How to Inhibit the RAS

Abstract

The present disclosure relates to methods of inhibiting RAS proteins. The present disclosure also includes methods of treating cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 192,837, filed May 25, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Cancer remains one of the most deadly threats to human health. In the United States, cancer affects approximately 1.3 million new cases each year and is the second leading cause of death after heart disease, accounting for approximately one in four deaths.

[0003] It has been well established in the literature that RAS proteins (KRAS, HRAS, and NRAS) play essential roles in various human cancers and are therefore suitable targets for anticancer therapeutics. Indeed, mutations in RAS proteins account for approximately 30% of all human cancers in the United States, many of which are fatal. Dysregulation of RAS proteins through activating mutations, overexpression, or upstream expression is common in human tumors, and activating mutations in RAS are frequently found in human cancers. RAS switches between a GDP-bound "off" state and a GTP-bound "on" state. The state switch is facilitated by the interaction of guanine nucleotide exchange factor (GEF) proteins (e.g., SOS1), which load GTP onto RAS, with GTPase-activating protein (GAP) proteins (e.g., NF1), which hydrolyze GTP, resulting in RAS inactivation. In addition, SH2 domain-containing protein tyrosine phosphatase 2 (SHP2) associates with the receptor signaling machinery and becomes active upon RTK activation, promoting RAS activation. Mutations in RAS proteins can lock the protein in the "on" state, resulting in a constitutively active signaling pathway that leads to uncontrolled cell proliferation. For example, activating mutations at codon 12 in RAS proteins function by inhibiting both the GAP-dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of RAS mutant proteins toward the "on" (GTP-bound) state (RAS(ON)), resulting in oncogenic MAPK signaling. Notably, RAS exhibits picomolar affinity for GTP, allowing RAS to be activated even in the presence of low concentrations of this nucleotide. Mutations at codon 13 (eg, G13D) and codon 61 (eg, Q61K) of RAS are also responsible for oncogenic activity in some cancers.

[0004] First-in-class covalent inhibitors of the "off" form of RAS (RAS(OFF)) have shown promising antitumor activity in cancer patients with oncogenic mutations in RAS. Furthermore, therapeutic inhibition of the RAS pathway, while initially effective, can ultimately prove ineffective in many cases because it can lead to overactivation of RAS pathway signaling through a number of mechanisms, including, for example, pathway reactivation through removal of negative feedback mechanisms that naturally operate in these pathways, or can lead to resistance to RAS(OFF) inhibitors. Mutations that contribute to resistance to such inhibitors have been reported (Tanaka et al., Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation, Cancer Discovery, April 6, 2021. DOI: 10.1158 / 2159-8290.CD-21-0365; Awad et al., Mechanisms of acquired resistance to KRAS G12C Inhibition in cancer, AACR Annual Meeting 2021, April 10, 2021. As a result, cells initially sensitive to such inhibitors can become resistant. Therefore, there is a need for methods to effectively inhibit the RAS pathway in cancer patients for whom RAS(OFF) inhibitors are ineffective or likely to be ineffective, including patients naive to RAS(OFF) therapy. Summary of the Invention

[0005] The present disclosure provides methods for inhibiting RAS and treating cancer. The inventors have observed that cancer cells treated with RAS(OFF) inhibitors can develop resistance, for example, by acquiring one or more mutations that weaken or render the RAS(OFF) inhibitor ineffective. The present disclosure is based, at least in part, on the observation that some cancers that are resistant to treatment with RAS(OFF) inhibitors remain responsive to treatment with RAS(ON) inhibitors. Thus, administering a RAS(ON) inhibitor to a subject with cancer can slow or interrupt oncogenic signaling or disease progression that renders the cancer resistant to treatment with a RAS(OFF) inhibitor. Furthermore, administration of a RAS(ON) inhibitor, for example, in combination with a RAS(OFF) inhibitor, can prevent the acquisition of one or more mutations in RAS that confer resistance to RAS(OFF) inhibitors. In addition, the compounds disclosed herein can provide clinical benefit to patients naive to RAS(OFF) therapy.

[0006] In any embodiment herein, the RAS(ON) inhibitor may be a tri-complex RAS(ON) inhibitor, as that term is defined herein.

[0007] It is specifically contemplated that any limitation discussed with respect to one embodiment of the present disclosure may apply to any other embodiment of the present disclosure. Furthermore, any compound or composition of the present disclosure may be used in any method of the present disclosure, and any method of the present disclosure may be used to produce or utilize any compound or composition of the present disclosure.

[0008] Numbered Embodiments

[0009] Embodiment 1. A method of treating cancer in a subject in need thereof, wherein the cancer is: (a) a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of Y96, H95, R68, G13, and Q61; or (b) a first RAS mutation at position G12; The cancer is resistant to treatment with a RAS(OFF) inhibitor, and the method comprises administering a RAS(ON) inhibitor to the subject.

[0010] Embodiment 2. The method of embodiment 1, wherein said cancer does not comprise a KRAS Y96D mutation.

