αv-integrin targeted small molecule drug conjugates

A chemical compound, comprising the following Markush structure:

• A-L1-PEG1-L2-PEG2-CL-X
• wherein A-L1-PEG1 is a targeting structure configured for targeting αv integrins in cancer cells and does not include a standard multivalent nitrogen moiety;
• wherein A is a structure that includes a standard carboxylic acid moiety;
• wherein L1 is a first linking structure selected from the group consisting of
• and NULL;
• wherein PEG1 is the following polyethylene glycol structure, wherein n2 is in a range of 5-72:
• wherein L2 is the following second linker structure, wherein n3 is in a range of 0-4:
• wherein PEG2 is the following polyethylene glycol repeating structure, wherein n4 is in a range of 0-67 and n2+n4 is in a range of 20-72:
• wherein CL is a cleavable linker;
• and
• wherein X is either Chemo1 or L3-Chemo2, wherein Chemo1 denotes a first chemotherapy, wherein Chemo2 denotes a second chemotherapy, and wherein L3 is the following linker that links Chemo2 to CL:
• wherein
• and
• wherein Ar is selected from the group consisting of
• wherein R5-R11 are each independently selected from the group consisting of:
• H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12n-alkyl, cyclopentyl, phenyl, F, Cl, Br, —CN, —CF3, —OCF3, —CHF2, —OCHF2, —SO2Me, —O-Alkyl, and -3,5-dimethyl-1-pyrazolyl;
• wherein Alkyl is selected from the group consisting of:
• Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12 n-alkyl, cyclopentyl, and cyclohexyl;
• and
• wherein Me denotes Methyl, Et denotes Ethyl, Pr denotes Propyl, and Bu denotes Butyl.

A chemical compound, comprising the following Markush structure:

• A-L1-PEG1-L2-PEG2-CL-X
• wherein A-L1-PEG1 is a targeting structure configured for targeting αv integrins in cancer cells and does not include a standard multivalent nitrogen moiety;
• wherein A is a structure that includes a standard carboxylic acid moiety;
• wherein L1 is a first linking structure selected from the group consisting of
• and NULL;
• wherein PEG1 is the following polyethylene glycol structure, wherein n2 is in a range of 5-72:
• wherein L2 is the following second linker structure, wherein n3 is in a range of 0-4:
• wherein PEG2 is the following polyethylene glycol repeating structure, wherein 114 is in a range of 0-67 and n2+n4 is in a range of 20-72:
• wherein CL is a cleavable linker;
• and
• wherein X is either Chemo1 or L3-Chemo2, wherein Chemo1 denotes a first chemotherapy, wherein Chemo2 denotes a second chemotherapy, and wherein L3 is the following linker that links Chemo2 to CL:
• wherein
• and
• wherein R4 is selected from the group consisting of hydrogen, Alkyl, and Ar;
• wherein Alkyl is selected from the group consisting of Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12 n-alkyl, cyclopentyl, and cyclohexyl;
• wherein Ar is selected from the group consisting of
• wherein R5-R11 are each independently selected from the group consisting of:
• H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12n-alkyl, cyclopentyl, phenyl, F, Cl, Br, —CN, —CF3, —OCF3, —CHF2, —OCHF2, —SO2Me, —O-Alkyl, and -3,5-dimethyl-1-pyrazolyl;
• wherein Alkyl is selected from the group consisting of:
• Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12 n-alkyl, cyclopentyl, and cyclohexyl;
• and
• wherein Me denotes Methyl, Et denotes Ethyl, Pr denotes Propyl, and Bu denotes Butyl.

