Macrocyclic compounds having farnesyltransferase inhibitory activity

Abstract

20 26 24 90 26 08 O ct 2 02 6 A B S T R A C T 2 0 2 6 2 4 9 0 2 6 0 8 O c t 2 0 2 6

Claims

1. A compound of Formula (I):A6 A1Formula (I) wherein:the dashed line indicates a single bond or double bond between A1 and A2;A1 is independently N, NRla, CRlb, or -C(=O)-;A2 is independently N, NR2a, CR2b, or -C(=O)-;A3 is independently CR3 or N;A4 is CR8orN;A5 and A6 are each independently CR8 or N, or A5 and A6 taken together are O, NR9, or S;W is a C6-12 aryl or a 5-12 membered heteroaryl, each of which is optionally substituted with 1-4 R4 substituents;Y is a bond or a linker having a length of up to 6 atoms;Z is a Ce-12 aryl or a 5-12 membered heteroaryl, each of which is optionally substituted with 1-4 R5 substituents;Rla and R2a are each independently R9, -OR9, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -S(O)PR9, or-S(O)2NR10Rn;Rlb, R2b, R3, R5 and R8, at each occurrence, are each independently R9, -OR9, halo, CN, NO2, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10Ru, -NR10S(O)2R9, -S(O)PR9, -S(O)2NR10Ru or -NR10S(O)2NR10Ru;R4, at each occurrence, is independently hydrogen, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkoxy, C1-6 heteroalkoxy, C3-6 cycloalkoxy, 3-6 membered2026249026   08 Oct 2026heterocycloalkoxy, -NR14R15, Ce-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 hydroxyalkoxy, Ci-6 heteroalkoxy, C3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, Ce-12 aryl, or 5-12 membered heteroaryl of the R4 is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O);R6 is CN, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10OR9, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -NR10C(NR10)NR10Rn, -S(O)PR9, -S(O)2NR10Rn, or -NR10S(O)2NR10R11;R7 is a 5-12 membered heteroaryl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -S(O)PR9, -S(O)2NR10Ru and -NR10S(O)2NR10Ru;R9, at each occurrence, is independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl of the R9 is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)OR12, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R12, -NR10C(O)OR12, -NR10C(O)NR10R11, -NR10S(O)2R12, -S(O)PR12, -S(O)2NR10Rn, and -NR10S(O)2NR10R11;R10 and R11, at each occurrence, are each independently hydrogen, hydroxy, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ce-12 aryl, or 5-12 membered heteroaryl, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl, wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ce-12 aryl, or 5-122026249026   08 Oct 2026membered heteroaryl of the R10 and the R11 is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)OR13, -C(O)NR14R15, -NR14R15, -NR14C(O)R13, -NR14C(O)OR13, -NR14C(O)NR14R15, -NR14S(O)2R13, -S(O)pR13, -S(O)2NR14R15, and -NR14S(O)2NR14R15;R12, at each occurrence, is independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl of the R12 is optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R13, -C(O)OR13, -OC(O)R13, -OC(O)OR13, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R13, -NR10C(O)OR13, -NR10C(O)NR10Ru, -NR10S(O)2R13, -S(O)PR13, -S(O)2NR10Rn, and -NR10S(O)2NR10Ru;R13, at each occurrence, is independently hydrogen, C1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, Cm hydroxyalkyl, C1.4 heteroalkyl, C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl;R14 and R15, at each occurrence, are each independently hydrogen, hydroxy, C1.4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1.4 haloalkyl, C1.4 hydroxyalkyl, C1.4 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or Ci-6 alkoxy, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl; andeach p is independently an integer of 0, 1 or 2. or a pharmaceutically acceptable form thereof.2026249026   08 Oct 20262. The compound of claim 1, wherein the compound is a compound of Formula (la):Formula (la) or a pharmaceutically acceptable form thereof.

3. The compound of claim 1, wherein the compound is a compound of Formula (lb):Formula (lb) or a pharmaceutically acceptable form thereof.