[0011] Embodiment 3. The method of embodiment 1, wherein the cancer does not contain any of the following mutations: KRAS G12D, KRAS G12V, KRAS G12C, KRAS G12R, KRAS G12A, KRAS G12S, KRAS G12F, KRAS G12L, HRAS G12S, HRAS G12D, HRAS G12C, HRAS G12V, HRAS G12A, HRAS G12N, HRAS G12R, NRAS G12D, NRAS G12S, NRAS G12C, NRAS G12V, NRAS G12A, or NRAS G12R, or any combination thereof.

[0012] Embodiment 4. The cancer is G12C amp 4. The method of any one of embodiments 1 to 3, wherein the KRAS mutation is selected from the group consisting of: G12D, G12R, G12V, G12W, G13D, Q61H, R68S, H95D, H95Q, H95R, and Y96C, or any combination thereof.

[0013] Embodiment 5. The method of any one of embodiments 1-4, further comprising administering to said subject a RAS(OFF) inhibitor.

[0014] Embodiment 6. The method of embodiment 5, wherein the RAS(ON) inhibitor and the RAS(OFF) inhibitor are administered simultaneously or sequentially.

[0015] 7. The method of embodiment 5 or 6, wherein the RAS(ON) inhibitor and the RAS(OFF) inhibitor are administered as a single formulation or as separate formulations.

[0016] Embodiment 8.

[0017] the RAS(OFF) inhibitor is administered for a first period of time; and the RAS(ON) inhibitor is administered for a second period of time; 7. The method of embodiment 6, wherein the first period and the second period do not overlap, and the first period precedes the second period.

[0018] Embodiment 9.

[0019] the RAS(OFF) inhibitor is administered for a first period of time; and the RAS(OFF) inhibitor and the RAS(ON) inhibitor are administered for a second period of time; 7. The method of embodiment 6, wherein the first period and the second period do not overlap, and the first period precedes the second period.

[0020] Embodiment 10. The method of any one of embodiments 5-9, wherein the subject's cancer progresses on the RAS(OFF) inhibitor.

[0021] Embodiment 11. The method of embodiment 1, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at position Y96.

[0022] Embodiment 12. The method of embodiment 1 or embodiment 11, wherein the second RAS mutation is selected from the group consisting of Y96C, Y96D, Y96F, Y96H, Y96N, and Y96S.

[0023] Embodiment 13. The method of embodiment 1 or embodiment 11, wherein the second RAS mutation is selected from the group consisting of Y96D, Y96F, Y96H, Y96N, and Y96S.

[0024] Embodiment 14. The method of embodiment 1 or embodiment 11, wherein the second RAS mutation is selected from the group consisting of Y96C, Y96F, Y96H, Y96N, and Y96S.

[0025] Embodiment 15. The method of embodiment 1 or embodiment 11, wherein the second RAS mutation is selected from the group consisting of Y96F, Y96H, Y96N, and Y96S.

[0026] Embodiment 16. The method of embodiment 1, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at position H95 or R68.

[0027] Embodiment 17. The method of embodiment 1 or embodiment 16, wherein the RAS mutation is G12C and the second RAS mutation is at position H95.

[0028] Embodiment 18. The method of any one of embodiments 1, 16, or 17, wherein the second RAS mutation is selected from the group consisting of H95D, H95L, H95N, H95P, H95Q, H95R, and H95Y.

[0029] Embodiment 19. The method of any one of embodiments 1, 16, or 17, wherein the second RAS mutation is selected from the group consisting of H95L, H95N, H95P, and H95Y.

[0030] Embodiment 20. The method of embodiment 1 or embodiment 16, wherein the RAS mutation is G12C and the second RAS mutation is at position R68.

[0031] Embodiment 21. The method of any one of embodiments 1, 16, or 20, wherein the second mutation is selected from the group consisting of R68G, R68K, R68M, R68S, R68T, and R68W.

[0032] Embodiment 22. The method of any one of embodiments 1, 16, or 20, wherein the second mutation is selected from the group consisting of R68G, R68K, R68M, R68T, and R68W.

[0033] Embodiment 23. The method of any one of embodiments 1-4, and 11-22, wherein the subject is being treated with a RAS(OFF) inhibitor.

[0034] Embodiment 24. A method of treating cancer in a subject in need thereof, wherein said cancer comprises an amino acid substitution at RAS Y96, H95, or R68, said method comprising administering to said subject a RAS(ON) inhibitor.

[0035] Embodiment 25. The method of embodiment 24, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at position Y96.

[0036] Embodiment 26. The method of embodiment 24 or embodiment 25, wherein the cancer does not comprise a Y96D RAS mutation.

[0037] Embodiment 27. The method of embodiment 25 or embodiment 26, wherein the second RAS mutation is selected from the group consisting of Y96C, Y96D, Y96F, Y96H, Y96N, and Y96S.

[0038] Embodiment 28. The method of embodiment 25 or embodiment 26, wherein the second RAS mutation is selected from the group consisting of Y96D, Y96F, Y96H, Y96N, and Y96S.

[0039] Embodiment 29. The method of embodiment 25 or embodiment 26, wherein the second RAS mutation is selected from the group consisting of Y96C, Y96F, Y96H, Y96N, and Y96S.

[0040] Embodiment 30. The method of embodiment 25 or embodiment 26, wherein the second RAS mutation is selected from the group consisting of Y96F, Y96H, Y96N, and Y96S.

[0041] Embodiment 31. The method of embodiment 25, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at position H95 or R68.

