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US 2025/0051364 A1Published application
KRAS G12D Proteolysis Targeting Chimeras
AssigneePAQ Therapeutics Inc.
InventorsNan Ji, Ning Yin, Hui Qiu
Life of this patent
Estimating the term…
Abstract
Provided herein are KRAS G12D proteolysis targeting chimeras (PROTACs), compositions comprising the KRAS G12D PROTACs, and methods of making and using the KRAS G12D PROTACs, e.g., to promote degradation of KRAS G12D and/or treat KRAS G12D-associated cancers. In an embodiment, the KRAS G12D PROTAC has the following structural formula: [KRAS G12Di]-L′-[Degron], or a pharmaceutically acceptable salt thereof, wherein values for the variables (e.g., KRAS G12Di, L′, Degron) are as described herein.
Claims52
A compound of the following formula:
- [KRAS G12Di]-L′-[Degron] (A),
- or a pharmaceutically acceptable salt thereof, wherein:
- KRAS G12Di is a KRAS G12D binding moiety;
- L′ is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-10 methylene units of L′ are independently replaced by X;
- each X is independently —C(D)(H)—, —C(D)2-, —C(H)(F)—, —C(F)2—, -Cy-, —O—, —N(R)—, —Si(R)2—, —Si(OH)(R)—, —Si(OH)2—, —P(O)(OR)—, —P(O)(R)—, —P(O)(NR2)—, —S—, —OC(O)—, —C(O)—, —S(O)—, —S(O)2—, —N(R)S(O)2—, —N(R)C(O)—, —OC(O)N(R)—, —N(R)C(O)N(R)—,
- 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 4-11 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 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 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;
- each R is independently hydrogen, deuterium, 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 on the same nitrogen are 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;
- r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
- and
- Degron is a cereblon binding moiety,
- provided the compound is not:
- or a salt thereof.
11 more elements
A compound of the following formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- X5 is O or CH2;
- two Ro, taken together with the same carbon atom, form a C3-7 cycloalkyl or a 4-7-membered heterocyloalkyl, wherein each (C3-C7)cycloalkyl or 4-7-membered heterocyloalkyl is optionally substituted with 1, 2 or 3 substitutents independently selected from halogen, oxo, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, hydroxyl, cyano, —S(O)2(C1-C4)alkyl, ═NH, ═N(C1-C4)alkyl, —NH2, —N(H)(C1-C4)alkyl or —N((C1-C4)alkyl)2, and when p is 3 or 4, each remaining Ro is independently selected from hydroxyl, halogen, oxo, cyano, —N((C1-C4)alkyl)2, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy;
- o is 2, 3 or 4;
- p is 0, 1 or 2;
- q is 0, 1 or 2;
- X4 is N or C(R42);
- R42 is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, —CN, (C1-C6)alkoxy, —S—(C1-C6)alkyl or —S—(C1-C6)haloalkyl;
- Y is a bond, O or NR5;
- R1 is hydrogen, hydroxy, halogen, (C1-C3)alkyl, (C1-C3)cyanoalkyl, (C1-C3)hydroxyalkyl, —C(O)H, —CO2R5, —CO2N(R)2 or (C5-C6)heteroaryl;
- R2 is hydrogen, —N(R5)2, (C3-C12)heterocyclyl, (C1-C6)alkyl, -L-(C3-C12)heterocyclyl, -L-(C6-C14)aryl, -L-(C5-C14)heteroaryl, -L-(C3-C12)cycloalkyl, -L-N(R5)2, -L-N(H)C(NH)NH2, -L-C(O)N(R5)2, -L-(C1-C6)haloalkyl, -L-OR5, -L-NR5C(O)—(C6-C14)aryl, -L-COOH or -L-C(O)O(C1-C6)alkyl, wherein the (C3-C12)heterocyclyl, the (C6-C14)aryl of -L-NR5C(O)—(C6-C14)aryl, the (C3-C12)heterocyclyl of -L-(C3-C12)heterocyclyl and the (C3-C12)cycloalkyl of -L-(C3-C12)cycloalkyl are optionally substituted with one or more R6, and the aryl of -L-(C6-C14)aryl and (C5-C14)heteroaryl of -L-(C5-C14)heteroaryl are optionally substituted with one or more R7;