4. The compound of any one of claims 1-3, wherein:(a) A1 is N or NRla and / or A2 is CR2b or -C(=O)-; or(b) the bond between A1 and A2 is a single bond; A1 is NRla; and A2 is -C(=O)-; or(c) the bond between A1 and A2 is a double bond; A1 is N; and A2 is CR2b; or(d) A1 is CRlb or -C(=O)- and / or A2 is N or NR2a; or(e) the bond between A1 and A2 is a double bond; A1 is CRlb; and A2 is N; or(f) the bond between A1 and A2 is a single bond; A1 is -C(=O)-; and A2 is NR2a.2026249026   08 Oct 20265. The compound of any one of claims 1-4, wherein:

6. The compound of any one of claims 1-5, wherein Y and the fused-ring system containing A1, A2, and A3 are attached to W in a 1,3-relationship.

7. The compound of any one of claims 1-6, wherein W is C6-12 aryl, or W is phenyl, or is W is 5-12 membered heteroaryl, or W is pyridyl, optionally wherein W is substituted with one, two, three or four R4 substituents, optionally wherein W is substituted with one R4 substituent.

8. The compound of any one of claims 1-7, wherein the -(C(R6)(R7)(fused-ring system containing A4, A5, and A6)) group, and Y are attached to Z in a 1,3-relationship.

9. The compound of any one of claims 1-8, wherein Z is C6-12 aryl, or Z is phenyl, or Z is 512 membered heteroaryl, or Z is pyridyl, optionally wherein Z is substituted with one, two, three or four R5 substituents, optionally wherein Z is substituted with one R5 substituent.2026249026   08 Oct 202610. The compound of any one of claims 1-9, wherein the compound is a compound of Formula (II):Formula (II)wherein:W1, W2, W3, and W4 are each independently N or CR4, or W1 and W2 taken together is O, NR4A, or S, or W2 and W3 taken together is O, NR4A, or S;Z1, Z2, Z3, and Z4 are each independently N or CR5, or Z2 and Z3 taken together is O, NR5A, or S, or Z3 and Z4 taken together is O, NR5A, or S; andR4A and R5A are independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl of the R4A and the R5A are optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O);or a pharmaceutically acceptable form thereof.2026249026   08 Oct 202611. The compound of claim 10, wherein the compound is a compound of Formula (Ila) or isa compound of Formula (lib):or a pharmaceutically acceptable form thereof.

12. The compound of claim 10, wherein the compound is a compound of Formula (II-l), (Ila-1), (IIb-1), (11-2), (IIa-2), or (IIb-2):R1aR5Formula (II-1)2026249026   08 Oct 20262026249026   08 Oct 202613. The compound of any one of claims 1-10, wherein the compound is a compound of Formula (III):Formula (III)wherein:W1, W2, W3, and W4 are each independently N or CR4, or W1 and W2 taken together is O, NR4A, or S, or W2 and W3 taken together is O, NR4A, or S;Z1, Z2, Z3, and Z4 are each independently N or CR5, or Z2 and Z3 taken together is O, NR5A, or S, or Z3 and Z4 taken together is O, NR5A, or S; andR4A and R5A are independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl of the R4A and the R5A are optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and(O);or a pharmaceutically acceptable form thereof.2026249026   08 Oct 202614. The compound of claim 13, wherein the compound is a compound of Formula (Illa) or isa compound of Formula (Illb):Formula (Illa)or a pharmaceutically acceptable form thereof.

15. The compound of claim 13, wherein the compound is a compound of Formula (III-1), (IIIa-1), (IIIb-1), (III-2), (IIIa-2), (IIIb-2), (III-3), (IIIa-3), or (IIIb-3):2026249026   08 Oct 2026Formula (III-3)Formula (IIIa-3)2026249026   08 Oct 2026or a pharmaceutically acceptable form thereof.

