Indolizine SPLA2inhibitors

An indolizine-1-acetic acid hydrazide compound or a pharmaceutically acceptable salt or an ester or amide prodrug derivative thereof where said compound is represented by the formula (IIA);

• wherein:
• X is oxygen or sulfur;
• each R11 is independently hydrogen, C1-C3 alkyl, or halo;
• R13 is selected from groups (a), (b) and (c) where;
• (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
• (b) is a member of (a) substituted with one or more independently selected non-interfering substituents;
• or
• (c) is the group —(L)—R80;
• where, —(L)— is a divalent linking group of 1 to 12 atoms and where R80 is a group selected from (a) or (b);
• R12 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, —O—(C1-C2 alkyl), —S—(C1-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
• R17 and R18 are independently selected from hydrogen, a non-interfering substituent, or the group, —(La)—(acidic group);
• wherein —(La)—, is an acid linker having an acid linker length of 1 to 10;
• provided, that at least one of R17 and R18 must be the group, —(La)—(acidic group);
• R15 and R16 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents;
• and
• provided that the non-interfering substituent for R13, R12, R17, R18, R15, or R16 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkyithio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —C(O)O(C1-C6 alkyl), —(CH2)n—O—(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, —(CONHSO2R), —CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, —(CH2)n—CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO3H, thioacetal, thiocarbonyl, or C1-C6 carbonyl;
• where n is from 1 to 8.

An indolizine-1-glyoxylamide compound or a pharmaceutically acceptable salt or an ester or amide prodrug derivative thereof;

• wherein said compound is represented by the formula (IIIA);
• X is oxygen or sulfur;
• R13 is selected from groups (a), (b) and (c) where;
• (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
• (b) is a member of (a) substituted with one or more independently selected non-interfering substituents;
• or
• (c) is the group —(L)—R80;
• where, —(L)— is a divalent linking group of 1 to 12 atoms and where R80 is a group selected from (a) or (b);
• R12 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, —O—(C1-C2 alkyl), —S—(C1-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
• R17 and R18 are independently selected from hydrogen, a non-interfering substituent, or the group, —(La)—(acidic group);
• wherein —(La)—, is an acid linker having an acid linker length of 1 to 10;
• provided, that at least one of R17 and R18 must be the group, —(La)—(acidic group);
• R15 and R16 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents;
• and
• provided that the non-interfering substituent for R13, R12, R17, R18, R15, or R16 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —C(O)O(C1-C6 alkyl), —(CH2)n—O—(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, —(CONHSO2R), —CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, —(CH2)n—CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO3H, thioacetal, thiocarbonyl, or C1-C6 carbonyl;
• where n is from 1 to 8.

An indolizine-3-acetamide compound or a pharmaceutically acceptable salt or an ester or amide prodrug derivative thereof;

• wherein said compound is represented by the formula (IB), as set out below:
• wherein;
• X is selected from oxygen or sulfur;
• each R3 is independently hydrogen, C1-C3 alkyl, or halo;
• R1 is selected from groups (a), (b) and (c) where;
• (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
• (b) is a member of (a) substituted with one or more independently selected non-interfering substituents;
• or
• (c) is the group —(L)—R80;
• where, —(L)— is a divalent linking group of 1 to 12 atoms and where R80 is a group selected from (a) or (b);
• R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, —O—(C1-C2 alkyl), —S—(C1-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
• R5 and R6 are independently selected from hydrogen, a non-interfering substituent, or the group, —(La)—(acidic group);
• wherein —(La)—, is an acid linker having an acid linker length of 1 to 10;
• provided, that at least one of R5 and R6 must be the group, —(La)—(acidic group);
• R7 and R8 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents;
• and
• provided that the non-interfering substituent for R3, R2, R5, R6, R7, or R8 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C2-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —C(O)O(C1-C6 alkyl), —(CH2)n—O—(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, —(CONHSO2R), —CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, —(CH2)n—CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO3H, thioacetal, thiocarbonyl, or C1-C6 carbonyl;
• where n is from 1 to 8.

A indolizine-3-hydrazide compound or a pharmaceutically acceptable salt or an ester or amide prodrug derivative thereof;

• wherein said compound is represented by the formula (IIB), as set out below:
• wherein;
• X is selected from oxygen or sulfur;
• each R3 is independently hydrogen, C1-C3 alkyl, or halo;
• R1 is selected from groups (a), (b) and (c) where;
• (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
• (b) is a member of (a) substituted with one or more independently selected non-interfering substituents;
• or
• (c) is the group —(L)—R80;
• where, —(L)— is a divalent linking group of 1 to 12 atoms and where R80 is a group selected from (a) or (b);
• R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, —O—(C1-C2 alkyl), —S—(C1-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
• R5 and R6 are independently selected from hydrogen, a non-interfering substituent, or the group, —(La)—(acidic group);
• wherein —(La)—, is an acid linker having an acid linker length of 1 to 10;
• provided, that at least one of R5 and R6 must be the group, —(La)—(acidic group);
• R7 and R8 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents;
• and
• provided that the non-interfering substituent for R3, R2, R5, R6, R7, or R8 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —C(O)O(C1-C6 alkyl), —(CH2)n—O—(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, —(CONHSC2R), —CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, —(CH2)n—CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO3H, thioacetal, thiocarbonyl, or C1-C6 carbonyl;
• where n is from 1 to 8.

A indolizine-3-glyoxylamide compound or a pharmaceutically acceptable salt or an ester or amide prodrug derivative thereof;

• wherein said compound is represented by the formula (IIIB), as set out below:
• wherein;
• each X is independently selected from oxygen or sulfur;
• each R3 is independently hydrogen, C1-C3 alkyl, or halo;
• R1 is selected from groups (a), (b) and (c) where;
• (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or
• (b) is a member of (a) substituted with one or more independently selected non-interfering substituents;
• or
• (c) is the group —(L)—R80;
• where, —(L)— is a divalent linking group of 1 to 12 atoms and where R80 is a group selected from (a) or (b);
• R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, —O—(C1-C2 alkyl), —S—(C1-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen;
• R5 and R6 are independently selected from hydrogen, a non-interfering substituent, or the group, —(La)—(acidic group);
• wherein —(La)—, is an acid linker having an acid linker length of 1 to 10;
• provided, that at least one of R5 and R6 must be the group, —(La)—(acidic group);
• R7 and R8 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents;
• and
• provided that the non-interfering substituent for R3, R2, R5, R6, R7, or R8 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, —C(O)O(C1-C6 alkyl), —(CH2)n—O—(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, —(CONHSO2R), —CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, —(CH2)n—CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO3H, thioacetal, thiocarbonyl, or C1-C6 carbonyl;
• where n is from 1 to 8.