METAP2 inhibitors and methods of treating obesity

A method for improving or restoring leptin sensitivity in a subject in need thereof comprising administering at least one compound, or a pharmaceutically acceptable salt, thereof, of the Formula

• wherein, independently for each occurrence,
• R4 is H or C1-C6 alkyl;
• R5 is H or C1-C6 alkyl;
• R6 is C2-C6 hydroxyalkyl;
• Z is —NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or —NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X—Y—C(O)—W;
• AA1 is glycine, alanine, or H2N(CH2)mCO2H, wherein m is 2, 3, 4 or 5;
• AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;
• AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;
• AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;
• AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine;
• AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2)mCO2H, wherein m is 2, 3, 4 or 5;
• L is —OH, —O-succinimide, —O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, —NH2, —NH(C2-C6 hydroxyalkyl), halide or perfluoroalkyloxy;
• Q is NR, O, or S;
• X is M-(C(R)2)p-M-J-M-(C(R)2)p-M-V;
• M is a bond, or C(O);
• J is a bond, or ((CH2)qQ)r, C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S;
• Y is NR, O, or S;
• R is H or alkyl;
• V is a bond or
• R9 is alkyl, aryl, aralkyl, or a bond;
• or R9 taken together with Y forms a heterocyclic ring;
• R10 is amido or a bond;
• R11 is H or alkyl;
• W is a methionine aminopeptidase-2 inhibitor moiety or alkyl;
• x is in the range of 1 to about 450;
• y is in the range of 1 to about 30;
• n is in the range of 1 to about 50;
• p is 0 to 20;
• q is 2 or 3;
• and
• r is 1, 2, 3, 4, 5, or 6;
• in a therapeutically effective amount to the subject.