16. The compound of any one of claims 1-10, wherein the compound is a compound of Formula (IV):Formula (IV)wherein:W1, W2, W3, and W4 are each independently N or CR4, or W1 and W2 taken together is O, NR4A, or S, or W2 and W3 taken together is O, NR4A, or S;Z1, Z2, Z3, and Z4 are each independently N or CR5, or Z2 and Z3 taken together is O, NR5A, or S, or Z3 and Z4 taken together is O, NR5A, or S; andR4A and R5A are independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl of the R4A and the R5A are optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O);or a pharmaceutically acceptable form thereof.2026249026   08 Oct 202617.    The compound of claim 16, wherein the compound is a compound of Formula (IVa) or isa compound of Formula (IVb):Formula (IVa)or a pharmaceutically acceptable form thereof.

18. The compound of claim 16, wherein the compound is a compound of Formula (IV-1),(IVa-1), (IVb-1), (IV-2), (IVa-2), or (IVb-2):Formula (IV-1)2026249026   08 Oct 20262026249026   08 Oct 202619. The compound of any one of claims 1-10, wherein the compound is a compound of Formula (V):Formula (V) wherein:W1, W2, W3, and W4 are each independently N or CR4, or W1 and W2 taken together are O, NR4A, or S, or W2 and W3 taken together are O, NR4A, or S;Z1, Z2, Z3, and Z4 are each independently N or CR5, or Z2 and Z3 taken together are O, NR5A, or S, or Z3 and Z4 taken together are O, NR5A, or S; andR4A and R5A are independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl of the R4A and the R5A is optionally independently substituted with 1-6 substituents independently selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O);or a pharmaceutically acceptable form thereof.

20. The compound of Formula 19, wherein the compound is a compound of Formula (Va) or Formula (Vb):2026249026   08 Oct 2026Formula (Va)or a pharmaceutically acceptable form thereof.

21. The compound of claim 19, wherein the compound is a compound of Formula (V-l),(Va-1), or (Vb-1):Formula (Va-1)Formula (Vb-1)or a pharmaceutically acceptable form thereof.2026249026   08 Oct 202622. The compound of any one of claims 1-10, wherein the compound is a compound of Formula (VI):Formula (VI) wherein:W1, W2, W3, and W4 are each independently N or CR4, or W1 and W2 taken together are O, NR4A, or S, or W2 and W3 taken together are O, NR4A, or S;Z1, Z2, Z3, and Z4 are each independently N or CR5, or Z2 and Z3 taken together are O, NR5A, or S, or Z3 and Z4 taken together are O, NR5A, or S; andR4A and R5A are independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-12 aryl, or 5-12 membered heteroaryl, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ce-12 aryl, or 5-12 membered heteroaryl of the R4A and the R5A is optionally independently substituted with 1-6 substituents independently selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O);or a pharmaceutically acceptable form thereof.

23. The compound of claim 22, wherein the compound is a compound of Formula (Via) or Formula (VIb):2026249026   08 Oct 2026or a pharmaceutically acceptable form thereof.R1bFormula (VIb)24. The compound of claim 22, wherein the compound is a compound of Formula (VI-1),Formula (VIa-1)Formula (VIb-1)or a pharmaceutically acceptable form thereof.

25. The compound of any one of claims 1-12, wherein Rla is independently R9.2026249026   08 Oct 202626. The compound of any one of claims 1-12, wherein Rla is hydrogen, Ci-6 alkyl, or C3-6 cycloalkyl, wherein the Ci-6 alkyl, or C3-6 cycloalkyl are optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)OR12, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R12, -NR10C(O)OR12, -NR10C(O)NR10Ru, -NR10S(O)2R12, -S(O)PR12, and -S(O)2NR10Rn27. The compound of claim 26, wherein Rla is hydrogen, C1.3 alkyl, or C3-4 cycloalkyl, wherein the C1.3 alkyl, or C3-4 cycloalkyl are optionally independently substituted with one, two, or three substituents selected from halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, (O), -C(O)R12, -C(O)OR12, -OC(O)R12, -OC(O)OR12, -C(O)NR10Ru, -NR1ORU, -NR10C(O)R12, -NR10C(O)OR12, -NR10C(O)NR10R11, -NR10S(O)2R12, -S(O)PR12, and -S(O)2NR10Ru.

28. The compound of claim 26, wherein Rla is:(a) hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, 2,3-dihydroxypropyl, or cyclopropyl; or(b) -CH3, -CD3, or cyclopropyl; or(c) -CH3 or -CD3; or(d) Rla is cyclopropyl.

29. The compound of any one of claims 1-9, 13-15, 19-20, or 22-23, wherein R2b is R9, -OR9, halo, CN, NO2, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10C(O)R9, -S(O)PR9, or -S(O)2NR10Rn30. The compound of any one of claims 1-9, 13-15, 19-20, or 22-23, wherein R2b is: (a) R9, -OR9, halo, CN, -C(O)NR10Ru, or-NR10Ru; or2026249026   08 Oct 2026(b) hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, hydroxy, Ci-6 alkoxy, C3-6 cycloalkoxy,C3-6 heterocycloalkoxy, halo, CN, -C(O)NR10Ru, or-NR10Ru;wherein R10 and R11, at each occurrence, are each independently hydrogen, Ci-6 alkyl,3-6 membered heterocycloalkyl, or together with the N to which each is attached are combined to form a 3-6 membered heterocycloalkyl; or(c) hydrogen, C1.3 alkyl, C3-4 cycloalkyl, C1.3 alkoxy, C3-4 cycloalkoxy, C3-4 heterocycloalkoxy, halo, CN, -C(O)NR10Ru, or-NR10Rn;wherein R10 and R11, at each occurrence, are each independently hydrogen, C1.3 alkyl, 3-4 membered heterocycloalkyl, or together with the N to which each is attached are combined to form a 4-6 membered heterocycloalkyl; or(d) hydrogen, -CH3, -CD3, -CH2CH3, -CD2CD3, isopropyl, cyclopropyl, -OCH3, -OCD3, -OCH2CH3, -OCD2CD3, isopropoxy, cyclopropoxy, 3-oxetanylalkoxy, chloro, CN, morpholino, piperazinyl, 3-oxetanylamino, or -C(O)NH2; or(e) R2b is -NH2.

31. The compound of any one of claims 1-9, 13-15, 19-20, or 22-23, wherein R2b is an electron-withdrawing group, optionally wherein R2b is:(a) halo, CN, NO2, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -S(O)PR9, or-S(O)2NR10Ru; or(b) chloro, CN, -C(O)H, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)NH2, -C(O)N(H)CH3, -C(O)N(CH3)2, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2N(H)CH3, or-S(O)2N(CH3)2.

32. The compound of any one of claims 1-11, 13-14, 16-17, or 22-23, wherein A3 is CR3, optionally wherein R3 is (a) independently R9, -OR9, halo, or CN; or (b) hydrogen.

33. The compound of any one of claims 1-11, 13-14, 16-17, 19-20, or 22-23, wherein A4 is CR8.

34. The compound of any one of claims 1-11, 13-14, 16-17, 19-20, or 22-23, wherein A4 is N.2026249026   08 Oct 202635. The compound of any one of claims any one of claims 1-11, 13-14, 16-17, 19-20, or 2223, wherein A5 is CR8.

36. The compound of any one of claims 1-11, 13-14, 16-17, 19-20, or 22-23, wherein A5 is N.

37. The compound of any one of claims 1-11, 13-14, 16-17, 19-20, or 22-23, wherein A6 is CR8.

38. The compound of any one of claims 1-11, 13-14, 16-17, 19-20, or 22-23, wherein A6 is N.

39. The compound of any one of claims 1-34, wherein:(a) A4 is N, and no more than one of A5 and A6 is N; or(b) A5 is N, and no more than one of A4 and A6 is N; or(c) A6 is N, and no more than one of A4 and A5 is N; or(d) A4, A5 and A6 are each independently CR8.

40. The compound of any one of claims 1-39, wherein R8 is independently R9, -OR9, halo, or CN, optionally wherein R8is hydrogen.

