Antiinflammation agents

A composition comprising a pharmaceutically acceptable excipient and a compound having the formula:

• 138
• wherein
• W and X are independently selected from the group consisting of N and CH;
• Y is selected from the group consisting of O, S and N(R);
• wherein R is selected from the group consisting of H, CN, NO2, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)alkenyl and (C2-C10)alkynyl;
• Z is selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl and NR2R3;
• R1, R2 and R3 are independently selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)alkenyl, (C2-C10)alkynyl, (C2-C10)heteroalkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)cycloheteroalkyl-alkyl, (C3-C10)cycloheteroalkyl, aryl, aryl(C1-C4)alkyl, aryl(C2-C4)heteroalkyl, heteroaryl(C2-C4)alkyl, heteroaryl(C2-C4)heteroalkyl and perfluoro(C1-C6)alkyl;
• and wherein when Z is NR2R3, R2 and R3 can be combined to form a 5- to 7-membered ring;
• and wherein when Y is N(R), R and R1 are optionally combined to form a 5- to 7-membered ring;
• R4 is selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkyl-alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl;
• A is a substituted or unsubstituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated;
• and
• B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF3, CF3O, (C1-C6)alkyl, perfluoro(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy, (C1-C6)thioalkoxy, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)cycloheteroalkyl, cyano, nitro, sulfonamido, (C1-C6)acyl, (C1-C6)acylamino, (C2-C6)alkoxycarbonyl, (C2-C6)alkoxycarbonyl(C1-C6)alkyl, carboxamido and (C1-C6)heteroalkoxy.

A method for treating an inflammatory, metabolic or malignant condition, said method comprising administering to a subject in need of such treatment, an effective amount of a compound having the formula:

• 142
• wherein
• W and X are independently selected from the group consisting of N and CH;
• Y is selected from the group consisting of O, S and N(R);
• wherein R is selected from the group consisting of H, CN, NO2, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)alkenyl and (C2-C10)alkynyl;
• Z is selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl and NR2R3;
• R1, R2 and R3 are independently selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)alkenyl, (C2-C10)alkynyl, (C2-C10)heteroalkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)cycloheteroalkyl-alkyl, (C3-C10)cycloheteroalkyl, aryl, aryl(C1-C4)alkyl, aryl(C2-C4)heteroalkyl, heteroaryl(C2-C4)alkyl, heteroaryl(C2-C4)heteroalkyl and perfluoro(C1-C6)alkyl;
• and wherein when Z is NR2R3, R2 and R3 can be combined to form a 5- to 7-membered ring;
• and wherein when Y is N(R), R and R1 are optionally combined to form a 5- to 7-membered ring;
• R4 is selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkyl-alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl;
• A is a substituted or unsubstituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated;
• and
• B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF3, CF3O, (C1-C6)alkyl, perfluoro(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy, (C1-C6)thioalkoxy, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)cycloheteroalkyl, cyano, nitro, sulfonamido, (C1-C6)acyl, (C1-C6)acylamino, (C2-C6)alkoxycarbonyl, (C2-C6)alkoxycarbonyl(C1-C6)alkyl, carboxamido and (C1-C6)heteroalkoxy.

A method for treating a condition or disorder mediated by IKK, comprising

• administering to a subject in need thereof a therapeutically effective amount of a compound having the formula:
• 146
• wherein
• W and X are independently selected from the group consisting of N and CH;
• Y is selected from the group consisting of O, S and N(R);
• wherein R is selected from the group consisting of H, CN, NO2, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)alkenyl and (C2-C10)alkynyl;
• Z is selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl and NR2R3;
• R1, R2 and R3 are independently selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)heteroalkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)cycloheteroalkyl-alkyl, (C3-C10)cycloheteroalkyl, aryl, aryl(C1-C4)alkyl, aryl(C1-C4)heteroalkyl, heteroaryl(C1-C4)alkyl, heteroaryl(C1-C4)heteroalkyl and perfluoro(C1-C6)alkyl;
• and wherein when Z is NR2R3, R2 and R3 can be combined to form a 5- to 7-membered heterocyclyl ring;
• R4 is selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkyl-alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl;
• A is a substituted or unsubstituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated;
• and
• B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF3, CF3O, (C1-C6)alkyl, perfluoro(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy, (C1-C6)thioalkoxy, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)cycloheteroalkyl, cyano, nitro, sulfonamido, (C1-C6)acyl, (C1-C6)acylamino, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl(C1-C6)alkyl, carboxamido and (C1-C6)heteroalkoxy.