A chemical compound, comprising the following Markush structure:

• A-L1-PEG1-N3
• wherein A-L1-PEG1 is a targeting structure configured for targeting αv integrins in cancer cells and does not include a standard multivalent nitrogen moiety;
• wherein A is a structure that includes a standard carboxylic acid moiety;
• wherein L1 is a first linking structure selected from the group consisting of;
• and
• wherein PEG1 is the following polyethylene glycol structure, wherein n2 is in a range of 5-72:
• wherein
• wherein n1 is in a range of 1-6;
• wherein Ar is selected from the group consisting of:
• wherein R5-R11 are each independently selected from the group consisting of:
• H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12 n-alkyl, cyclopentyl, phenyl, F, Cl, Br, —CN, —CF3, —OCF3, —CHF2, —OCHF2, —SO2Me, —O-Alkyl, and -3,5-dimethyl-1-pyrazolyl,
• wherein Alkyl is selected from the group consisting of:
• Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12 n-alkyl, cyclopentyl, and cyclohexyl;
• and wherein Me denotes Methyl, Et denotes Ethyl, Pr denotes Propyl, and Bu denotes Butyl.

A chemical compound, comprising the following Markush structure:

• A-L1-PEG1-OMethyl
• wherein A-L1-PEG1 is a targeting structure configured for targeting αv integrins in cancer cells and does not include a standard multivalent nitrogen moiety;
• wherein A is a structure that includes a standard carboxylic acid moiety;
• wherein L1 is a first linking structure selected from the group consisting of
• and NULL;
• wherein PEG1 is the following polyethylene glycol structure, wherein n2 is in a range of 5-72:
• wherein
• wherein n1 is in a range of 1-6:
• wherein Ar is selected from the group consisting of
• wherein R5-R11 are each independently selected from the group consisting of:
• H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12n-alkyl, cyclopentyl, phenyl, F, Cl, Br, —CN, —CF3, —OCF3, —CHF2, —OCHF2, —SO2Me, —O-Alkyl, and -3,5-dimethyl-1-pyrazolyl;
• and
• wherein Alkyl is selected from the group consisting of:
• Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12 n-alkyl, cyclopentyl, and cyclohexyl;
• wherein Me denotes Methyl, Et denotes Ethyl, Pr denotes Propyl, and Bu denotes Butyl.

A method for treating cancer in a mammal, said method comprising:

• administering a therapeutically effective amount of a chemical compound to the mammal;
• wherein αv integrins are overexpressed in tumors comprising cancer cells of the cancer in the mammal;
• said chemical compound comprising the following Markush structure:
• A-L1-PEG1-L2-PEG2-CL-X
• wherein A-L1-PEG1 is a targeting structure configured for targeting the αv integrins in cancer cells and does not include a standard multivalent nitrogen moiety;
• wherein A is a structure that includes a standard carboxylic acid moiety;
• wherein
• wherein n1 is in a range of 1-6;
• wherein Ar is selected from the group consisting of
• wherein R5-R11 are each independently selected from the group consisting of:
• H, Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12n-alkyl, cyclopentyl, phenyl, F, Cl, Br, —CN, —CF3, —OCF3, —CHF2, —OCHF2, —SO2Me, —O-Alkyl, and -3,5-dimethyl-1-pyrazolyl;
• wherein Alkyl is selected from the group consisting of:
• Me, Et, iPr, nPr, nBu, iBu, secBu, tBu, C5-C12 n-alkyl, cyclopentyl, and cyclohexyl;
• wherein Me denotes Methyl, Et denotes Ethyl, Pr denotes Propyl, and Bu denotes Butyl;
• wherein L1 is a first linking structure selected from the group consisting of
• wherein PEG1 is the following polyethylene glycol structure, wherein n2 is in a range of 5-72:
• wherein L2 is the following second linker structure, wherein n3 is in a range of 0-4:
• wherein PEG2 is the following polyethylene glycol repeating structure, wherein n4 is in a range of 0-67 and n2+n4 is in a range of 20-72:
• Wherein CL is a cleavable linker;
• and
• wherein X is either Chemo1 or L3-Chemo2, wherein Chemo1 denotes a first chemotherapy, wherein Chemo2 denotes a second chemotherapy, and wherein L3 is the following linker that links Chemo2 to CL: