DHFR ENZYME INHIBITORS

摘要

Compounds of formula (1) or (II) are dihydrofolate reductase inhibitors, useful for the treatment of, for example, cell proliferative diseases: wherein A and D are independently -CHR<SUB>7</SUB>- or -NR<SUB>7</SUB>-; E and G are independently =CR<SUB>7</SUB>- or =N-; each R<SUB>6</SUB> independently represents hydrogen or - OR<SUB>7</SUB>; R<SUB>7</SUB> is hydrogen or C<SUB>1</SUB>C<SUB>6</SUB> alkyl; R<SUB>1</SUB> is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group; R<SUB>2</SUB> is the side chain of a natural or non-natural alpha amino acid which does not contain a carboxyl, or carboxyl ester group; Y is a bond, -C(=O)-, -S(=O)<SUB>2</SUB>-, -C(=O)NR<SUB>3</SUB>-, -C(=S)-NR<SUB>3</SUB>, -C(=NH)NR<SUB>3</SUB> or -S(=O)2NR<SUB>3</SUB>- wherein R<SUB>3</SUB> is hydrogen or optionally substituted C<SUB>1</SUB>-C<SUB>6</SUB> alkyl; L<SUP>1</SUP> is a divalent radical of formula -(Alk<SUP>1</SUP>)<SUB>m</SUB>(Q)<SUB>n</SUB>(Alk<SUP>2</SUP>)<SUB>p</SUB>- wherein m, n and p are independently 0 or 1, and Q, AIk<SUP>1</SUP> and AIk<SUP>2</SUP> are as defined in the claims; X<SUP>1</SUP> represents a bond; -C(=O); or -S(=O)<SUB>2</SUB>-; - NR<SUB>4</SUB>C(=O) -C(=O)NR<SUB>4</SUB>-,-NR<SUB>4</SUB>C(=O)NR<SUB>5</SUB>-, -NR<SUB>4</SUB>S(=O)2-, or -S(=O)2NR<SUB>4</SUB>- wherein R<SUB>4</SUB> and R<SUB>5</SUB> are independently hydrogen or optionally substituted C<SUB>1</SUB>C<SUB>6</SUB> alkyl; and z is 0 or 1.