41. The compound of any one of claims 1-40, wherein Y is a bond.

42. The compound of any one of claims 1-40, wherein Y is a linker having a length of up to 5atoms, up to 4 atoms, up to 3 atoms, or up to 2 atoms.

43. The compound of any one of claims 1-40 or 42, wherein Y is in the direction of Z-Y-W.

44. The compound of any one of claims 1-40, 42, or 43, wherein Y is a Ci-6 alkylene,wherein one or more -CH2- is optionally independently replaced by -O-, -C(O)-, -N(R10)-,2026249026   08 Oct 2026-N(R10)C(O)-, -C(O)N(R10)-, -N(R10)C(O)N(Ru)- -S(O)P- -N(R10)S(O)2- -S(O)2N(R10)-or -N(R10)S(O)2N(Rn)-.

45. The compound of any one of claims 1-40 or 42-44, wherein:Y is -(CR16R17)q- -(CR16R17)mO(CR16R17)n- -(CR16R17)mC(O)(CR16R17)n-4CR16R17)mN(R10)(CR16R17)n-, -(CR16R17)mN(R10)C(O)(CR16R17)n--(CR16R17)mC(O)N(R10)(CR16R17)n- -(CR16R17)mN(R10)C(O)N(R11)(CR16R17)n--(CR16R17)mS(O)p(CR16R17)n- -(CR16R17)mN(R10)S(O)2(CR16R17)n--(CR16R17)mS(O)2N(R10)(CR16R17)n- or -(CR16R17)mN(R10)S(O)2N(Ru)(CR16R17)n-; and wherein:R16 and R17, at each occurrence, are each independently hydrogen, halo, hydroxy, CN, NO2, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 hydroxyalkoxy, Ci-6 heteroalkoxy, or 3-6 membered heterocycloalkoxy, or together with the C to which each is attached are combined to form a C(O), C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl;each m is independently an integer of 0, 1, 2 or 3;each n is independently an integer of 0, 1, 2 or 3;wherein the sum of m and n is 0, 1, 2, 3, 4, 5, or 6;each p is independently an integer of 0, 1 or 2; andeach q is independently an integer of 0, 1, 2, 3, 4, 5, or 6;optionally wherein m is 0, 1, or 2; and optionally wherein n is 0, 1, or 2.

46. The compound of claim 45, wherein Y is:(a) -(CR16R17)q-, -(CR16R17)mO(CR16R17)n-, 4CR16R17)mC(O)(CR16R17)n-, -(CR16R17)mN(R10)(CR16R17)n-, -(CR16R17)mN(R10)C(O)(CR16R17)n-, -(CR16R17)mC(O)N(R10)(CR16R17)n-, -(CRl6Rl7)mN(Rl0)S(O)2(CRl6R17^ or -(CR16R17)mS(O)2N(R10)(CR16R17)n-; or(b) -(CR16R17)q- -(CR16R17)mO(CR16R17)n-, -(CR16R17)mN(R10)C(O)(CR16R17^ or -(CR16R17)mC(O)N(R10)(CR16R17)n-; or2026249026   08 Oct 2026(c) -(CR16R17)q-; or(d) -(CR16R17)mO(CR16R17)n-; or(e) -(CR16R17)mN(R10)C(O)(CR16R17)n-; or(f) -(CR16R17)mC(O)N(R10)(CR16R17^47. The compound of claim 45 or claim 46 wherein:(a) R16 and R17, at each occurrence, are each independently hydrogen, halo, hydroxy, CN, NO2, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1.3 haloalkyl, C1.3 hydroxyalkyl, C1.3 heteroalkyl, C3-5 cycloalkyl, 3-5 membered heterocycloalkyl, C1.3 alkoxy, C1.3 haloalkoxy, C1.3 hydroxyalkoxy, C1.3 heteroalkoxy, or 3-5 membered heterocycloalkoxy, or together with the C to which each is attached are combined to form a C(O), C3-5 cycloalkyl, or 3-5 membered heterocycloalkyl; or(b) R16 and R17, at each occurrence, are each independently hydrogen, chloro, hydroxy, CN, NO2, methyl, ethyl, isopropyl, -CF3, -CH2CF3, -CH2OH,-(CH2)2OH, -(CH2)2OCH3, cyclopropyl, 3-oxetanyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, -OCF3, -OCH2CF3, -O(CH2)2OH, -O(CH2)2OCH3, or 3-oxetanylalkoxy, or together with the C to which each is attached are combined to form a C(O), cyclopropyl, or 3-5 membered heterocycloalkyl; or(c) R16 and R17 are each hydrogen.