[0042] Embodiment 32. The method of embodiment 25 or embodiment 31, wherein the RAS mutation is G12C and the second RAS mutation is at position H95.

[0043] Embodiment 33. The method of any one of embodiments 25, 31, or 32, wherein the second RAS mutation is selected from the group consisting of H95D, H95L, H95N, H95P, H95Q, H95R, and H95Y.

[0044] Embodiment 34. The method of any one of embodiments 25, 31, or 32, wherein the second RAS mutation is selected from the group consisting of H95L, H95N, H95P, and H95Y.

[0045] Embodiment 35. The method of embodiment 25 or embodiment 31, wherein the RAS mutation is G12C and the second RAS mutation is at position R68.

[0046] Embodiment 36. The method of any one of embodiments 25, 31, or 35, wherein the second mutation is selected from the group consisting of R68G, R68K, R68M, R68S, R68T, and R68W.

[0047] Embodiment 37. The method of any one of embodiments 25, 31, or 35, wherein the second mutation is selected from the group consisting of R68G, R68K, R68M, R68T, and R68W.

[0048] Embodiment 38. The method of embodiment 1, wherein the second mutation is Q61H.

[0049] Embodiment 39. The method of embodiment 1, wherein the second mutation is G13D.

[0050] Embodiment 40. The method of any one of embodiments 27-39, wherein the subject is being treated with a RAS(OFF) inhibitor.

[0051] Embodiment 41. The method of any one of embodiments 27-40, wherein the cancer is resistant to treatment with a RAS(OFF) inhibitor.

[0052] Embodiment 42. The method of embodiment 40 or embodiment 41, wherein the subject's cancer progresses on the RAS(OFF) inhibitor.

[0053] Embodiment 43. The method of any one of embodiments 1 to 42, wherein any RAS mutation is a KRAS mutation.

[0054] Embodiment 44. The method of any one of embodiments 1 to 42, wherein any RAS mutation is an NRAS mutation.

[0055] Embodiment 45. The method of any one of embodiments 1 to 42, wherein any RAS mutation is an HRAS mutation.

[0056] Embodiment 46. A method of treating cancer in a subject in need thereof, wherein said cancer comprises a RAS mutation selected from the group consisting of G12H, G12I, G12K, G12M, G12N, G12P, G12Q, G12T, G12W, and G12Y, or a combination thereof, said method comprising administering to said subject a RAS(ON) inhibitor.

[0057] Embodiment 47. The method of embodiment 46, wherein the cancer further comprises a G12C RAS ​​mutation.

[0058] Embodiment 48. The method of embodiment 46 or 47, wherein the subject is being treated with a RAS(OFF) inhibitor.

[0059] Embodiment 49. The method of any one of embodiments 46-48, wherein the cancer is resistant to treatment with a RAS(OFF) inhibitor.

[0060] Embodiment 50. The method of embodiment 48 or embodiment 49, wherein the subject's cancer progresses on the RAS(OFF) inhibitor.

[0061] Embodiment 51. A method of inhibiting RAS in a cell, wherein said RAS comprises an amino acid substitution at Y96, H95, or R68, said method comprising contacting said cell with a RAS(ON) inhibitor.

[0062] Embodiment 52. A method of inhibiting RAS in a cell, wherein said RAS comprises an amino acid substitution at H95, or R68, said method comprising contacting said cell with a RAS(ON) inhibitor.

[0063] Embodiment 53. The method of embodiment 51 or embodiment 52, wherein the cell is in vitro.

[0064] Embodiment 54. The method of embodiment 51 or claim 52, wherein the cell is in vivo.

[0065] Embodiment 55. The method of any one of embodiments 1 to 54, wherein the RAS(ON) inhibitor is an inhibitor that is selective for RAS G12C, G13D, or G12D.

[0066] Embodiment 56. The RAS(ON) inhibitor is a RAS(ON) inhibitor. MULTI The method of any one of embodiments 1 to 54, wherein the inhibitor is an

[0067] Embodiment 57. The method of any one of embodiments 1 to 56, wherein the RAS(ON) inhibitor is a tri-complex RAS(ON) inhibitor.

[0068] Embodiment 58. The method of any one of embodiments 1 to 57, wherein the RAS(ON) inhibitor is selected from the compounds disclosed in WO2020132597.

[0069] Embodiment 59. The RAS(ON) inhibitor is a compound of formula AI: [ka] or a pharmaceutically acceptable salt thereof: wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; B is absent or -CH(R 9 )- or >C=CR 9 R 9 ' [wherein carbon is -N(R 11 )C(O)—, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8)-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is hydrogen, cyano, S(O)R', optionally substituted amino, optionally substituted amido, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, CO-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 1is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 1 and R 2 combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, R 11 is hydrogen or C1-C3 alkyl, R 16 is hydrogen or C1-C3 alkyl.

[0070] Embodiment 60. The method of any one of embodiments 1-57, wherein the RAS(ON) inhibitor is selected from the compounds set forth in Table A1 or Table A2, or a pharmaceutically acceptable salt thereof.

