Pyrrolotriazine derivatives having spla2-inhibitory activities

A compound represented by the formula (II):

• wherein R8 is —(CH2)m—R12 wherein m is an integer from 1 to 6, and R12 is (d) a group represented by the formula:
• wherein a, c, e, n, q, and t are independently an integer from 0 to 2;
• R13 and R14 are independently selected from the group consisting of a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heterocyclic groups, and C1 to C10 haloalkyl;
• α is an oxygen atom or a sulfur atom;
• L3 is —(CH2)v-, —C═C—, —C≡C—, —O—, or —S— wherein v is an integer from 0 to 2;
• β is —CH2— or —(CH2)2—;
• γ is an oxygen atom or a sulfur atom;
• b is an integer from 0 to 3;
• d is an integer from 0 to 4;
• f, p, and w are independently an integer from 0 to 5;
• g is an integer from 0 to 2;
• r is an integer from 0 to 7;
• and u is an integer from 0 to 4, or (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy, C1 to C6 haloalkyl, aryl, and a halogen;
• R9 is C1 to C3 alkyl C2 to C3 alkenyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, C1 to C2 haloalkyl, C1 to C3 alkyloxy, or C1 to C3 alkylthio;
• R10 is -(L4)-R15 wherein L4 is represented by the formula:
• wherein M is —CH2—, —O—, —N(R18)—, or —S—;
• R16 and R17 are independently a hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, carboxy, or a halogen, and R18 is a hydrogen atom or C1 to C6 alkyl;
• and
• R15 is represented by the formula:
• wherein R19 is a hydrogen atom, a metal, or C1 to C10 alkyl;
• R20 is independently a hydrogen atom or C1 to C10 alkyl;
• h is an integer from 1 to 8;
• R11 is a non-interfering substituent selected from the group consisting of a hydrogen atom, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C7 to C12 aralkyl, C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C1 to C8 alkyloxy, C2 to C8 alkenyloxy, C2 to C8 alkynyloxy, C2 to C12 alkyloxyalkyl, C2 to C12 alkyloxyalkyloxy, C2 to C12 alkylcarbonyl, C2 to C12 alkylcarbonylamino, C2 to C12 alkyloxyamino, C2 to C12 alkyloxyaminocarbonyl, C1 to C12 alkylamino, C1 to C6 alkylthio, C2 to C12 alkylthiocarbonyl, C1 to C8 alkylsulfinyl, C1 to C8 alkylsulfonyl, C2 to C8 haloalkyloxy, C1 to C8 haloalkylsulfonyl, C2 to C8 haloalkyl, C1 to C8 hydroxyalkyl, —C(O)O(C1 to C8 alkyl), —(CH2)z-O—(C1 to C8 alkyl), benzyloxy, aryloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, —(CONHSO2R21) wherein R21 is C1 to C6 alkyl or aryl, formyl, amino, amidino, halogen, carboxy, —(CH2)z-COOH wherein z is an integer from 1 to 8, cyano, cyanoguanidyl, guanidino, hydrazide, hydrazino, hydroxy, hydroxyamino, nitro, phosphono, and —SO3H;
• and
• RB is a group represented by the formula:
• wherein Z is —NH2 or —NHNH2, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.

A compound represented by the formula (III):

• wherein R22 is a group represented by the formula:
• wherein L5 is a bond, —CH2—, —C═C—, —C≡C—, —O—, or —S—;
• R13 and R14 are independently selected from a group consisting of a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heterocyclic groups, and C1 to C10 haloalkyl;
• b is an integer from 0 to 3;
• d is an integer from 0 to 4;
• f, p, and w are independently an integer from 0 to 5;
• g is an integer from 0 to 2;
• r is an integer from 0 to 7;
• u is an integer from 0 to 4;
• α is an oxygen atom or a sulfur atom;
• β is —CH2— or —(CH2)2—;
• and γ is an oxygen atom or a sulfur atom;
• R23 is C1 to C3 alkyl or C3 to C4 cycloalkyl;
• L6 is —O—CH2—, —S—CH2, —N(R26)—CH2—, —CH2—CH2—, —O—CH(CH3)—, or —O—CH((CH2)2Ph)— wherein R26 is a hydrogen atom or C1 to C6 alkyl, Ph is phenyl;
• R24 is —COOH, —SO3H, or P(O)(OH)2;
• R25 is a hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, a halogen, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, carbocyclic groups, or heterocyclic groups;
• and
• RB is a group represented by the formula:
• wherein Z is —NH2 or —NHNH2, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.

A compound represented by the formula (IV):

• wherein R22 is a group represented by the formula:
• wherein L5 is a bond, —CH2—, —C═C—, —C≡C—, —O—, or —S—;
• R13 and R14 are independently selected from the group consisting of a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heterocyclic groups, and C1 to C10 haloalkyl;
• b is an integer from 0 to 3;
• d is an integer from 0 to 4;
• f, p, and w are independently an integer from 0 to 5;
• g is an integer from 0 to 2;
• r is an integer from 0 to 7;
• u is an integer from 0 to 4;
• α is an oxygen atom or a sulfur atom;
• β is —CH2— or —(CH2)2—;
• and γ is an oxygen atom or a sulfur atom;
• R23 is C1 to C3 alkyl or C3 to C4 cycloalkyl;
• R25 is a hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, a halogen, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, aryloxy C1 to C8 alkyl, arylthio, arylthio C1 to C8 alkyl, cyano C1 to C8 alkyl, carbocyclic groups, or heterocyclic groups;
• RB is a group represented by the formula:
• wherein Z is —NH2 or —NHNH2;
• and k is an integer from 1 to 3, its prodrug, their pharmaceutically acceptable salt, or solvate thereof.