Aminopyrimidine and aminopyridine anti-inflammation agents

A method for the preparation of anti-inflammation agents comprising contacting a precursor compound having the formula:

• 156
• wherein
• one of either V or X is N and the other is —CRa, or both V and X are —CRa (where each Ra is independently hydrogen, alkyl, cycloalkyl or cycloalkylalkyl;
• R4 is selected from the group consisting of H, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl;
• A is selected from the group consisting of H, (C1-C10)alkyl, (C1-C10)haloalkyl, (C3-C10)alkenyl, (C2-C10)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-alkyl, (C1-C10)heteroalkyl, heterocyclylalkyl, heterocyclyl, heterosubstituted cycloalkyl, aryl, aryl(C1-C4)alkyl, aryl(C1-C4)heteroalkyl, heteroaryl, heteroaryl(C1-C4)alkyl, heteroaryl(C1-C4)heteroalkyl and RaNHC(═X)— wherein Ra is (C1-C4)alkyl or aryl and X is O or S;
• B is a substituted or unsubstituted five- or six-membered aromatic ring 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, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, cyano, nitro, sulfonamido, acyl, acylamino and carboxamido;
• U is NR5, O or S;
• and,
• R5 is H or (C1-C6)alkyl with a compound having the formula:
• 157
• wherein
• Y is selected from the group consisting of O, S and NR;
• wherein R is selected from the group consisting of H, CN, NO2, (C1-C10)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-alkyl, (C3-C10)alkenyl and (C2-C10)alkynyl;
• Z is selected from the group consisting of H, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and N(R2)(R3);
• R1 is selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)alkenyl, (C2-C10)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-alkyl, (C1-C10)heteroalkyl, heterocyclylalkyl, heterocyclyl, aryl, aryl(C1-C4)alkyl, aryl(C1-C4)heteroalkyl, heteroaryl(C1-C4)alkyl, heteroaryl(C1-C4)heteroalkyl, —C(O)R11 or alkylene-C(O)R11;
• and
• R2 and R3 are each members independently selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)heteroalkyl, (C3-C7)cycloalkyl, or (C3-C7)cycloalkyl-alkyl, or R2 and R3 can be combined to form a 5-7-membered heterocyclyl ring;
• under conditions sufficient to produce compounds having the formula:
• 158
• wherein each of A, B, R1, R4, U, V, X Y and Z have the meanings provided above.

A compound having the formula:

• 159
• wherein
• one of either V or X is N and the other is —CRa, or both V and X are —CRa (where each Ra is independently hydrogen, alkyl, cycloalkyl or cycloalkylalkyl;
• R4 is selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)haloalky (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl;
• A is selected from the group consisting of H, (C1-C10)alkyl, (C3-C10)alkenyl, (C2-C10)alkynyl, (C1-C10)heteroalkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-alkyl, (C3-C7) heterocyclylalkyl, heterocyclyl, heterosubstituted cycloalkyl, aryl, aryl(C1-C4)alkyl, aryl(C1-C4)heteroalkyl, heteroaryl, heteroaryl(C1-C4)alkyl, heteroaryl(C1-C4)heteroalkyl, and RaNHC(═X)— wherein Ra is (C1-C4)alkyl or aryl and X is O or S;
• B is a substituted or unsubstituted five- or six-membered aromatic ring 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, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, cyano, nitro, sulfonamido, acyl, acylamino, and carboxamido;
• U is NR5, O or S;
• and,
• R5 is H or (C1-C6)alkyl.