[0071] Embodiment 61. The RAS(ON) inhibitor is a compound of formula BI: [ka] or a pharmaceutically acceptable salt thereof: wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; B is absent or -CH(R 9 )-,>C=CR 9 R 9 ', or >CR 9 R 9 ' [wherein carbon is -N(R 11 )C(O)—, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a vinyl ketone, vinyl sulfone, ynone, haloacetyl, or alkynyl sulfone; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 1 and R 2 combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, or R 9 and R 9’ combine with the atom to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, R 11 is hydrogen or C1-C3 alkyl, and R 21 is hydrogen or C1-C3 alkyl].

[0072] Embodiment 62. The method of any one of embodiments 1 to 57, wherein the RAS(ON) inhibitor is selected from the compounds set forth in Table B1 or Table B2, or a pharmaceutically acceptable salt thereof.

[0073] Embodiment 63. The method of any one of embodiments 1-57, wherein said RAS(ON) inhibitor is a compound of formula CI, or a pharmaceutically acceptable salt thereof.

[0074] [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; B is -CH(R 9 )- or >C=CR 9 R 9 ' [wherein carbon is -N(R 11 )C(O)—, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethylcarbamate, a chloroethylthiocarbamate, an aziridine, a trifluoromethylketone, a boronic acid, a boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an isoEEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 1 and R 2 combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, and R 11 is hydrogen or C1-C3 alkyl, and R 34 is hydrogen or C1-C3 alkyl].

[0075] Embodiment 64. The method of any one of embodiments 1 to 57, wherein the RAS(ON) inhibitor is selected from the compounds set forth in Table C1 or Table C2, or a pharmaceutically acceptable salt thereof.

[0076] Embodiment 65. The RAS(ON) inhibitor is a compound of formula DIa: [ka] or a pharmaceutically acceptable salt thereof: wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, an optionally substituted 5- to 6-membered heteroarylene, an optionally substituted C2-C4 alkylene, or an optionally substituted C2-C4 alkenylene; Y is [ka] and W is hydrogen, C1-C4 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted 3-10 membered cycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; X 1 and X 4 are each independently CH or NH, R 1 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, an optionally substituted 3- to 6-membered cycloalkenyl, an optionally substituted 3- to 15-membered heterocycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, and R 10 is hydrogen, hydroxy, optionally substituted C1-C3 alkyl, or optionally substituted C1-C6 heteroalkyl.

[0077] Embodiment 66. The method of any one of embodiments 1 to 57, wherein the RAS(ON) inhibitor is selected from the compounds set forth in Table D1a or Table D1b, or a pharmaceutically acceptable salt thereof.

[0078] Embodiment 67. The RAS(ON) inhibitor is a compound of formula EI: [ka] or a pharmaceutically acceptable salt thereof: wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; L 1 is absent or is a linker, W is a bridging group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone; R 1 is hydrogen, an optionally substituted 3-10 membered heterocycloalkyl, or an optionally substituted C1-C6 heteroalkyl; R 2 is an optionally substituted C1-C6 alkyl, and R 3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl.

[0079] Embodiment 68. The method of any one of embodiments 1 to 57, wherein the RAS(ON) inhibitor is selected from the compounds set forth in Table E1, or a pharmaceutically acceptable salt thereof.

[0080] Embodiment 69. The method of any one of embodiments 1 to 57, wherein the RAS(ON) inhibitor is a compound of formula FI: [ka] wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; W is a bridging group comprising an aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethylcarbamate, chloroethylthiocarbamate, trifluoromethylketone, boronic acid, boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, oxazolium, or glycal; X 1 is CH2 or O, m is 1 or 2; n is 0 or 1, R 1 is hydrogen or an optionally substituted 3- to 10-membered heterocycloalkyl; R 2 is an optionally substituted C1-C6 alkyl, and R 3 is optionally substituted C1-C6 alkyl or optionally substituted 3- to 6-membered cycloalkyl.

[0081] Embodiment 70. The method of any one of embodiments 1-57, wherein said RAS(ON) inhibitor is selected from a compound set forth in Table F1, Table F2, Table F3, Table F4, Table F5, or Table F6.

[0082] Embodiment 71. The method of any one of embodiments 1-23, 40-45, or 48-50, wherein the RAS(OFF) inhibitor selectively targets RAS G12C.

[0083] Embodiment 72. The method of any one of embodiments 1-23, 40-45, or 48-50, wherein the RAS(OFF) inhibitor is selected from sotorasib (AMG 510), adagrasib (MRTX849), MRTX1257, JNJ-74699157 (ARS-3248), LY3537982, LY3499446, ARS-853, ARS-1620, GDC-6036, JDQ443, BPI-421286, JAB-21000, RSC-1255, ERAS-3490, D-1553, JAB-21822, GH-35, ICP-915, IBI351, and BI1823911.

[0084] Embodiment 73. The method of any one of embodiments 1-72, wherein the cancer is selected from colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendix cancer, acute myeloid leukemia, small intestine cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophageal cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, bladder cancer, and melanoma.

[0085] Embodiment 74. The method of embodiment 76, wherein the cancer is non-small cell lung cancer.

