4,6-Diaminosubstituted-2-[oxy or aminoxy]-[1,3,5]triazines as protein tyrosine kinase inhibitors

A compound of Formula II:

• 39
• or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein
• R is
• —CORa, —CONRaRb, —SO2Ra or —PO3RaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, polyalkoxyalkyl, aryl or aralkyl;
• A1 is
• a 5- to 6-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with C1-6 alkyl, amino, alkylamino, halogen, hydroxy, alkoxy, —OCO-alkyl, —OCO-alkylamino, —OCO-alkylamido, aryloxy, arylalkoxy, —CF3, —OCF3, —CORc, —COORc, —CONRcRd, —NHCORcRd, —NHSO2Rc, —SO2Rc, —SO3Rc, or —SO2NRcRd, wherein Rc and Rd are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
• R1 is
• hydrogen, alkyl, hydroxy or alkoxy;
• R2 is
• hydrogen, alkyl, carboxyalkyl, cycloalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, aminoalkyl, hydroxy, alkoxy or polyalkoxyalkyl;
• R3 is
• a direct link or
• C1-6 alkyl, C1-6 alkoxy, C1-6 thioalkyl, C1-6 hydroxyalkyl or C1-6 carboxyalkyl;
• and
• A2 is
• phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C1-4 alkyl, amino, aminoalkyl, halogen, hydroxy, —CF3, alkoxy, aryloxy, arylalkoxy, —OCF3, —CORe, —COORe, —CONReRf, —N(R1)CORe, —SO2Rc, —SO3Re or —SO2NRe Rf;
• a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with C1-6 alkyl, amino, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, —CF3, —OCF3, —CORe, —COORe, —CONReRf, —NHCOReRf, NHSO2Ra, —SO2Ra, —SO3Ra or —SO2NRaRb;
• or
• —CORe, —COORe or —CONReRf, wherein
• Re and Rf are independently hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.

A compound of Formula III:

• 40
• or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein
• R is
• —OH or —NHORa, wherein Ra is hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
• A1 is
• a 5- to 6-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with C1-6 alkyl, amino, alkylamino, halogen, hydroxy, alkoxy, —OCO-alkyl, —OCO-alkylamino, —OCO-alkylamido, aryloxy, arylalkoxy, —CF3, —OCF3, —CORA, —COORa, —CONRaRb, —NHCORaRb, —NHSO2Ra, —SO2Ra, —SO3Ra or —SO2NRaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
• R1 is
• hydrogen, alkyl, hydroxy or alkoxy;
• and
• 41
• wherein
• Rc and Rd are independently hydrogen or alkyl;
• X is N, O or S;
• and
• A2 is
• phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C1-4 alkyl, amino, aminoalkyl, halogen, hydroxy, —CF3, alkoxy, aryloxy, arylalkoxy, —OCF3, —CORe, —COORe, —CONReRf, —N(R1)CORe, —SO2Re, —SO3Re or —SO2NReRf;
• or
• a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with C1-6 alkyl, amino, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, —CF3, —OCF3, —CORe, —COO, —CONReRf, —NHCOReRf, NHSO2Re, —SO2Re, —SO3Re or —SO2NReRf, wherein
• Re and Rf are independently hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.

A compound of Formula IV:

• 42
• or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein
• R is
• —CORa, —CONRaRb, —SO2Ra or —PO3RaRb, wherein Ra and Rb are independently hydrogen, alkyl, cycloalkyl, polyalkoxyalkyl, aryl or aralkyl;
• A1 is
• a 5- to 6-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with C1-6 alkyl, amino, alkylamino, halogen, hydroxy, alkoxy, —OCO-alkyl, —OCO-alkylamino, —OCO-alkylamido, aryloxy, arylalkoxy, —CF3, —OCF3, —CORc, —COORc, —CONRcRd, —NHCORcRd, —NHSO2Rc, —SO2Rc, —SO3Rc or —SO2NRcRd, wherein Rc and Rd are independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
• R1 is
• hydrogen, alkyl, hydroxy or alkoxy;
• and
• 43
• wherein
• Re and Rf are independently hydrogen or alkyl;
• X is N, O or S;
• and
• A2 is
• phenyl, naphthyl or biphenyl, each of which may be optionally substituted with one or more of C1-4 alkyl, amino, aminoalkyl, halogen, hydroxy, —CF3, alkoxy, aryloxy, arylalkoxy, —OCF3, —CORg, —COORg, —CONRgRh, —N(R1)CORg, —SO2Rg, —SO3Rg or —SO2NRgRh;
• or
• a 5- to 7-membered mono- or a 8- to 10-membered bicyclic heteroaromatic ring having from one to four heteroatoms selected from N, O or S, and may be optionally substituted with C1-6 alkyl, amino, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, —CF3, —OCF3, —CORg, —COORg, —CONRgRh, —NHCORgRh, NHSO2Rg, —SO2Rg, —SO3Rg or —SO2NRgRh, wherein
• Rg and Rh are independently hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl.

