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

A compound of the formula Ia:

• LAa—Ww—Yy—D)p Ia;
• or a pharmaceutically acceptable salt thereof,
• wherein,
• L— is a Ligand unit;
• —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 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 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);
• A 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, —C1-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.

A compound of the formula:

• or a pharmaceutically acceptable salt thereof;
• wherein, independently at each location:
• R2 is selected from the group consisting of —H and —C1-C8 alkyl;
• R3 is selected from the group consisting of —H, —C1-C8 alkyl, —C3-C8 carbocycle, —O—(C1-C8 alkoxy), -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 alkoxy), -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 alkoxy), -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 alkoxy);
• R9 is selected from the group consisting of —H and —C1-C8 alkyl;
• 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 carbocyle, —O—(C1-C8 alkoxy), -aryl, —C1-C8-alkyl-aryl, —C1-C8 alkyl-(C3-C8 carbocycle), —C3-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle);
• each R14 is independently —H or —C1-C8 alkyl;
• R16 is A′a-Ww-Yy-
• 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;
• —A′ is a Stretcher unit;
• and
• a is 1.

A composition comprising drug-linker-ligand conjugates having Formula Ia:

• LAa—Ww—Yy—D)p Ia
• or a pharmaceutically acceptable sail thereof;
• wherein,
• L— is a Ligand unit;
• —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 5 and is the average number of —Aa—Ww—Yy—D units per ligand in the composition;
• 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 selected from the group consisting of —H and —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, —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 independently —H or —C1-C8 alkyl.

A composition comprising drug-linker-ligand conjugates having Formula Ia:

• LAa—Ww—Yy—D)p Ia;
• or a pharmaceutically acceptable salt thereof
• wherein,
• L— is a Ligand unit;
• —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 5 and is the average number of —Aa—Ww—Yy—D units per ligand in the composition;
• 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 —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, —C2-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), —C1-C8 heterocycle and —C1-C8 alkyl-(C3-C8 heterocycle) when n is 1.