Bicyclic peptide ligands and uses thereof

A method of treating a CAIX-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• each of L1, L2, and L3 is independently a covalent bond or a C1-8 bivalent hydrocarbon chain wherein one, two or three methylene units of the chain are optionally and independently replaced by —S—, —N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, —N(R)C(O)—, —S(O)—, —S(O)2— or —N(R)CH2C(0)—;
• each R is independently hydrogen or C1-4 alkyl;
• Scaffold is a trivalent group that connects and orients a cyclic peptide;
• Loop A is
• and Loop B is
• indicates the site of attachment to the N-terminus of the Bicycle;
• indicates the site of attachment to the C-terminus of the Bicycle;
• Peptide1 is hydrogen, or a natural or unnatural amino acid wherein the acid is connected to the N-terminus of the Bicycle via an amide bond;
• Peptide2 is —OH, —NH2, or a natural or unnatural amino acid wherein the amino group is connected to the C-terminus of the Bicycle via an amide bond;
• each of R1 and R2 is independently
• each of R4 is independently hydrogen or C1-4 aliphatic;
• each of n is independently 0 or 1;
• and
• wherein a value of n=0 for R1 results in a terminal amine, —NH2, and a value of n=0 for R2 results in a terminal carboxamide, —C(O)NH2, or a pharmaceutical composition thereof.

A method of treating an MT1-MMP-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I:

• or a pharmaceutically acceptable salt thereof, wherein:
• each of L′, L2, and L3 is independently a covalent bond or a C1-8 bivalent hydrocarbon chain wherein one, two or three methylene units of the chain are optionally and independently replaced by —S—, —N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, —N(R)C(O)—, —S(O)—, —S(O)2—or —N(R)CH2C(O)—each R is independently hydrogen or C1-4 alkyl;
• Scaffold is a trivalent group that connects and orients a cyclic peptide;
• Loop A is
• and Loop B is
• indicates the site of attachment tothe N-terminus of the Bicycle;
• indicates the site of attachment tothe C-terminus of the Bicycle;
• Peptide1 is hydrogen, ora natural or unnatural amino acid wherein the acid is connected to the N-terminus of the Bicycle via an amide bond;
• Peptide2 is —OH, —NH2, or a natural or unnatural amino acid wherein the amino group is connected to the
• C-terminus of the Bicycle via an amide bond;
• each of R1 and R2 is independently each of R4 is independently hydrogen or C1-4 aliphatici each of n is independently 0 or 1L and wherein a value of n=0 for fil results in a terminal amine, —NH2, and a value of n=0 for R2 results in a terminal carboxamide, —C(O)NH2, or a pharmaceutical composition thereof.