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 method of treating a patient having a lymphoma, comprising administering to said patient a compound according to formula I: cells would be therapeutically beneficial in a
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl;
Ring B is
or
Ring C is where Ring
where Ring C can be bonded to another 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—,
wherein:
each -Cy- is independently is
mAb is a monoclonal antibody selected from; adalimumab, cetuximab, daratumumab, rituximab;
each R is independently hydrogen or an optionally substituted group selected from 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 hydrogen, halogen, —CN, —NO 2 , or C 1-3 aliphatic;
m is 0, 1, 2, 3, 4 or 5;
each instance of n is independently selected from 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.
2. The method of claim 1 , wherein the lymphoma is Hodgkins lymphoma, Non-Hodgkins lymphoma, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, or intravascular large B-cell lymphoma.
3. The method of claim 1 , where the compound of formula I is a compound of formula I-a or I-b:
4. The method of claim 1 , wherein Ring A is selected from phenyl or 2,5-dimethyoxy-phenyl.
5. The method of claim 1 , wherein
Ring B is
6. The method of claim 1 , wherein
L 1 is a covalent bond or —CH 2 —;
L 2 is a covalent bond, —NHC (O)—, —C(O)NH—, —CH 2 —, —CH (R)—, —C(O)—, or —S(O) 2 —; and
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—
7. The method of claim 1 , wherein m is 0, 1, 2, 3, or 4;
p is 0 or 1; and
q is 0, 1, 2, or 3.
8. The method of claim 3 , wherein the compound is of formula I-a:
9. The method of claim 3 , wherein
10. The method of claim 1 , wherein Ring C is
where Ring C is bonded to another Ring.
11. Selected The method of claim 1 , wherein the compound is a compound selected from