US 12,150,995 B2
IRAK degraders and uses thereof
Nello Mainolfi, Belmont, MA (US); Nan Ji, Arlington, MA (US); Matthew M. Weiss, Boston, MA (US); Xiaozhang Zheng, Lexington, MA (US); Yi Zhang, Belmont, MA (US); Paul R. Fleming, Lexington, MA (US); and Xiao Zhu, Winchester, MA (US)
Assigned to Kymera Therapeutics, Inc., Watertown, MA (US)
Filed by Kymera Therapeutics, Inc., Watertown, MA (US)
Filed on Dec. 30, 2021, as Appl. No. 17/646,556.
Claims priority of provisional application 63/132,332, filed on Dec. 30, 2020.
Prior Publication US 2023/0101353 A1, Mar. 30, 2023
Int. Cl. A61K 47/55 (2017.01); A61K 47/54 (2017.01)
CPC A61K 47/55 (2017.08) [A61K 47/545 (2017.08)] 15 Claims
 
1. A compound of formula I-d-5:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
each Rx is independently —OC1-6 aliphatic or —CR2(OR);
each R is independently hydrogen or C1-6 aliphatic;
each Ry is independently Rz, fluoro, chloro, —CN, or —OR;
each Rz is a C1-6 aliphatic optionally substituted with one or more fluoro;
Ring T is selected from phenyl or a 5-9 membered mono- 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;
Lx is —C(O)N(H)—, wherein either the carbon or nitrogen atom of —C(O)N(H)— is attached to Ring T;
X is a covalent bond

OG Complex Work Unit Chemistry
x is 0 or 1;
y is 0, 1, or 2;
L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-30 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —CRF—, —CF2—, —O—, —N(R)—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —N(R)S(O)2—, —S(O)2N(R)—, —N(R)C(O)—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)C(O)O—, wherein
each -Cy- is independently an optionally substituted bivalent ring selected from a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-11 membered saturated or partially unsaturated spiro carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and
DIM is a degradation inducing moiety selected from a cereblon E3 ubiquitin ligase binding moiety of formula I-ccc-1:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
X1 is —C(O)—;
X2a is —C(O)—;
X3a is —CH2— or —C(O)—;
R1 is hydrogen;
each of R2 is independently fluoro, chloro, C1-4 aliphatic, or —OC1-4 aliphatic;
Ring Aa is a fused 6-membered aryl containing 0-1 nitrogen atoms; and
m is 0, or 1.