Drug conjugates and their use for treating cancer, an autoimmune disease or an infectious disease

A compound of the formula Ia:

• or a pharmaceutically acceptable salt thereof,
• wherein,
• L- is an antibody that binds to an antigen expressed on an activated human lymphocyte, wherein the activated human lymphocyte is associated with an autoimmune disease;
• -A- is a Stretcher unit;
• a is 1;
• each —W— is independently an Amino Acid unit;
• —Y— is a Spacer unit;
• w is an integer ranging from 2 to 12;
• y is 1 or 2;
• p ranges from 1 to about 20;
• and
• -D is a Drug unit having the structure:
• the wavy line indicates the point of attachment to the Spacer unit, and independently at each location:
• R2 is selected from the group consisting of —H and -methyl;
• R3 is selected from the group consisting of —H, -methyl, and -isopropyl;
• R4 is selected from the group consisting of —H and -methyl;
• R5 is selected from the group consisting of -isopropyl, -isobutyl, -sec-butyl, -methyl and -t-butyl or R4 and R5 join and form a ring with the carbon atom to which they are attached and R4 and R5 have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from the group consisting of —H, —C1-C8 alkyl, and —C3-C8 carbocycle, and n is selected from the group consisting of 2, 3, 4, 5 and 6;
• R6 is selected from the group consisting of —H and -methyl;
• each R8 is independently selected from the group consisting of —OH, -methoxy and -ethoxy;
• R10 is selected from the group consisting of:
• R24 is selected from the group consisting of H and —C(O)R25—;
• R25 is selected from the group consisting of —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
• Z is —O—, —NH—, —OC(O)—, —NHC(O)—, or —NR28C(O)—;
• R28 is selected from the group consisting of —H and —C1-C8 alkyl;
• n is 0 or 1;
• and
• R27 is selected from the group consisting of —H, —N3, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) when n is 0;
• and R27 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) when n is 1;
• wherein upon delivery of the compound of Formula Ia into the activated human lymphocyte, the drug unit is liberated.

A method for treating an autoimmune disease, comprising administering to an animal in need thereof an effective amount of a compound of Formula Ia:

• or a pharmaceutically acceptable salt thereof,
• wherein,
• L- is an antibody that binds to an antigen expressed on an activated human lymphocyte, wherein the activated human lymphocyte is associated with an autoimmune disease;
• -A- is a Stretcher unit;
• a is 1;
• each —W— is independently an Amino Acid unit;
• —Y— is a self-immolative Spacer unit;
• w is an integer ranging from 2 to 12;
• y is 1 or 2;
• p ranges from 1 to about 20;
• and
• -D is a Drug unit of the formula:
• the wavy line indicates the point of attachment to the Spacer unit, and independently at each location:
• R2 is —C1-C8 alkyl;
• R3 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
• R4 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
• R5 is selected from the group consisting of —H and -methyl;
• or R4 and R5 join and form a ring with the carbon atom to which they are attached and R4 and R5 have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from the group consisting of —H, —C1-C8 alkyl and —C3-C8 carbocycle and n is selected from the group consisting of 2, 3, 4, 5 and 6;
• R6 is selected from the group consisting of —H and —C1-C8 alkyl;
• R7 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
• each R8 is independently selected from the group consisting of —H, —OH, —C1-C8 alkyl, —C3-C8 carbocycle and —O—(C1-C8 alkyl);
• R9 is selected from the group consisting of —H and —C1-C8 alkyl;
• R10 is selected from the group consisting of:
• Z is —O—, —S—, —NH— or —N(R14)—;
• R11 is selected from the group consisting of —H, —OH, —NH2, —NHR14, —N(R14)2, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
• or R11 is an oxygen atom which forms a carbonyl unit (C═O) with the carbon atom to which it is attached and a hydrogen atom on this carbon atom is replaced by one of the bonds in the (C═O) double bond;
• each R12 is independently selected from the group consisting of -aryl and —C3-C8 heterocycle;
• R13 is selected from the group consisting of —H, —OH, —NH2, —NHR14, —N(R14)2, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkyl), -aryl, -C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), C3-C8 heterocycle and —C1-8 alkyl-(C3-C8 heterocycle);
• and each R14 is independently —H or —C1-C8 alkyl;
• wherein upon delivery of the compound of Formula Ia into the activated human lymphocyte, the drug unit is liberated.

A method for treating an autoimmune disease, comprising administering to an animal in need thereof an effective amount of a compound of formula Ia:

• or a pharmaceutically acceptable salt thereof,
• wherein,
• L- is an antibody that binds to an antigen expressed on an activated human lymphocyte, wherein the activated human lymphocyte is associated with an autoimmune disease;
• -A- is a Stretcher unit;
• a is 1;
• each —W— is independently an Amino Acid unit;
• —Y— is a self-immolative Spacer unit;
• w is an integer ranging from 2 to 12;
• y is 1 or 2;
• p ranges from 1 to about 20;
• and
• -D is a Drug unit having the structure:
• the wavy line indicates the point of attachment to the Spacer unit, and independently at each location:
• R2 is -methyl;
• R3 is selected from the group consisting of —H, -methyl, and -isopropyl;
• R4 is selected from the group consisting of —H and -methyl;
• R5 is selected from the group consisting of -isopropyl, -isobutyl, -sec-butyl, -methyl and -t-butyl or R4 and R5 join and form a ring with the carbon atom to which they are attached and R4 and R5 have the formula —(CRaRb)n— wherein Ra and Rb are independently selected from the group consisting of —H, —C1-C8 alkyl, and —C3-C8 carbocycle, and n is selected from the group consisting of 2, 3, 4, 5 and 6;
• R6 is selected from the group consisting of —H and -methyl;
• each R8 is independently selected from the group consisting of —OH, -methoxy and -ethoxy;
• R16 is selected from the group consisting of:
• R24 is selected from the group consisting of H and —C(O)R25—;
• R25 is selected from the group consisting of —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
• Z is —O—, —NH—, —OC(O)—, —NHC(O)—, or —NR28C(O)—;
• R28 is selected from the group consisting of —H and —C1-C8 alkyl;
• n is 0 or 1;
• and
• R27 is selected from the group consisting of —H, —N3, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) when n is 0;
• and R27 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, -aryl, —C1-C8 alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) when n is 1;
• wherein upon delivery of the compound of Formula Ia into the activated human lymphocyte, the drug unit is liberated.