Bicyclic peptide ligands and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
each of L 1 , L 2 , and L 3 is independently a covalent bond or a C 1-8 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)CH 2 C(O)—;
each R is independently hydrogen or C 1-4 alkyl;
Scaffold is selected from the group consisting of
Loop A
and Loop B is
or
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;
Peptide 1 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;
Peptide 2 is —OH, —NH 2 , 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 R 1 and R 2 is independently
each of R 4 is independently hydrogen, C 1-4 aliphatic, and
each of n is independently 0 or 1, and
wherein a value of n=0 for R′ results in a terminal amine, —NH 2 , and a value of n=0 for R 2 results in a terminal carboxamide, —C(O)NH 2 .
2. The compound of claim 1 , wherein each of L 1 , L 2 , and L 3 is a C 1-8 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)CH 2 C(O)—.
3. The compound of claim 1 , wherein R is hydrogen.
4. The compound of claim 1 , wherein Peptide 1 is a natural or unnatural amino acid wherein the acid is connected to the N-terminus of the Bicycle via an amide bond.
5. The compound of claim 1 , wherein Peptide 2 is —OH or —NH 2 .
6. The compound of claim 1 , wherein n=0 for R 2 .
7. The compound of claim 1 , wherein the compound is selected from:
I-1
I-2
I-3
I-4
I-5
I-6
I-7
I-8
I-9
I-10
I-11
I-12
I-13
I-14
I-15
I-16
I-17
I-18
I-19
I-20
I-21
I-22
I-23
I-24
I-25
I-26
I-27
I-28
I-29
I-30
I-31
I-32
I-33
I-34
I-52
I-53
I-54
I-55
I-56
I-57
I-58
I-59
I-60
I-61
I-62
I-63
I-64.
8. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
9. The compound of claim 1 , wherein Loop A is
and Loop B is
10. The compound of claim 9 , wherein Scaffold is
11. The compound of claim 9 , wherein Scaffold is
12. The compound of claim 9 , wherein Scaffold is
13. The compound of claim 10 , wherein R 1 is
14. The compound of claim 13 , wherein n=0 for R 2 .
15. The compound of claim 1 , wherein Loop A is
and Loop B is
16. The compound of claim 15 , wherein Scaffold is
17. The compound of claim 15 , wherein Scaffold is
18. The compound of claim 15 , wherein Scaffold is
19. The compound of claim 16 , wherein R 1 is
20. The compound of claim 19 , wherein n=0 for R 2 .