[0086] Embodiment 75. The method of any one of embodiments 1 to 74, wherein said method comprises administering to said subject or said cell an additional anti-cancer therapy. [Brief explanation of the drawings]

[0087] [Figure 1]Compound AA, a tri-complex KRASG12C(ON) inhibitor, disclosed herein as compound of Formula B1, and also disclosed herein as compound of Table B1 and found in WO 2021 / 091982, is active against second-site mutations that confer resistance to the KRASG12C(OFF) inhibitors MRTX849 and AMG 510. Figure 1A is a heat map depicting cellular RAS / RAF disruption for various KRAS mutations in the presence of different RAS inhibitors. Certain mutations (e.g., Y96C, Y96D, H95D, H95Q, H95R, R68S) have been observed in patients treated with AMG 510 (Tanaka et al., Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation, Cancer Discovery, April 6, 2021. DOI: 10.1158 / 2159-8290.CD-21-0365; Awad et al., Mechanisms of acquired resistance to KRASG12C inhibition in cancer, AACR Annual Meeting 2021, April 10, 2021). Figure 1B shows the IC50 values ​​associated with each colored bar in the heatmap. See Example 1. [Figure 2]Compound A, a tri-complex KRASMULTI(ON) inhibitor, disclosed herein as compound of formula D1, also disclosed herein as compound of Table D1 and also found in WO2022 / 060836, is active against the RAS oncogene switching mutations observed in KRASG12C(OFF) resistance. Figure 2A is a heat map showing cellular RAS / RAF disruption in the presence of different RAS inhibitors for various KRAS mutations. Specific mutations (e.g., G12C, G12F, G12R, G12V, G12W) have been observed in patients treated with AMG 510 (Tanaka et al.; Awad et al.). Figure 2B shows the IC50 values ​​associated with each colored bar in the heat map. See Example 2. [Figure 3] Figure 1 shows the in vitro efficacy of Compound A, a tri-complex KRASMULTI(ON) inhibitor disclosed herein, in multiple RAS-driven cancer cell lines. Each graph shows cell proliferation (percent of control) versus log M[Compound A]. In vitro cell growth inhibition potency of Capan-1 (KRASG12V), AsPC-1 (KRASG12D), HCT116 (KRASG13D), SK-MEL-30 (NRASQ61K), NCI-H1975 (EGFRT790M / L858R), and A375 (BRAFV600E) cells exposed to Compound A for 120 hours. Data represent the average of multiple experiments. See Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0088] The present disclosure generally relates to methods for inhibiting RAS and methods for treating cancer. In some embodiments, the present disclosure provides methods for delaying, preventing, or treating acquired resistance to RAS(OFF) inhibitors by administering a RAS(ON) inhibitor. In some embodiments, administration of a RAS(ON) inhibitor, for example, in combination with a RAS(OFF) inhibitor, can prevent the acquisition of one or more mutations in RAS that confer resistance to RAS(OFF) inhibitors. In addition, the compounds disclosed herein can provide clinical benefit to patients naive to RAS(OFF) therapy.

[0089] The heat maps shown in Figures 1A and 2A represent the overall potency observed in cellular assays that measure the amount of protein complexes between the active forms of RAS, RAS(ON), and its signaling partner, RAF kinase. Each tri-complex KRAS(ON) inhibitor inhibits KRAS. G12C The most disruptive factor was the (ON) / CRAF complex (data not shown), which is involved in the KRAS / RAF complex of the RAF and MAPK cascades. G12C This shows a block in activation.

[0090] Recently, two groups reported that adagrasib therapy (a KRAS inhibitor currently in clinical development) G12C published the first description of genetic mutations observed in ctDNA samples from patients who developed resistance to KRAS (OFF) inhibitor MRTX849. G12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation,Cancer Discovery,April 6,2021.DOI: 10.1158 / 2159-8290.CD-21-0365;Awad et al.,Mechanisms of acquired resistance to KRAS G12Cinhibition in cancer, AACR Annual Meeting 2021, April 10, 2021. Some of these mutations were studied herein, as described below.

[0091] One set of mutations (Figure 1A, Figure 1B) is KRAS G12C These mutations alter the binding site of the inhibitor class, thereby inhibiting KRAS activity. G12C This resistance is clearly depicted in the heatmap (Figure 1A) reflecting the fold change in IC50 of the inhibitors for the indicated double mutants compared to the single G12C mutation, with yellow representing the largest fold change. G12C For the (OFF) inhibitors MRTX849 and AMG 510, the majority of double mutants result in decreased potency (i.e., increased fold change) compared to the single G12C mutant (all second-site mutations measured in cis with G12C). G12C The (ON) inhibitor Compound AA was active against all tested second-site mutations with minimal fold changes in potency compared to the single G12C mutation, indicating that these mutations are not sufficient to confer resistance to Compound AA, or, more broadly, as the inventors speculate, tri-complex G12C(ON) inhibitors in general (see, e.g., Tanaka et al.), and Compound AA and other tri-complex RAS(ON) inhibitors disclosed herein may inhibit (e.g., ongoing) KRAS G12C We demonstrate that this approach may be clinically effective in treating patients naive to such therapy whose tumors harbor one or more of these second-site mutations, as well as the corresponding positions in HRAS and NRAS, as well as patients resistant to (OFF) inhibitors.

