 8 together with the nitrogen to which they are attached, form a heterocyclyl;
wherein R 9 is selected from an alkyl consisting of 1 or 3-18 carbon atoms or a unsaturated alkyl group consisting of 1-18 carbon atoms, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl; and
wherein X 1 is nitrogen; X 2 is selected from NH or oxygen; and n is an integer between 0 and 8; or pharmaceutical compositions thereof.
2. The compound of claim 1 wherein R 1 is hydrogen and R 2 is 4-fluoro-phenyl.
3. A composition comprising a compound of formula (1):
wherein R 1 and R 2 are independently selected from hydrogen, 2- or or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylkalkyl;
wherein R 3 is selected from —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), R 6 , or —C(O)—R 6 , —O—R 6 , —S(O) y —R 6 (wherein y=0, 1, or 2), —P(O)—(R 4 R 5 ) or —N(R 7 R 8 );
wherein R 6 is selected from alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl;
wherein R 4 and R 5 are independently selected from hydrogen, hydroxyl, aryloxy, or 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 hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl or heterocyclylalkyl; R 7 and R 8 are both oxygen to form a nitro group; or R 6 and R 7 together with the nitrogen to which they are attached, form a heterocyclyl; and
wherein X 1 is nitrogen; X 2 is —S(O) y —, wherein y=0, 1, or 2; and n is an integer between 1 and 8; or pharmaceutical compositions thereof.
4. The pharmaceutical composition of claim 3 , wherein R 1 is hydrogen and R 2 is 4-fluoro-phenyl.
5. A composition comprising a compound of formula (1):
wherein R 1 and R 2 are independently selected from hydrogen, 2- or 3- or 4-halo-phenyl, heteroalkyl, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylkalkyl;
wherein R 3 is selected from —B(R 4 R 5 ), —R 6 —B(R 4 R 5 ), alkyl with 2-18 carbon atoms, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, or —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 alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;
wherein R 4 and R 5 are independently selected from hydrogen, hydroxyl, aryloxy, or 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 hydrogen, alkyl, haloalkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heterocyclyl or heterocyclylalkyl; R 7 and R 8 are both oxygen to form a nitro group; or R 6 and R 7 together with the nitrogen to which they are attached, form a heterocyclyl; and
wherein X 1 is nitrogen; X 2 is —S(O) y —, wherein y=0, 1, or 2; and n is an integer between 0 and 8; or pharmaceutical compositions thereof.