5-membered heterocycle-based P38 kinase inhibitors

A method of treating or ameliorating one or more symptoms of p38 kinase-mediated diseases or disorders selected from the group consisting of chronic obstructive pulmonary disease, and renal reperfusion injury, comprising administering to a subject in need thereof a compound of the formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is hydrogen, acyl or —P(O)(OH)2;
• R2 is hydrogen, halo, alkyl, or alkylthio;
• G is phenyl substituted with R3 and R4;
• B is phenyl;
• C is a pyrazole or imidazole;
• D is C(O)NH(cyclopropyl);
• R3 is selected from the group consisting of:
• (a) amino, alkylamino or dialkylamino;
• (b) acylamino;
• (c) optionally substituted phenyl or naphthyl;
• (d) heteroalkylcarbonyl;
• (e) —Y-(alkylene)-R9 where:
• Y is a single bond, —O—, —NH— or —S(O)n— (where n is an integer from 0 to 2);
• and R9 is halo, cyano, optionally substituted phenyl, —COOH, —COR10, —COOR11, —CONR12R13, —SO2R14, —SO2NR15R16, —NHSO2R17 or —NHSO2NR18R19, where R10 is alkyl, R11 is alkyl, and R12, R13, R14, R15, R16, R17, R18 and R19 are, independently of each other, hydrogen or alkyl;
• (f) —CONR25R26 where R25 and R26 independently represent hydrogen, alkyl, heteroalkyl, or R25 and R26 together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring;
• (g) —S(O)nR27 where n is an integer from 0 to 2, and R27 is alkyl, heteroalkyl, or —NR28R29 where R28 and R29 are, independently of each other, hydrogen, alkyl or heteroalkyl;
• (h) cycloalkylalkyl, cycloalkylalkenyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;
• (i) Z-alkylene-NR30R31 or Z-alkylene-OR32 where Z is —NH—, —N(lower alkyl)- or —O—, and R30, R31 and R32 are independently of each other, hydrogen, alkyl or heteroalkyl;
• (j) —OC(O)-alkylene-CO2H or —OC(O)—NR′R″ where R′ and R″ are independently hydrogen or alkyl;
• (k) hydrogen;
• (l) halo;
• (m) cyano;
• (n) hydroxy;
• (o) optionally substituted alkoxy;
• (p) C(L)R40, where L is O;
• R40 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phenyl, optionally substituted cycloalkyl, C(L)R56, halo, OR55, SR55, NR57R58 or SiR52R53R54;
• where R52, R53 and R54 are selected as in (i) or (ii) as follows (i) R52, R53 and R54 are each independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR55 or NR62R63;
• or (ii) any two of R52, R53 and R54 together form alkylene, alkenylene, alkynylene, heteroalkylene;
• and the other is selected as in (i);
• R55 is hydrogen, alkyl, alkenyl, alkynyl, phenyl or cycloalkyl;
• R56 is hydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR55 or NR64R65;
• where R64 and R65 are each independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR66 or NR62R63, or R64 and R65 together form alkylene, alkenylene, alkynylene, heteroalkylene, where R66 is hydrogen, alkyl, alkenyl, alkynyl, phenyl or cycloalkyl;
• R57 and R58 are selected as in (i) or (ii) as follows (i) R57 and R58 are each independently hydrogen, optionally substituted alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR55, NR67R68 or C(L)R69, where R67 and R68 are each independently hydrogen, alkyl, alkenyl, alkynyl, phenyl or cycloalkyl, or together form alkylene, alkenylene, alkynylene, heteroalkylene;
• and R69 is hydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR70 or NR62R63, where R70 is alkyl, alkenyl, alkynyl, phenyl or cycloalkyl;
• or (ii) R57 and R58 together form alkylene, alkenylene, alkynylene, heteroalkylene, or alkylenoxyalkylene;
• R62 and R63 are each independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, or R62 and R63 together form alkylene, alkenylene, alkynylene, heteroalkylene;
• and
• (q) optionally substituted alkyl;
• R4 is selected from the group consisting of:
• (a) hydrogen;
• (b) halo;
• (c) alkyl;
• (d) alkoxy;
• and
• (e) hydroxy;
• R5 is selected from the group consisting of
• (a) hydrogen;
• (b) halo;
• and
• (c) alkyl;
• R6 is selected from the group consisting of:
• (a) hydrogen;
• (b) halo;
• (c) alkyl;
• and
• (d) alkoxy.