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US 2025/0051338 A1Published application
Tyk2 degraders and uses thereof
AssigneeKymera Therapeutics, Inc.
InventorsIsaac MARX, Christopher M. YATES, Xiao ZHU, Lewis Dale PENNINGTON, Eamon COMER, Melissa FORD
Life of this patent
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Abstract
The present invention provides compounds, compositions thereof, and methods of using the same. Compounds and compositions thereof that are useful, for example, for targeting, inhibiting, and/or degrading TYK2. In certain embodiments, provided are TYK2 inhibitors and/or degraders and methods of making same. More specifically, TYK2 degraders, compositions which comprise TYK2 degraders, and methods of treating TYK2-associated conditions are provided.
Claims158
A compound of Formula (II):
- or a pharmaceutically acceptable salt thereof, wherein
- TBM is a TYK binding moiety capable of binding to TYK2 protein;
- L is a bivalent moiety that connects TBM to ring A and wherein:
- Ring AAA is selected from:
- R100 is C1-C6 alkyl or H;
- X1 is a bivalent moiety selected from a covalent bond, —CH2—, —CHCF3—, —SO2—, —S(O)—, —P(O)R—, —
- P(O)OR—, —P(O)NR2—, —C(O)—, —C(S)—, or
- X2 is a carbon atom, a nitrogen atom, or silicon atom;
- X3 is a bivalent moiety selected from a covalent bond, —CR2—, —NR—, —O—, —S—, or —Si(R)2—;
- R1 is absent, hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R, —S(O)2R, —N(R)2, —P(O)(OR)2, —P(O)(NR2)OR, —P(O)(NR2)2, —Si(OH)2R, —Si(OH)(R)2, —Si(R)3, or an optionally substituted C1-4 aliphatic;
- each R2 is independently hydrogen, deuterium, —R6, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —Si(R)3, —S(O)2R, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)OR, —C(R)2N(R)C(O)R, —C(R)2N(R)C(O)N(R)2, —OC(O)R, —OC(O)N(R)2, —OP(O)R2, —OP(O)(OR)2, —OP(O)(OR)(NR2), —OP(O)(NR2)2—, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)N(R)2, —N(R)S(O)2R, —NP(O)R2, —N(R)P(O)(OR)2, —N(R)P(O)(OR)(NR2), —N(R)P(O)(NR2)2, or —N(R)S(O)2R,
- Ring A is selected from the group consisting of
- 6-membered aryl optionally substituted with one or more occurrences of halogen, and null,
- Ring B is a fused ring selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
- R3 is selected from hydrogen, halogen, —OR, —N(R)2, or —SR;
- each R4 is independently hydrogen, —R6, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O) 2NR2, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —OC(O)R, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR2, or —N(R)S(O)2R;
- R5 is hydrogen, C1-C4 aliphatic, or —CN;
- each R6 is independently an optionally substituted group selected from C1-6 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;
- L1 is a covalent bond or a C1-C3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —O—, —C(O)—, —C(S)—, —C(R)2—, —CH(R)—, —C(F)2—, —N(R)—, —S—, —S(O)2— or —(C)═CH—;
- m is 0, 1, 2, 3 or 4;
- and
- each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 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 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 nitrogen, independently selected from nitrogen, oxygen, and sulfur.
20 more elements
The compound of claim 230, wherein -Cy- is each independently an optionally substituted bivalent ring selected from phenylenyl, a 4 or 6 membered saturated or partially unsaturated carbocyclylenyl, a 9 membered saturated or partially unsaturated spiro carbocyclylenyl, a 4 or 6 membered saturated or partially unsaturated heterocyclylenyl having 1-2 nitrogen atoms, a 4 or 6 membered saturated or partially unsaturated spiro heterocyclylenyl, having 1-2 nitrogen atoms, or a 5 or 6 membered heteroarylenyl having 1-3 nitrogen atoms.