[0092] The second set of mutations (Figures 2A and 2B) are alternative oncogenic RAS mutations. We previously identified the tri-complex KRAS MULTIWe disclose cellular data demonstrating the ability of (ON) inhibitors to inhibit the growth of cancer cells harboring a range of oncogenic RAS mutations (Figure 3). A heat map (Figure 2A) shows the KRAS tricomplex inhibitors disclosed herein. MULTI Compound A, an ON inhibitor, inhibits KRAS G12X This completes the case for Compound A, which is capable of inhibiting the formation of the KRAS / RAF complex and, therefore, of inhibiting signaling driven by any possible G12 mutant of KRAS. Compound A, or more broadly, the tri-complex in general (see, e.g., Tanaka et al.), as we speculate, inhibits (e.g., ongoing) KRAS signaling. G12C These data demonstrate that clinical benefit may be achieved in treating not only patients resistant to (OFF) inhibitors, but also naive patients whose tumors harbor one or more of these alternative KRAS mutations, as well as the corresponding 12 positions in HRAS and NRAS.

[0093] General method The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell culture, molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of the art. Such techniques are described in Molecular Cloning: A Laboratory Manual, third edition (Sambrook et al., 2001) Cold Spring Harbor Press; Oligonucleotide Synthesis (P. Herdewijn, ed., 2004); Animal Cell Culture (RI Freshney), ed., 1987); Methods in Enzymology (Academic Press, Inc.); CCBlackwell, eds.); Gene Transfer Vectors for Mammalian Cells (JMMiller & MPCalos, eds., 1987); Current Protocols in Molecular Biology (FMAusubel et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (JEColigan et al. al., eds., 1991);Short Protocols in Molecular Biology(Wiley and Sons, 1999); Manual of Clinical Laboratory Immunology (B. Detrick, NRRose, and JDFolds eds., 2006); Immunochemical Protocols (J. Pound, ed., 2003); Lab Manual in Biochemistry: Immunology and Biotechnology (A. Nigam and A. Ayyagari, eds.2007); Immunology Methods Manual: The Comprehensive Sourcebook of Techniques (Ivan Lefkovits, ed., 1996); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane, eds., 1988); and others.

[0094] definition In this application, unless otherwise clear from the context, (i) the term "a" means "one or more," (ii) is used to mean "and / or" unless expressly indicated to refer to alternatives only or that the alternatives are mutually exclusive, but the present disclosure supports definitions that refer to alternatives only and to "and / or," (iii) the terms "comprising" and "including" are understood to encompass the itemized components or steps, whether presented by themselves or with one or more additional components or steps, and (iv) when ranges are presented, the endpoints are included.

[0095] As used herein, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method being used to determine the value. In certain embodiments, the term "about" refers to a range of values ​​that is included by 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (above or below) the stated value, unless otherwise stated or otherwise apparent from the context (e.g., where such number may exceed 100% of the possible values).

[0096] As used herein, the term "adjacent" in the context of describing adjacent atoms means divalent atoms that are directly joined by a covalent bond.

[0097] Those of skill in the art will understand that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., one or more atoms replaced with a different isotope of that atom, such as hydrogen replaced with deuterium) forms. Unless otherwise specified, or apparent from context, the depicted structures can be understood to represent any such isomeric or isotopic forms, individually or in combination.

[0098] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials, such as by resolution of racemic mixtures or stereoselective synthesis, are known in the art. Many geometric isomers of olefins, C=N double bonds, and the like, can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0099] In some embodiments, one or more compounds described herein can exist in different tautomeric forms. Unless explicitly excluded, as is clear from the context, reference to such a compound encompasses all such tautomeric forms. In some embodiments, a tautomeric form results from the exchange of a single bond with an adjacent double bond and the accompanying migration of a proton. In certain embodiments, a tautomeric form can be a prototropic tautomer, which is an isomeric protonation state having the same empirical formula and total charge as the referenced form. Examples of moieties having prototropic tautomeric forms are ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. In some embodiments, the tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, the tautomeric forms arise from acetal interconversion.

[0100] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present disclosure include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Isotopically labeled compounds (e.g.,3 H and 14 C) can be useful in compound or substrate tissue distribution assays. 3 H), and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Additionally, heavier isotopes, such as deuterium (i.e., 2 Substitution with, for example, H, may result in greater metabolic stability and may confer certain therapeutic advantages (e.g., longer in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms may be 2 H or 3 H or one or more carbon atoms are replaced by 13 C or 14 It is replaced by C-enriched carbon. 15 O. 13 N, 11 C and 18 Positron-emitting isotopes, such as F, are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by following procedures similar to those disclosed for the compounds of the present disclosure described herein, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0101] As is known in the art, many chemical entities can be adopted in a variety of different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates), etc. In some embodiments, the compounds of the present disclosure can be utilized in any such form, including any solid form. In some embodiments, the compounds described or illustrated herein can be provided or utilized in hydrate or solvate form.

[0102] Those of skill in the art reading this disclosure will understand that certain compounds described herein can be provided or utilized in any of a variety of forms, such as, for example, salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may refer to a particular form of that compound. In some embodiments, reference to a particular compound may refer to that compound in any form. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of that compound from a racemic mixture of that compound, a particular salt of a compound may be considered a different form from another salt form of that compound, a preparation containing a structural isomer of a double bond ((Z) or (E)) may be considered a different form from one containing the other structural isomer of that double bond ((E) or (Z)), and a preparation in which one or more atoms are isotopically different from those present in a reference preparation may be considered a different form.