48. The compound of any one of claims 45-47, wherein Y is -(CH2)O-, or Y is -O(CH2)-, or Y is -(CH2)2O-, or Y is -O(CH2)2- or Y is -(CH2)2-.

49. The compound of any one of claims 10-11, 13-14, 16-17, 19-20, 22-23, or 25-48, wherein at least one of W1, W2, W3, and W4 is N, optionally, wherein:W1, W2, and W3 are each independently CR4, and W4 is N;W1, W2, and W4 are each independently CR4, and W3 is N;W1, W3, and W4 are each independently CR4, and W2 is N; orW2, W3, and W4 are each independently CR4, and W1 is N.2026249026   08 Oct 202650. The compound of any one of claims 10-11, 13-14, 16-17, 19-20, 22-23, or 25-48, wherein W1, W2, W3, and W4 are each independently CR4.

51. The compound of any one of claims 49-50, wherein:(a) R4 is independently hydrogen, halo, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 hydroxyalkoxy, Ci-6 heteroalkoxy, C3-6 cycloalkoxy, 3-6 membered heterocycloalkoxy, or-NR14R15, wherein each Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 hydroxyalkoxy, Ci-6 heteroalkoxy, C3-6 cycloalkoxy, or 3-6 membered heterocycloalkoxy, of the R4 are optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O); or(b) R4 is independently hydrogen, halo, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, Ci-6 alkoxy, or Ci-6 haloalkoxy, wherein each Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, Ci-6 alkoxy, or Ci-6 haloalkoxy of the R4 are optionally independently substituted with one, two, three, four, five, or six substituents selected from halo, hydroxy, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 heteroalkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, and (O); or(c) R4 is independently hydrogen, halo, C1.3 alkyl, C1.3 haloalkyl, C3-5 cycloalkyl, C1.3 alkoxy, or C1.3 haloalkoxy; or(d) each R4 is independently hydrogen.

52. The compound of any one of claims 10-11, 13-14, 16-17, 19-20, 22-23, or 25-51, wherein at least one of Z1, Z2, Z3, and Z4 is N, optionally wherein:Z1, Z2, and Z3 are each independently CR5, and Z4 is N;Z1, Z2, and Z4 are each independently CR5, and Z3 is N;Z1, Z3, and Z4 are each independently CR5, and Z2 is N; orZ2, Z3, and Z4 are each independently CR5, and Z1 is N.2026249026   08 Oct 202653. The compound of any one of claims 10-11, 13-14, 16-17, 19-20, 22-23, or 25-51, wherein Z1, Z2, Z3, and Z4 are each independently CR5.

54. The compound of any one of claims 52-53, wherein R5, at each occurrence, is independently R9, -OR9, halo, CN, NO2, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -S(O)PR9, or -S(O)2NR10Ru; or R5, at each occurrence, is independently hydrogen, halo, CN, NO2, -C(O)CH3, -C(O)OH, -C(O)OCH3, -C(O)N(CH3)2, -S(O)2CH3, or -S(O)2N(CH3)2; or each R5 independently is hydrogen, halo or CN; or each R5 independently is hydrogen.

55. The compound of any one of claims 52-53, wherein R5 is independently an electronwithdrawing group, optionally wherein R5 independently is chloro or R5 independently is CN.