A compound is represented by Formula (II-ABC′):
- or a pharmaceutically acceptable salt thereof,
- wherein:
- R1 is H, —C(CH3)2—CN,
- R3 is H or C1-C6 aliphatic;
- R4 is H,
- or R3 and R4 are joined together to form a 5 or 6-membered heterocyclic ring;
- Z2 is a covalent bond or —NH—;
- Z4 is a covalent bond, —NH—, or —O—;
- R2A is
- each RK1 is independently hydrogen, halo, C1-C6 aliphatic, halo substituted C1-C6 aliphatic, or —O—(C1-C6 aliphatic);
- Ring Xb is a ring selected from the group consisting of phenyl, a 4 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from N, O, and S, and a 5 to 6-membered heteroaryl with 1-4 heteroatoms independently selected from N, O, and S, and each of which is optionally substituted with one or more of RK;
- each RK is independently hydrogen, —F, —Cl, —Br, —I, —OH, —O—(C1-C6 aliphatic), —NO, —NO2, —NO3, —O—NO, —N3, —NH2, —NH—(C1-C6 aliphatic), —N(C1-C6 aliphatic)2, —N(C1-C6 aliphatic) 3+, —N(C1-C6 aliphatic)-OH, —O—N(C1-C6 aliphatic)2, —N(C1-C6 aliphatic)-O—(C1-C6 aliphatic), —CN, —NC, —C(O)—C1-C6 aliphatic, —CHO, —CO2H, —CO2(C1-C6 aliphatic), —C(O)—S—(C1-C6 aliphatic), —O—C(O)—H, —O—C(O)—(C1-C6 aliphatic), —S—C(O)—(C1-C6 aliphatic), —C(O)—NH2, —C(O)—N(C1-C6 aliphatic)2, —C(O)—NHNH2, —O—C(O)—NHNH2, —C(S)—NH2, —C(S)—N(C1-C6 aliphatic)2, —N(C1-C6 aliphatic)-CHO, —N(C1-C6 aliphatic)-C(O)—(C1-C6 aliphatic), —SCN, —NCS, —NSO, —SS(C1-C6 aliphatic), —SO2(C1-C6 aliphatic), —SO2—N(C1-C6 aliphatic)2, —S(O)—O(C1-C6 aliphatic), —S(O)—C1-C6 aliphatic, —Si(C1-C6 aliphatic)3, —CF3, —O—CF3, a C1-C6 aliphatic group, or two RK groups attached to the same carbon or sulfur atom are optionally taken together to form ═O;
- n is 1-4;
- wherein each #indicates the point of attachment to Z2 and each & indicates the point of attachment to Z4;
- and
- L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-C8 alkylene chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NRC—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —N(RC)S(O)2—, —S(O)2N(RC)—, —N(RC)C(O)—, —C(O)N(RC)—, —OC(O)N(RC)—, and —N(RC)C(O)O—, C2-C3 alkynylene and combinations thereof,
- wherein -Cy- is independently at each occurrence an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 5-11 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 5-11 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, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and
- each RC is independently at each occurrence hydrogen, or an optionally substituted group selected from a C1-C6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and combinations thereof.
15 more elements
A compound is represented by Formula (II-ABC):
- or a pharmaceutically acceptable salt thereof,
- wherein:
- R1 is H, —C(CH3)2—CN,
- Z2 is a covalent bond or —NH—;
- Z4 is a covalent bond, —NH—, or —O—;
- R2A is
- each RK1 is independently hydrogen, halo, C1-C6 aliphatic, halo substituted C1-C6 aliphatic, or —O—(C1-C6 aliphatic);
- Ring Xb is a ring selected from the group consisting of phenyl, a 4 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl with 1-3 heteroatoms independently selected from N, O, and S, and a 5 to 6-membered heteroaryl with 1-4 heteroatoms independently selected from N, O, and S, and each of which is optionally substituted with one or more of RK;
- each RK is independently hydrogen, —F, —Cl, —Br, —I, —OH, —O—(C1-C6 aliphatic), —NO, —NO2, —NO3, —O—NO, —N3, —NH2, —NH—(C1-C6 aliphatic), —N(C1-C6 aliphatic)2, —N(C1-C6 aliphatic)3+, —N(C1-C6 aliphatic)-OH, —O—N(C1-C6 aliphatic)2, —N(C1-C6 aliphatic)-O—(C1-C6 aliphatic), —CN, —NC, —C(O)—C1-C6 aliphatic, —CHO, —CO2H, —CO2(C1-C6 aliphatic), —C(O)—S—(C1-C6 aliphatic), —O—C(O)—H, —O—C(O)—(C1-C6 aliphatic), —S—C(O)—(C1-C6 aliphatic), —C(O)—NH2, —C(O)—N(C1-C6 aliphatic)2, —C(O)—NHNH2, —O—C(O)—NHNH2, —C(S)—NH2, —C(S)—N(C1-C6 aliphatic)2, —N(C1-C6 aliphatic)-CHO, —N(C1-C6 aliphatic)-C(O)—(C1-C6 aliphatic), —SCN, —NCS, —NSO, —SS(C1-C6 aliphatic), —SO2(C1-C6 aliphatic), —SO2—N(C1-C6 aliphatic)2, —S(O)—O(C1-C6 aliphatic), —S(O)—C1-C6 aliphatic, —Si(C1-C6 aliphatic)3, —CF3, —O—CF3, a C1-C6 aliphatic group, or two RK groups attached to the same carbon or sulfur atom are optionally taken together to form ═O;
- n is 1-4;
- wherein each #indicates the point of attachment to Z2 and each & indicates the point of attachment to Z4;
- and
- L is a covalent bond or a bivalent, saturated or partially unsaturated, straight or branched C1-C8 alkylene chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, —O—, —NRC—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)2—, —N(RC)S(O)2—, —S(O)2N(RC)—, —N(RC)C(O)—, —C(O)N(RC)—, —OC(O)N(RC)—, and —N(RC)C(O)O—, C2-C3 alkynylene and combinations thereof,
- wherein -Cy- is independently at each occurrence an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 5-11 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 5-11 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, and an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and
- each RC is independently at each occurrence hydrogen, or an optionally substituted group selected from a C1-C6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, and a 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, and combinations thereof.
12 more elements
A method of modulating TYK2 in a subject or biological sample comprising administering to the subject, or contacting the biological sample with the compound according to any one of claims 1-0, or the pharmaceutical composition of any one of claims 144-146, or the pharmaceutical dosage form of claim 147.
Dependencies are inferred from the claim text.