- L is (C1-C4)alkylene optionally substituted with hydroxy, (C1-C4)hydroxyalkyl or (C5-C14)heteroaryl;
- R3 is (C6-C14)aryl or (C5-C14)heteroaryl, wherein the (C6-C14)aryl or (C5-C14)heteroaryl is optionally substituted with one or more R8;
- R4 is hydrogen, halogen or (C1-C3)alkyl;
- each R5 is independently hydrogen or (C1-C3)alkyl;
- each R6 is independently halogen, hydroxy, (C1-C3)hydroxyalkyl, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)alkoxy, cyano, -Q-phenyl, -Q-phenyl-SO2F, —N(H)C(O)-phenyl, —N(H)C(O)-phenyl-SO2F, (C1-C3)alkyl-substituted pyrazole, (C6-C14)aryl(C1-C3)alkyl, tert-butyldimethylsilyloxy-CH2—, —N(R5)2, (C1-C3)alkoxy(C1-C3)alkyl, (C1-C3)alkyl-C(O)—, oxo, (C1-C3)haloalkyl-C(O)—, —SO2F, (C1-C3)alkoxy(C1-C3)alkoxy, —CH2OC(O)N(R5)2, —CH2N(H)C(O)O—(C1-C6)alkyl, —CH2N(H)C(O)N(R5)2, —CH2N(H)C(O)(C1-C6)alkyl, —CH2(pyrazolyl), —CH2N(H)S(O)2(C1-C6)alkyl, —CH2OC(O)(C3-C12)heterocyclyl, —OC(O)N(R5)2, —OC(O)N(H)(C1-C3)alkyl-O—(C1-C3)alkyl, —OC(O)N(H)(C1-C3)alkyl-O—(C1-C3)alkyl-phenyl-(C1-C3)alkyl-N(CH3)2, —OC(O)N(H)(C1-C3)alkyl-O—(C1-C3)alkyl-phenyl, —OC(O)(C3-C12)heterocyclyl or —CH2—(C3-C12)heterocyclyl, wherein the phenyl of —N(H)C(O)phenyl and —OC(O)N(H)(C1-C3)alkyl-O—(C1-C3)alkyl-phenyl is optionally substituted with —C(O)H or —OH, and the (C3-C12)heterocyclyl of —CH2—(C3-C12)heterocyclyl is optionally substituted with oxo;
- Q is a bond or O;
- each R7 is independently halogen, hydroxy, —C(O)H, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)hydroxyalkyl or —N(R5)2;
- each R8 is independently halogen, cyano, hydroxy, (C1-C4)alkyl, —S—(C1-C3)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C2-C4)hydroxyalkynyl, (C1-C3)cyanoalkyl, triazolyl, (C1-C3)haloalkyl, —O—(C1-C3)haloalkyl, —S—(C1-C3)haloalkyl, (C1-C3)alkoxy, (C1-C3)hydroxyalkyl, —CH2C(O)N(R5)2, (C3-C4)alkynyl-N(R5)2, N(R5)2, deutero(C2-C4)alkynyl, (C1-C3)alkoxy(C1-C3)haloalkyl or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl is optionally substituted with halogen or (C1-C3)alkyl;
- L′ is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-C25 hydrocarbon chain wherein 0-10 methylenes of L′ are replaced by X;
- each X is independently —O—, —N(R)—, —S—, —OC(O)—, —C(O)—, —C(H)(F)—, —C(F)2—, -Cy-, —S(O)—, —S(O)2—, —N(R)S(O)2—, —N(R)C(O)—, —OC(O)N(R)—, —N(R)C(O)N(R)—,
- 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, 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 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-3 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;
- each R is independently hydrogen or (C1-C3)alkyl;
- and
- Degron is a cereblon binding moiety,
- provided the compound is not:
- or a salt thereof.
24 more elements
The compound of 28, wherein each -Cy- is a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1 nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, a 4-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1 nitrogen atom and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1 nitrogen atom and optionally 1 additional heteroatom independently selected from nitrogen, oxygen, and sulfur, and is linked via a nitrogen atom.
A compound of Table 1, or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.