56. The compound of any one of claims 1-55, wherein R7 is an imidazolyl, a triazolyl, a tetrazolyl, an oxazolyl, a thiazolyl, an oxadiazolyl, a thiadiazolyl, a pyridyl, or a pyrimidinyl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -OC(O)R9, -OC(O)OR9, -CXOJNR"^1-NR1ORU, -NR10C(O)R9, -NR10C(O)OR9, -NR10C(O)NR10R11, -NR10S(O)2R9, -S(O)PR9, -S(O)2NRl0R'or -NR10S(O)2NR10R11;optionally R7 is imidazolyl or triazolyl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -C(O)NR10Rn, -NR10Rn, -NR10C(O)R9, -S(O)PR9, or -S(O)2NR10Rn;optionally R7 is a C-linked imidazolyl or a C-linked triazolyl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -C(O)NR10Ru, -NR10Rn, -NR10C(O)R9, -S(O)PR9, or -S(O)2NR10Rn57. The compound of any one of claims 1-55, wherein R7 is an TV-linked imidazolyl or an TV-linked triazolyl, optionally substituted with 1-4 substituents independently selected from halo, CN, NO2, R9, -OR9, -C(O)R9, -C(O)OR9, -C(O)NR10Rn, -NR1ORU, -NR10C(O)R9, -S(O)PR9, or -S(O)2NR10Rn; optionally wherein R7 is a methyl-substituted imidazolyl or a methylsubstituted triazolyl, or2026249026   08 Oct 2026R7 is a C-methyl-substituted imidazolyl or a C-methyl-substituted triazolyl, optionally wherein58. The compound of any one of claims 1-57, wherein R6 is CN, R9, -OR9, -OC(O)R9, -OC(O)OR9, -NR10Rn, -NR10OR9, -NR10C(O)R9, or -NR10C(NR10)NR10R11, or wherein R6 is CN, R9, -OR9, -NR1ORU, or -NR10OR9, or wherein R6 is CN, R9, -OR9, or -NR10Rn, optionally wherein R9 is independently hydrogen or C1.3 alkyl, wherein the C1.3 alkyl is optionally substituted with CN, and optionally wherein R10 and R11 are each independently hydrogen, Ci-6 alkyl or Ci-6 alkoxy.

59. The compound of claim 58, wherein R6 is hydrogen, -CH3, hydroxy, -OCH3, -OCD3, -NH2, -NHCH3, or -NH(OCH3), or R6 is hydroxy, or R6 is hydrogen, or R6 is NH2, or R6 is -NH(CH2CH2)C1, -NH(CH2CH2)F, orN-linked morpholino.

60. The compound of any one of claims 1-59, wherein:the compound has a MW of no more than 1,000 g / mol; orthe compound has a MW of no more than 900 g / mol, no more than 800 g / mol, no more than 700 g / mol, no more than 600 g / mol, or no more than 500 g / mol; orthe compound has a MW of no more than 600 g / mol; orthe compound has a MW of no more than 500 g / mol.

61. The compound of claim 1, wherein the compound is selected from Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,2026249026   08 Oct 202632, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, and 77, or a pharmaceutically acceptable form thereof.

62. The compound of claim 1, wherein the compound is selected from Compounds 78 to 91, Compounds 92 to 135, including (R)- or (5)-stereoisomers and racemates thereof, and pharmaceutically acceptable forms thereof.

63. The compound of any one of claims 1-62, wherein the pharmaceutically acceptable form of the compound is exclusive of a salt form.

64. The compound of any one of claims 1-63, wherein the compound is a racemate or a mixture of diasteromers or stereoisomers.

65. The compound of any one of claims 1-63, wherein the compound is a single enantiomer or a single diasteromer.

66. The compound of any one of claims 1-63 or 65, wherein the compound is an (A’)-enantiomer.

67. The compound of any one of claims 1-63 or 65, wherein the compound is an (5)-enantiomer.

68. A pharmaceutical composition comprising the compound or pharmaceutically acceptable form thereof, of any one of claims 1-67, and a pharmaceutically acceptable carrier, excipient or diluent.

