IRAK degraders and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same.
1 . A method of treating an IRAK4-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I-a-5:
or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein:
each R x is independently hydrogen, R z , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —CFR 2 , —CF 2 R, —CF 3 , —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O)OR, —C(O) NR 2 , —C(S)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O) NR 2 , —N(R)S(O) 2 R, —N + (O − )R 2 , —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 , —P(O)R 2 , —SiR 3 , —Si(OR)R 2 , or
or
two R x groups are optionally taken together to form an optionally substituted 5-6 membered partially unsaturated or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the carbon or nitrogen, independently selected from nitrogen, oxygen, and sulfur;
each R y is independently hydrogen, R z , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —CF 2 R, —CF 3 , —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O) OR, —C(O) NR 2 , —C(S)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, —OP(O)R 2 , —OP(O)(OR) 2 , —OP(O)(OR)NR 2 , —OP(O)(NR 2 ) 2 , —SiR 3 , —SF 5 , or
each R z is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
Ring T is selected from phenyl or a 5-10 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Ring T is further optionally substituted with 1-2 oxo groups;
x is 0, 1, 2, or 3;
y is 0, 1, 2, 3 or 4;
L 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—, —N(R)—, —Si(R) 2 —, —Si(OH)(R)—, —Si(OH) 2 —, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR 2 )—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—
each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-12 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-12 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
LBM is an IMiD-based cereblon E3 ubiquitin ligase binding moiety selected from:
(i)
or a pharmaceutically acceptable salt thereof, wherein:
Y is a bond;
X 1 -X 2 is C(H)═N or C(C 1 -C 4 alkyl)═N;
each R 1 is independently hydrogen, halogen, —NH 2 , —OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 3 is hydrogen;
two R 4 , together with the carbon atom to which they are attached, form C(O);
R 5 is hydrogen or C 1 -C 3 alkyl;
t is 1;
m is 0, 1, 2 or 3; and
n is 0; and
(ii)
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is —C(O)—;
X 2 is —C(O)—;
X 3 is —CH 2 — or —C(O)—;
R 1 is hydrogen or C 1-4 aliphatic;
each of R 2 is independently hydrogen, halogen, C 1-4 aliphatic or —OC 1-4 aliphatic;
Ring A is a fused 6-membered aryl containing 0-1 nitrogen atoms; and
m is 0, 1, 2, or 3,
wherein the IRAK4-mediated disorder, disease or condition is lymphoma, leukemia, myeloma, or a MyD88 driven disorder.
2 . The method of claim 1 , further comprising administration of an additional therapeutic agent, wherein the additional therapeutic agent is rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone or prednisolone, bortezomib, dexamethasone, chlorambucil, fludarabine, cladribine, a hedgehog signaling inhibitor, a BCL2 inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, or combinations thereof.
3 . The method of claim 1 , wherein the lymphoma, leukemia, or myeloma is selected from multiple myeloma, Hodgkin's or Non-Hodgkin's lymphoma, smoldering or indolent multiple myeloma, 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, and intravascular large B-cell lymphoma.
4 . The method of claim 1 , wherein the MyD88 driven disorder is selected from ABC DLBCL, Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.
5 . The method of claim 1 , wherein said compound is selected from either of the following formulae:
or a pharmaceutically acceptable salt thereof.
6 . The method of claim 1 , wherein said compound is selected from either of the following formulae:
or a pharmaceutically acceptable salt thereof.
7 . The method of claim 1 , wherein Ring T is selected from phenyl or a 5-9 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
8 . The method of claim 1 , wherein Ring T is
9 . The method of claim 1 , wherein R y is hydrogen, C 1-6 aliphatic, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —CFR 2 , —CF 2 R, —CF 3 , —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O) OR, —C(O) NR 2 , —C(S) NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R.
10 . The method of claim 1 , wherein R y is —CF 3 , —CF 2 Me, —CFMe 2 , —Me, —OCF 3 , fluoro,
11 . The method of claim 1 , wherein R x is hydrogen, C 1-6 aliphatic, halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —CFR 2 , —CF 2 R, —CF 3 , —CR 2 (OR), —CR 2 (NR 2 ), —C(O)R, —C(O)OR, —C(O)NR 2 , —C(S)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R.
12 . The method of claim 1 , wherein R x is
—CF 2 H, —CF 3 , —OMe, —Me, —OCF 2 H, —OCF 3 ,
13 . The method of claim 1 , wherein R x is
or —OMe.
14 . The method of claim 1 , wherein x is 1 or 2 and y is 1, 2, or 3.
15 . The method of claim 1 , wherein Ring A of formula I-ccc-1 is benzo.
16 . The method of claim 1 , wherein m is 0 or 1.
17 . The method of claim 1 , wherein R 1 is hydrogen.
18 . The method of claim 1 , wherein L is a bivalent, saturated or unsaturated, straight or branched C 1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —N(R)—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O) 2 —, —N(R)S(O) 2 —, —S(O) 2 N (R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, or —N(R)C(O)O—.
19 . The method of claim 1 , wherein -Cy- is
20 . The method of claim 1 , wherein said compound is selected from any one of the compounds depicted below:
or a pharmaceutically acceptable salt thereof.