A method of preparing the compounds of Formulae I and III where R is —OH, comprising the steps of:

• a) displacing one of three displaceable groups at the 2-, 4- and 6-positions, respectively, of a 1,3,5-triazine ring with 4-methoxybenzyl alcohol to give a 2-(4-methoxybenzyloxy)-[1,3,5]triazine;
• b) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (i) to give a 4-amino-2-(4-methoxybenzyloxy)-[1,3,5]triazine;
• and
• c) displacing the third displaceable group with a primary or secondary alkyl or aromatic amine (ii) under microwave conditions with concomitant loss of the p-methoxybenzyl group to give a 4,6-diamino-(2-hydroxy)-[1,3,5]triazine.

A method of preparing the compounds of Formulae II and IV, comprising the steps of:

• a) displacing one of three displaceable groups at the 2-, 4- and 6-positions, respectively, of a 1,3,5-triazine ring with 4-methoxybenzyl alcohol to give a 2-(4-methoxybenzyloxy)-[1,3,5]triazine;
• b) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (i) to give a 4-amino-2-(4-methoxybenzyloxy)-[1,3,5]triazine;
• c) displacing the third displaceable group with a primary or secondary alkyl or aromatic amine (ii) under microwave conditions with concomitant loss of the p-methoxybenzyl group to give a 4,6-diamino-(2-hydroxy)-[1,3,5]triazine;
• and
• d) adding an acylating, sulfonylating or phosphorylating agent to the 4,6-diamino-(2-hydroxy)-[1,3,5]triazine to give a 4,6-diamino-(2-O-acyl)-[1,3,5]triazine, a 4,6-diamino-(2-O-sulfonyl)-[1,3,5]triazine or a 4,6-diamino-(2-O-phosphoryl)-[1,3,5]triazine, respectively.

A method of preparing the compounds of Formulae I and III where R is —OH, comprising the steps of:

• aa) displacing one of three displaceable groups at the 2-, 4- and 6-positions, respectively, of a 1,3,5-triazine ring with a primary or secondary alkyl or aromatic amine (i) to give a 2-amino-[1,3,5]triazine;
• bb) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (ii) to give a 2,4-diamino-[1,3,5]triazine;
• and
• cc) displacing the third displaceable group with water under acidic conditions to give a 4,6-diamino-(2-hydroxy)-[1,3,5]triazine.

A method of preparing the compounds of Formulae I and III where R is —NHOH, comprising the steps of:

• aa) displacing one of three displaceable groups at the 2-, 4- and 6-positions, respectively, of a 1,3,5-triazine ring with a primary or secondary alkyl or aromatic amine (i) to give a 2-amino-[1,3,5]triazine;
• bb) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (ii) to give a 2,4-diamino-[1,3,5]triazine;
• and
• cc) displacing the third displaceable group with hydroxylamine under acidic conditions to give a 4,6-diamino-([1,3,5]triazin-2-yl)-hydroxylamine.

A method of preparing the compounds of Formulae II and IV, comprising the steps of:

• aa) displacing one of three displaceable groups at the 2-, 4- and 6-positions, respectively, of a 1,3,5-triazine ring with a primary or secondary alkyl or aromatic amine (i) to give a 2-amino-[1,3,5]triazine;
• bb) displacing the second displaceable group with a primary or secondary alkyl or aromatic amine (ii) to give a 2,4-diamino-[1,3,5]triazine;
• cc) displacing the third displaceable group with water under acidic conditions to give a 4,6-diamino-(2-hydroxy)-[1,3,5]triazine;
• and
• dd) adding an acylating, sulfonylating or phosphorylating agent to the 4,6-diamino-(2-hydroxy)-[1,3,5]triazine to give a 4,6-diamino-(2-O-acyl)-[1,3,5]triazine, a 4,6-diamino-(2-O-sulfonyl)-[1,3,5]triazine or a 4,6-diamino-(2-O-phosphoryl)-[1,3,5]triazine, respectively.