[0103] At various places herein, substituents for compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, when a compound contains multiple positions where a substituent is disclosed in a group or range, unless otherwise specified, the disclosure is intended to cover individual compounds containing each and every individual subcombination of the elements at each position, as well as groups (e.g., genera and subgenera) of compounds.

[0104] The term "optionally substituted X" (e.g., optionally substituted alkyl) is intended to be equivalent to "X, where X is optionally substituted" (e.g., "alkyl, where the alkyl is optionally substituted"). The feature "X" (e.g., alkyl) itself is not intended to imply optionality. As described herein, certain compounds of interest can contain one or more "optionally substituted" moieties. Generally, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent, e.g., any of the substituents or groups described herein. Unless otherwise specified, an "optionally substituted" group can have a suitable substituent at each suitable position of the group. Also, when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents can be either the same or different at each position. For example, in the term "optionally substituted C-C alkyl-C-C heteroaryl," the alkyl portion, the heteroaryl portion, or both can be optionally substituted. Combinations of substituents contemplated by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that remain substantially unchanged when subjected to conditions that foresee their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0105] Suitable monovalent substituents at a substitutable carbon atom of an "optionally substituted" group are independently deuterium, halogen, -(CH)O-4R°, -(CH)O-4OR°, -O(CH)O-4R°, -O-(CH)O-4C(O)OR°, -(CH)O-4CH(OR°), -(CH)O-4SR°, -(CH)O-4Ph [optionally substituted with R°], -(CH)O(CH)O-1Ph [optionally substituted with R°], -CH=CHPh [optionally substituted with R°], -(CH)O(CH)O-1-pyridyl [optionally substituted with R°]. ], 4-8 membered saturated or unsaturated heterocycloalkyl (e.g., pyridyl), 3-8 membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), -NO2, -CN, -N3, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)R°, -N(R°)C(S)R°;-(CH2)0-4N(R°)C(O)NR°2;-N(R°)C(S) NR°2;-(CH2)0-4N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2)0- 4C(O)R°;-C(S)R°;-(CH2)0-4C(O)OR°;-(CH2)0-4-C(O)-N(R°)2;-(CH2)0-4-C(O)-N(R°)-S(O)2-R°;-C(NCN)N R°2;-(CH2)0-4C(O)SR°;-(CH2)0-4C(O)OSiR°3;-(CH2)0-4OC(O)R°;-OC(O)(CH2)0-4SR°;-SC(S)SR°;-(CH2) 0-4SC(O)R°;-(CH2)0-4C(O)NR°2;-C(S)NR°2;-C(S)SR°;-(CH2)0-4OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R° ;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2)0-4SSR°;-(CH2)0-4S(O)2R°;-(CH2)0-4S(O)2OR°;-(CH2)0-4OS(O)2R °;-S(O)2NR°2;-(CH2)0-4S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NOR°)NR°2;-C(NH)NR°2;-P(O)R°; -P(O)R°2; -P(O)(OR°)2; -OP(O)R°2; -OP(O)(OR°)2; -OP(O)(OR°)R°, -SiR°3; -(C1-4 straight or branched chain alkylene)ON(R°)2; or -(C1-4 straight or branched chain alkylene)C(O)ON(R°)2, wherein each R° is optionally substituted as defined below and independently represents hydrogen, -C1-6 aliphatic, -CH2Ph, -O(CH2)0-1Ph, -CH2-(5-6 membered heteroaryl) or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independently occurring R° together with the atom(s) between them form a 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below;

[0106] Suitable monovalent substituents on R° (or a ring formed by taking two independently occurring R° together with the atoms between them) are independently halogen, —(CH)O-R ● , -(Haro R ● ), -(CH2)0-2OH, -(CH2)0-2OR ● , -(CH2)0-2CH(OR ● )2, -O(HaloR ● ), -CN, -N3, -(CH2)0-2C(O)R ● , -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR ● , -(CH2)0-2SR ● , -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR ● , -(CH2)0-2NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● , -(C1-4 straight or branched chain alkylene)C(O)OR ●, or -SSR ● wherein each R ● is unsubstituted or, where preceded by "halo," is substituted only with one or more halogens, independently selected from C aliphatic, -CHPh, -O(CH)Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R include =0 and =S.

[0107] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2))2-3O-, or -S(C(R * 2) 2-3S-, wherein each R * is selected from hydrogen, a C1-6 aliphatic, which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2-3O-, wherein each R * is selected from hydrogen, a C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0108] R * Suitable substituents on the aliphatic group include -R ● , (Halo R ● ), -OH, -OR ● , -OR● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, where preceded by "halo", substituted only with one or more halogens and is independently a C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0109] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R†, -NR † 2, -C(O)R†, -C(O)OR†, -C(O)C(O)R†, -C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R†)S(O)2R † wherein each R † are independently hydrogen, C1-6 aliphatic, unsubstituted -OPh which may be substituted as defined below, or an unsubstituted 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the definition above, two independently occurring R † together with the intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0110] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ●), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, where preceded by "halo", substituted only with one or more halogens, and is independently a C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R † Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0111] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0112] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a preparation comprising a compound described herein) to a subject or system. Administration also includes administering to a subject a prodrug derivative or analog of a compound or a pharmaceutically acceptable salt of a compound or composition, which can form an equivalent amount of the active compound in the subject's body. Administration to an animal subject (e.g., a human) can be by any suitable route. For example, in some embodiments, administration can be bronchial (including bronchial infusion), buccal, enteral, interdermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, nasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, intranasal, oral, rectal, subcutaneous, sublingual, topical, intratracheal (including intratracheal infusion), transdermal, intravaginal, or intravitreal.