69. A method of inhibiting a farnesyltransferase, comprising contacting the farnesyltransferase with an effective amount of the compound or pharmaceutically acceptable form thereof, of any one of claims 1-67, or with the pharmaceutical composition of claim 68, optionally wherein the farnesyltransferase is present in a cell,2026249026   08 Oct 2026optionally wherein the contacting of the farnesyltransferase takes place in a cell, optionally wherein the cell is in a subject, optionally wherein the cell is a mammalian cell, optionally wherein the cell is a human cell, andoptionally wherein the subject suffers from a cancer dependent on a famesylated protein.

70. A method of treating cancer dependent on a famesylated protein in a subject, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable form thereof, of any one of claims 1-67, or the pharmaceutical composition of claim 68, to the subject having cancer dependent on a famesylated protein, optionally wherein the subject is human.

71. The method of claim 69 or claim 70, wherein the cancer dependent on a famesylated protein is a cancer dependent on famesylated H-Ras protein, optionally wherein the cancer dependent on a famesylated protein has an H-Ras protein mutation, optionally wherein the H-Ras protein mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from G12, G13, Q61, Q22, KI 17, A146, and any combination thereof, in the corresponding mutant H-Ras protein;optionally wherein the presence or absence of the H-Ras mutation has been determined by analysis of nucleic acids obtained from a sample from the subject, optionally wherein the sample is a tissue biopsy or is a tumor biopsy, optionally wherein the H-Ras mutation has been determined by sequencing, Polymerase Chain Reaction (PCR), DNA microarray, Mass Spectrometry (MS), Single Nucleotide Polymorphism (SNP) assay, denaturing high-performance liquid chromatography (DHPLC), or Restriction Fragment Length Polymorphism (RFLP) assay.

72. The method of any one of claims 69-71, wherein the cancer dependent on a famesylated protein is a cancer dependent on famesylated N-Ras protein, optionally wherein the cancer dependent on a famesylated protein has an N-Ras protein mutation, optionally wherein the N-Ras mutation is or comprises a modification in a codon that encodes an amino acid substitution at a specific position selected from G12, G13, Q61, Q22, KI 17, A146, and any combination thereof, in the corresponding mutant N-Ras protein;2026249026   08 Oct 2026optionally wherein determining the presence or absence of the N-Ras mutation comprises analyzing nucleic acids obtained from a sample from the subject, optionally wherein the N-Ras mutation is determined by sequencing, Polymerase Chain Reaction (PCR), DNA microarray, Mass Spectrometry (MS), Single Nucleotide Polymorphism (SNP) assay, denaturing high-performance liquid chromatography (DHPLC), or Restriction Fragment Length Polymorphism (RFLP) assay, optionally wherein the sample is a tissue biopsy or a tumor biopsy.

73. The method of any one of claims 69-72, wherein the cancer dependent on a farnesylated protein is melanoma, acute myeloid leukemia (AML), thyroid carcinoma, lung adenocarcinoma, rectal carcinoma, endometrial carcinoma, or colorectal carcinoma.

74. The method of any one of claims 69-72, wherein the cancer dependent on a farnesylated protein is carcinoma, melanoma, sarcoma, or chronic granulomatous disease.

75. The method of any one of claims 69-72, wherein the cancer dependent on a farnesylated protein is thyroid cancer, head and neck cancers, urothelial cancers, salivary cancers, cancers of the upper digestive tract, bladder cancer, breast cancer, ovarian cancer, brain cancer, gastric cancer, prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, or pancreatic cancer.

76. The method of any one of claims 69-72, wherein the cancer dependent on a farnesylated protein is head and neck cancer, optionally wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC); orwherein the cancer dependent on a farnesylated protein is Squamous Cell Carcinoma (SCC), optionally wherein the SCC is head and neck SCC (HNSCC), lung SCC (LSCC), thyroid SCC (TSCC), esophagus SCC (ESCC), bladder SCC (BSCC) or urothelial carcinoma (UC), optionally wherein the SCC is HNSCC, optionally wherein the HNSCC is HNSCC of the trachea, HNSCC of the maxilla, HNSCC of the oral cavity.

77. The method of any one of claims 69-78, wherein the cancer dependent on a farnesylated protein is a solid tumor.