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US 2025/0145643 A1Published application
Ras inhibitors
AssigneeRevolution Medicines, Inc.
InventorsElena S. KOLTUN, James CREGG, Adrian L. GILL, John E. KNOX, Yang LIU, G. Leslie BURNETT
Life of this patent
Estimating the term…
Abstract
The disclosure features macrocyclic compounds, and pharmaceutical compositions and protein complexes thereof, capable of inhibiting Ras proteins, and their uses in the treatment of cancers.
Claims27
A compound having the structure of Formula I:
- wherein A is optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
- L1 is absent or a linker of Formula III:
- A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-(C2)j-(B4)k-A2 Formula III,
- wherein
- A1 is a bond between the linker and CH(R3);
- A2 is a bond between W and the linker;
- B1, B2, B3, and B4 each, independently, is selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NRN;
- each RN is independently, hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl;
- C1 and C2 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, or phosphoryl;
- f, q, h, i, j, and k are each, independently, 0 or 1;
- and
- D1 is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted 3 to 14-membered heterocycloalkylene, optionally substituted 5 to 10-membered heteroarylene, optionally substituted 3 to 8-membered cycloalkylene, optionally substituted 6 to 10-membered arylene, optionally substituted C2-C10 polyethylene glycolene, or optionally substituted C1-C10 heteroalkylene, or a chemical bond linking A1-(B1)f—(C1)g—(B2)h-to —(B3)i—(C2)j—(B4)k-A2;
- W is a cross-linking group comprising a vinyl ketone, vinyl sulfone, ynone, or an alkynyl sulfone;
- R1 is hydrogen, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl;
- R2 is optionally substituted C1-C6 alkyl;
- and
- R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;
- or a pharmaceutically acceptable salt thereof.
15 more elements
8-9. (canceled)
(canceled)
A compound, or a pharmaceutically acceptable salt thereof, selected from Table 1.
A conjugate, or salt thereof, comprising the structure of Formula V:
- M-L-P Formula V,
- wherein L is a linker;
- P is a monovalent organic moiety;
- and
- M has the structure of Formula VIa:
- wherein A is optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
- R2 is optionally substituted C1-C6 alkyl;
- R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;
- X2 is O, C(R11)2, NR12, S, or SO2;
- r is 1 or 2;
- each t is, independently, 0, 1, or 2;
- R11 and R12 are each, independently, hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 heteroalkyl, or optionally substituted 3 to 5-membered cycloalkyl;
- each R13 is, independently, —CH3;
- and
- R4, R5, and R6 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
- or
- R4 and R5 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl;
- or
- R4 and R6 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl.
16 more elements
A conjugate, or salt thereof, comprising the structure of Formula V:
- M-L-P Formula V,
- wherein L is a linker;
- P is a monovalent organic moiety;
- and
- M has the structure of Formula VIb:
- wherein A is optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
- R2 is optionally substituted C1-C6 alkyl;
- R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;
- R14 is fluoro, hydrogen, or C1-C3 alkyl;
- u is 0 or 1;
- and
- R4, R5, and R6 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
- or
- R4 and R5 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl;
- or
- R4 and R6 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl.
13 more elements
A conjugate, or salt thereof, comprising the structure of Formula V:
- M-L-P Formula V,
- wherein L is a linker;
- P is a monovalent organic moiety;
- and
- M has the structure of Formula VIc:
- wherein A is optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
- R2 is optionally substituted C1-C6 alkyl;
- R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;
- and
- R4, R5, and R6 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
- or
- R4 and R5 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl;
- or
- R4 and R6 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl.
11 more elements
A conjugate, or salt thereof, comprising the structure of Formula V:
- M-L-P Formula V,
- wherein L is a linker;
- P is a monovalent organic moiety;
- and
- M has the structure of Formula VId:
- wherein A is optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
- R2 is optionally substituted C1-C6 alkyl;
- R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;
- and
- R4, R5, and R6 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
- or
- R4 and R5 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl;
- or
- R4 and R6 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl.
11 more elements
(canceled)
A compound of formula:
- wherein
- R1 is hydrogen, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl;
- R2 is optionally substituted C1-C6 alkyl;
- each RINT is independently H, C1-3 alkyl, or TBDPS;
- and
- PNG is H, Boc, or Cbz.
3 more elements
Dependencies are inferred from the claim text.