6-[(Substituted)phenyl]triazolopyrimidines as anticancer agents

A process for the preparation of a compound of Formula (I)

• wherein:
• R1 is
• R2 is a moiety
• n is an integer of 2, 3, or 4;
• X is Cl or Br;
• Y is O, S, or NR4;
• Q is selected from —NR6R7 and —OH;
• L1 and L2 are each independently H, F, Cl, Br or CF3;
• R3 is CF3 or C2F5;
• R4 and R5 are each independently H or C1-C3 alkyl;
• R6 and R7 are each independently H or C1-C3 alkyl;
• or
• R6 and R7 when optionally taken together with the nitrogen atom to which each is attached form a 4 to 6 membered saturated heterocyclic ring with 1-2 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, and optionally substituted with R8;
• R8 is C1-C3 alkyl;
• comprising the step of reacting a compound of formula (II)
• where L3 is a leaving group with a compound of the formula HY—(CH2)nQ in the presence of a strong base optionally in the presence of an aprotic solvent to give a compound of Formula (I) and pharmaceutically acceptable salts thereof.

A process for the preparation of a compound of Formula (I)

• wherein:
• R1 is
• R2 is a moiety of the group
• n is an integer of 2, 3, or 4;
• X is Cl or Br;
• Y is CH2;
• Q is —NR6R7;
• L1 and L2 are each independently H, F, Cl, Br or CF3;
• R3 is CF3 or C2F5;
• R5 is H or C1-C3 alkyl;
• R6 and R7 are each independently H or C1-C3 alkyl;
• or
• R6 and R7 when optionally taken together with the nitrogen atom to which each is attached form a 4 to 6 membered saturated heterocyclic ring with 1-2 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, and optionally substituted with R8;
• R8 is C1-C3 alkyl;
• and pharmaceutically acceptable salts thereof
• comprising the steps of:
• a) reacting diester (III)
• with 2-amino-1,3,4-triazole in the presence of a tertiary base to afford a compound (V) of the formula
• b) halogenating compound (V) with POX3 to afford 5,7-dihalo compound (VI)
• c) reacting the 5,7-dihalo compound (VI) with amine (VII)
• in the presence of base in an aprotic solvent to afford compounds of Formula (I) where Y is —CH2—.
• and pharmaceutically acceptable salts thereof.

A process for the preparation of a pharmaceutically acceptable salt of a compound of Formula (I)

• wherein:
• R1 is
• R2 is a moiety
• n is an integer 3;
• X is Cl;
• Y is O;
• Q is —NR6R7;
• L1 and L2 are each F;
• R3 is CF3;
• R5 is CH3;
• R6 is H;
• R7 is CH3;
• comprising the step of reacting a compound of Formula (I)
• where R1, R2 and X are hereinbefore defined with a pharmaceutically acceptable salt forming acid optionally in the presence of an strong base in a solvent to give a pharmaceutically acceptable salt of Formula (I).

A compound of Formula (I)

• wherein:
• R1 is
• R2 is a moiety
• n is an integer of 2, 3, or 4;
• X is Cl or Br;
• Y is O, S, or NR4;
• Q is selected from —NR6R7 and —OH;
• L1 and L2 are each independently H, F, Cl, Br or CF3;
• R3 is CF3 or C2F5;
• R4 and R5 are each independently H or C1-C3 alkyl;
• R6 and R7 are each independently H or C1-C3 alkyl;
• or
• R6 and R7 when optionally taken together with the nitrogen atom to which each is attached form a 4 to 6 membered saturated heterocyclic ring with 1-2 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, and optionally substituted with R8;
• R8 is C1-C3 alkyl;
• and pharmaceutically acceptable salts thereof,
• produced by the process which comprises the step of reacting a compound of Formula (II)
• where L3 is a leaving group with a compound of the formula HY—(CH2)nQ in the presence of a strong base optionally in the presence of an aprotic solvent to give a compound of Formula (I) and pharmaceutically acceptable salts thereof.

A compound of Formula (I)

• wherein:
• R1 is
• R2 is a moiety of the group
• n is an integer of 2, 3, or 4;
• X is Cl or Br;
• Y is CH2;
• Q is —NR6R7;
• L1 and L2 are each independently H, F, Cl, Br or CF3;
• R3 is CF3 or C2F5;
• R5 is H or C1-C3 alkyl;
• R6 and R7 are each independently H or C1-C3 alkyl;
• or
• R6 and R7 when optionally taken together with the nitrogen atom to which each is attached form a 4 to 6 membered saturated heterocyclic ring with 1-2 nitrogen atoms, 0-1 oxygen atoms and 0-1 sulfur atoms, and optionally substituted with R8;
• R8 is C1-C3 alkyl;
• and pharmaceutically acceptable salts thereof, produced by the process which comprises the steps of:
• a) reacting diester (III)
• with 2-amino-1,3,4-triazole in the presence of a tertiary amine base to afford a compound (V) of the formula
• b) halogenating compound (V) with POX3 to afford 5,7-dihalo compound (VI)
• c) reacting the 5,7-dihalo compound (VI) with amine (VII)
• in the presence of base in an aprotic solvent to afford compounds of Formula (I) where Y is —CH2—,
• and pharmaceutically acceptable salts thereof.

A pharmaceutically acceptable salt of a compound of Formula (I)

• wherein:
• R1 is
• R2 is a moiety
• n is an integer 3;
• X is Cl;
• Y is O;
• Q is —NR6R7;
• L1 and L2 are each F;
• R3 is CF3;
• R5 is CH3;
• R6 is H;
• R7 is CH3;
• produced by the process which comprises the step of reacting a compound of Formula (I)
• where R1, R2 and X are hereinbefore defined with a pharmaceutically acceptable salt forming acid optionally in the presence of an strong base in a solvent to give a pharmaceutically acceptable salt of Formula (I).