Bicyclic peptide ligands with detectable moieties and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same.
1. A compound of formula I which selectively binding to Eph receptor tyrosine kinase A2 (EphA2):
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 of R is independently hydrogen or C 1-4 alkyl;
each of m, n, o, and p is independently 0 or 1, wherein at least one of n and p is 1;
each of q and r is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;
R 1 is R or —C(O)R;
each of R 4 and R 6 is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each of R 4′ and R 6′ is independently hydrogen or methyl;
each of R 2 , R 3 , R 5 , and R 7 is independently hydrogen, or C 1-4 aliphatic, or:
an R 5 group and its adjacent R 4 group are optionally taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
an R 7 group and its adjacent R 6 group are optionally taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Scaffold is a trivalent group that connects and orients a cyclic peptide;
Loop A is
and Loop B is
or
Loop A is
and Loop B is
or
Loop A is
and Loop B is
or
Loop A is
and Loop B is
or
Loop A is
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;
Detectable Moiety 1 is any moiety capable of being detected;
Detectable Moiety 2 is any moiety capable of being detected;
Linker 1 is hydrogen, —C(O)R,
or a bivalent moiety that connects the N-terminus of the Bicycle with Detectable Moiety 1 , wherein when n is 0, Linker 1 is hydrogen, —C(O)R, or
Linker 2 is —NH 2 or a bivalent moiety that connects the C-terminus of the Bicycle with Detectable Moiety 2 , wherein when p is 0, Linker 2 is —NH 2 .
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, 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 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or —C(O)CH 3 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Linker 1 is a covalent bond,
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 0 and Linker 2 is —NH 2 .
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Scaffold is
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Detectable Moiety 1 is
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Detectable Moiety 1 is
wherein M is selected from the group consisting of 67 Ga, 68 Ga, 111 In, 177 Lu, 86 Y, 90 Y, 89 Zr, and 95 Zr.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Detectable Moiety 1 is a fluorophore selected from the group consisting of Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, Alexa Fluor 680, AMCA, AMCA-S, BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665, Carboxyrhodamine 6G, carboxy-X-rhodamine, Cascade Blue, Cascade Yellow, Coumarin 343, Cy3, Cy5, Cy3.5, Cy5.5, Cy7, Cy7.5, Dansyl, Dapoxyl, Dialkylaminocoumarin, 4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, IRD40, IRD 700, IRD 800, JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine, Carboxytetramethylrhodamine, Texas Red, and Texas Red-X.
10. A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
11. A method of treating an EphA2-mediated disorder, disease, or condition in a patient comprising administering to said patient the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Loop A is
and Loop B is
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Loop A is
and Loop B is
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Loop A is
and Loop B is
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Loop A is
and Loop B is
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Loop A is
and Loop B is
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Loop A is
and Loop B is
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Linker 2 is
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Detectable Moiety 2 is
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Detectable Moiety 2 is
wherein M is selected from the group consisting of 67 Ga, 68 Ga, 177 Lu, 86 Y, 90 Y, 89 Zr, and 95 Zr.
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Detectable Moiety is a fluorophore selected from the group consisting of Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, Alexa Fluor 680, AMCA, AMCA-S, BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665, Carboxyrhodamine 6G, carboxy-X-rhodamine, Cascade Blue, Cascade Yellow, Coumarin 343, Cy3, Cy5, Cy3.5, Cy5.5, Cy7, Cy7.5, Dansyl, Dapoxyl, Dialkylaminocoumarin, 4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, IRD40, IRD 700, IRD 800, JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine, Carboxytetramethylrhodamine, Texas Red, and Texas Red-X.
22. The compound of claim 1 , which is selected from:
or a pharmaceutically acceptable salt thereof.