Process for preparing substituted 5-amino-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines

A process for preparing compounds of formula 7

• or a pharmaceutically acceptable salt or solvate thereof, wherein;
• L is alkylene;
• R is aryl, heteroaryl, R1-aryl, R1-heteroaryl or cycloalkenyl;
• Y is —N(R2)CH2CH2N(R3)—, —OCH2CH2N(R2)—, —(CH2)2—NH—, or
• and
• Z is aryl, R5-aryl, aralkyl, R5-aralkyl, heteroaryl, R5-heteroaryl, (aryl)2alkyl-, R6—C(O)—,
• R6—SO2—,
• R5-aryl-CH(OH)— or aryl-CH(OH)—;
• or when Q is
• Z is also phenylamino or pyridylamino;
• or
• Z and Y together are
• R1 is 1 to 3 substituents independently selected from the group consisting of hydrogen, alkyl, —CF3, halogen, —NO2, —NR12R13, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl;
• R2 and R3 are independently selected from the group consisting of hydrogen and alkyl;
• m and n are each independently 2 or 3;
• Q is
• R4 is 1 to 2 substituents independently selected from the group consisting of hydrogen and alkyl, or two R4 substituents on the same carbon can form ═O;
• R5 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, —CN, dialkyl-amino, —CF3, —OCF3, acetyl, —NO2, hydroxyalkoxy, alkoxyalkoxy, dialkoxy-alkoxy, alkoxy-alkoxy-alkoxy, carboxy-alkoxy, alkoxycarbonylalkoxy, cycloalkyl-alkoxy, dialkyl-amino-alkoxy, morpholinyl, alkyl-SO2—, alkyl-SO2-alkoxy, tetrahydropyranyloxy, alkylcarbonyl-alkoxy, alkoxycarbonyl, alkylcarbonyloxy-alkoxy, —SO2NH2, or phenoxy;
• or adjacent R5 substituents together are —O—CH2—O—, —O—CH2CH2—O—, —O—CF2—O— or —O—CF2CF2—O— and form a ring with the carbon atoms to which they are attached;
• R5 is alkyl, aryl, R5-aryl, aralkyl, R5-aralkyl, heteroaryl, R5-heteroaryl, R5-cycloalkyl, cycloalkyl, alkyl-OC(O)—NH—(C1-C6)alkyl-, dialkyl-aminomethyl or
• R9 is 1 to 2 substituents independently selected from the group consisting of hydrogen, alkyl, hydroxy, alkoxy, halogen, —CF3 and alkoxy-alkoxy;
• R10 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, —CN, —NH2, alkylamino, dialkylamino, —CF3, —OCF3 and —S(O)0-2alkyl;
• R12 is hydrogen or alkyl;
• and
• R13 is alkyl-C(O)— or alkyl-SO2—;
• comprising
• a) halogenating and formylating a compound of formula 6
• to obtain a compound of formula 5
• wherein X is halogen
• (b) coupling the compound of formula 5 with a hydrazine of formula 4
• in the presence of a base to form a compound of formula 3
• (c) reacting the compound of formula 3 with a compound of formula HO-L-NHNH2 to form a compound of formula 2
• (d) concurrently (1) cyclizing and (2) halogenating the compound of formula 2 by reacting the compound of formula 2 in the presence of catalytic amount of a metal halide or a catalytic amount of a halide salt and a dehydrating agent to form a compound of formula 1
• wherein A is halogen;
• and
• (e) preparing the compound of formula 7 by coupling the compound of formula 1 with a compound of formula 8
• Z-Y—H formula 8
• in the presence of a base.