A method for modulating IKK, comprising

• contacting a cell with a compound having the formula:
• 147
• wherein
• W and X are independently selected from the group consisting of N and CH;
• Y is selected from the group consisting of O, S and N(R);
• wherein R is selected from the group consisting of H, CN, NO2, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)alkenyl and (C2-C10)alkynyl;
• Z is selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl and NR2R3;
• R1, R2 and R3 are independently selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)heteroalkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)cycloheteroalkyl-alkyl, (C3-C10)cycloheteroalkyl, aryl, aryl(C1-C4)alkyl, aryl(C1-C4)heteroalkyl, heteroaryl(C1-C4)alkyl, heteroaryl(C1-C4)heteroalkyl and perfluoro(C1-C6)alkyl;
• and wherein when Z is NR2R3, R2 and R3 can be combined to form a 5- to 7-membered heterocyclyl ring;
• R4 is selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkyl-alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl;
• A is a substituted or unsubstituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated;
• and
• B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF3, CF3O, (C1-C6)alkyl, perfluoro(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy, (C1-C6)thioalkoxy, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)cycloheteroalkyl, cyano, nitro, sulfonamido, (C1-C6)acyl, (C1-C6)acylamino, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl(C1-C6)alkyl, carboxamido and (C1-C6)heteroalkoxy.

A method for the preparation of antiinflammation agents comprising contacting a precursor compound having the formula:

• 148
• wherein
• W and X are independently selected from the group consisting of N and CH;
• R4 is selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkyl-alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl;
• A is a substituted or unsubstituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated;
• and
• B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF3, CF3O, (C1-C6)alkyl, perfluoro(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy, (C1-C6)thioalkoxy, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)cycloheteroalkyl, cyano, nitro, sulfonamido, (C1-C6)acyl, (C1-C6)acylamino, (C2-C6)alkoxycarbonyl, (C2-C6)alkoxycarbonyl(C1-C6)alkyl, carboxamido and (C1-C6)heteroalkoxy
• with a compound having the formula:
• 149
• wherein
• Y is selected from the group consisting of O, S and N(R);
• wherein R is selected from the group consisting of H, CN, NO2, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)alkenyl and (C2-C10)alkynyl;
• Z is selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl and NR2R3;
• R1, R2 and R3 are independently selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)alkenyl, (C2-C10)alkynyl, (C2-C10)heteroalkyl, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)cycloheteroalkyl-alkyl, (C3-C10)cycloheteroalkyl, aryl, aryl(C1-C4)alkyl, aryl(C2-C4)heteroalkyl, heteroaryl(C2-C4)alkyl, heteroaryl(C2-C4)heteroalkyl and perfluoro(C1-C6)alkyl;
• and wherein when Z is NR2R3, R2 and R3 can be combined to form a 5- to 7-membered ring;
• and wherein when Y is N(R), R and R1 are optionally combined to form a 5- to 7-membered ring;
• under conditions sufficient to produce compounds having the formula:
• 150
• wherein each of A, B, R1, R4, W, X, Y and Z have the meanings provided above.

A compound having the formula:

• 151
• wherein
• W and X are independently selected from the group consisting of N and CH;
• R4 is selected from the group consisting of H, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkyl-alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl;
• A is a substituted or unsubstituted fused carbocyclic or heterocyclic ring system, said ring system being mono- or bicyclic wherein said mono- or bicyclic rings are selected from the group consisting of five- and six-membered rings that are aromatic or partially or completely saturated;
• and
• B is a substituted or unsubstituted five- or six-membered ring which is aromatic or partially or completely saturated, containing at least one nitrogen atom, and from 0 to 3 additional heteroatoms, wherein the B ring substituents are selected from the group consisting of halogen, CF3, CF3O, (C1-C6)alkyl, perfluoro(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)heteroalkyl, (C1-C6)alkoxy, (C1-C6)thioalkoxy, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C3-C10)cycloalkyl, (C4-C10)cycloalkyl-alkyl, (C3-C10)cycloheteroalkyl, cyano, nitro, sulfonamido, (C1-C6)acyl, (C1-C6)acylamino, (C2-C6)alkoxycarbonyl, (C2-C6)alkoxycarbonyl(C1-C6)alkyl, carboxamido and (C1-C6)heteroalkoxy.