CD16A binding agents and uses thereof
Among other things, the present disclosure provides compounds, compositions thereof, and methods of using the same. In some embodiments, compounds of the present disclosure bind to Fc receptors, e.g., CD16a. In some embodiments, compounds of the present disclosure are useful for treating various conditions, disorders or diseases including cancer.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl;
Ring B is
Ring C is
where Ring C can be bonded to another, independently selected Ring C;
L 1 is a covalent bond, —CH 2 —, —CH(R)—, or —C(R) 2 —;
L 2 is a covalent bond, —NHC(O)—, —C(O)NH—, —CH 2 —, —CH(R)—, —C(R) 2 —, —C(O)—, or —S(O) 2 —;
L 3 is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C 1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,
or
wherein:
each -Cy- is independently
mAb is a monoclonal antibody selected from adalimumab, cetuximab, daratumumab, or rituximab;
each R is independently hydrogen or an optionally substituted C 1-6 aliphatic;
each instance of R 1 is independently hydrogen, halogen, —CN, —NO 2 , —C(O)R, —C(O)OR, —C(O)N(R) 2 , —N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRC(O)OR, —NRS(O) 2 R, —NRS(O) 2 N(R) 2 , —OR, —P(O)(R) 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)(NH)R, —S(O) 2 N(R) 2 , or R;
each instance of R 2 is independently halogen, —CN, —NO 2 , or C 1-3 aliphatic;
R 3 is H, halogen, —CN, —CF 3 , —OR, or R;
m is 0, 1, 2, 3, 4, or 5;
each instance of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
p is 0, 1, or 2;
q is 0, 1, 2, 3, or 4;
r is 1; and
s is 1.
2. The compound of claim 1 of formula I-a or I-b:
3. The compound of claim 1 , wherein Ring A is selected from phenyl or 2, 5-dimethoxy-phenyl.
4. The compound of claim 1 , wherein Ring B is
5. The compound of claim 1 , wherein L 1 is a covalent bond or —CH 2 .
6. The compound of claim 1 , wherein L 2 is a covalent bond, —NHC(O)—, —C(O)NH—, —CH 2 —, —CH(R)—, —C(O)—, or —S(O) 2 —.
7. The compound of claim 1 , wherein L 3 is a bivalent, saturated or unsaturated, straight or branched C 1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,
or
8. The compound of claim 1 , wherein m is 0, 1, 2, 3, or 4.
9. The compound of claim 1 , wherein p is 0 or 1.
10. The compound of claim 1 , wherein q is 0, 1, 2, or 3.
11. The compound of claim 2 , wherein the compound is of formula I-a:
12. The compound of claim 2 , wherein the compound is of formula I-b:
13. The compound of claim 12 , wherein Ring C
where Ring C is bonded to another Ring C.
14. The compound of claim 12 , wherein L 2 is a covalent bond, —NHC(O)—, —C(O)NH—, —CH 2 —, —CH(R)—, —C(O)—, or —S(O) 2 —.
15. A compound selected from,
I-43
I-44
I-45
I-46
I-47
I-48
I-49
I-50
I-51
I-52
I-53
I-54
I-55
I-56
I-57
I-58
I-59
I-60
I-61
I-98
I-99
I-100
16. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.