[0113] As used herein, the term "alkoxy" refers to an -O-C 20 It refers to an alkyl group and an alkoxy group that are attached to the remainder of the compound through an oxygen atom.

[0114] As used herein, the term "alkyl" refers to a saturated, straight- or branched-chain monovalent hydrocarbon group containing 1 to 20 (e.g., 1 to 10, or 1 to 6) carbons. In some embodiments, alkyl groups are unbranched (i.e., straight-chain), and in some embodiments, alkyl groups are branched. Alkyl groups are exemplified by, but not limited to, methyl, ethyl, n- and isopropyl, n-, sec-, iso- and tert-butyl, and neopentyl.

[0115] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by removing two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like. x -C y "Alkylene" refers to an alkylene group having x to y carbons. Exemplary values ​​of x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​of y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C6). 10 , C2-C 20 , C2-C6, C2-C 10 , or C2-C 20 In some embodiments, the alkylene can be further substituted with 1, 2, 3, or 4 substituents, as defined herein.

[0116] As used herein, the term "alkenyl," unless otherwise specified, represents a monovalent straight- or branched-chain group of 2 to 20 carbons (e.g., 2 to 6, or 2 to 10 carbons) containing one or more carbon-carbon double bonds, and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl includes both cis and trans isomers. As used herein, the term "alkenylene," unless otherwise specified, represents a divalent straight- or branched-chain group of 2 to 20 carbons (e.g., 2 to 6, or 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0117] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain group of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl and 1-propynyl.

[0118] As used herein, the term "alkynyl sulfone" refers to a group having the structure [ka] wherein R is any suitable chemical substituent as described herein.

[0119] As used herein, the term "amino" refers to -N(R†)2, e.g., -NH2 and -N(CH3)2.

[0120] As used herein, the term "aminoalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more amino moieties.

[0121] As used herein, the term "amino acid" refers to a molecule having a side chain, an amino group, and an acidic group (e.g., -COH or -SOH), where the amino acid is attached to the parent molecular group by the side chain, the amino group, or the acidic group (e.g., the side chain). As used herein, the term "amino acid" in its broadest sense refers to any compound or substance that can be incorporated into a polypeptide chain, for example, by the formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure HN-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid, in some embodiments, an amino acid is a D-amino acid, and in some embodiments, an amino acid is an L-amino acid. A "standard amino acid" refers to any of the 20 standard L-amino acids commonly found in naturally occurring peptides. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxylnorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0122] As used herein, "amino acid substitution" refers to the substitution of a wild-type amino acid in a protein with a non-wild-type amino acid. Amino acid substitutions can occur through genetic mutations and can alter one or more properties of a protein (e.g., conferring altered binding affinity or specificity, altered enzymatic activity, altered structure, or altered function). For example, if a RAS protein contains an amino acid substitution at position Y96, this notation indicates that the wild-type amino acid at position 96 of a RAS protein is tyrosine (Y), and that a RAS protein containing an amino acid substitution at position Y96 contains any amino acid other than tyrosine (Y) at position 96. The notation Y96D indicates that the wild-type tyrosine (Y) residue at position 96 has been substituted with an aspartic acid (D) residue.

[0123] As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system formed by carbon atoms, wherein the ring attached to the pendant group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl. An aryl ring can be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms can be optionally substituted.

[0124] As used herein, the term "C" represents a bond. For example, part of the term -N(C(O)-(C-C alkylene-H)- includes -N(C(O)-(C alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0125] As used herein, the terms "carbocyclic" and "carbocyclyl" refer to a monovalent, optionally substituted C- 12 "Carbocyclic" refers to a monocyclic, bicyclic, or tricyclic ring structure, which may be optionally bridged, fused, or spirocyclic, in which all rings are formed by carbon atoms and at least one ring is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decalinyl, and the like. A carbocyclic ring can be attached to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms can be optionally substituted.

[0126] As used herein, the term "carbonyl" refers to a C(O) group, which can also be represented as C=O.

[0127] As used herein, the term "carboxyl" refers to -CO2H, (C=O)(OH), COOH, or C(O)OH, or the unprotonated corresponding groups.

[0128] The term "combination therapy" refers to a therapeutic method comprising administering to a subject at least two therapeutic agents, optionally as one or more pharmaceutical compositions, as part of a treatment regimen. For example, combination therapy can include the administration of a single pharmaceutical composition comprising at least two therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. Combination therapy can include the administration of two or more pharmaceutical compositions, each comprising one or more therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. In various embodiments, at least one of the therapeutic agents is a RAS(ON) inhibitor (e.g., any one or more KRAS(ON) inhibitors disclosed herein or known in the art). In various embodiments, at least one of the therapeutic agents is a RAS(OFF) inhibitor (e.g., any one or more KRAS(OFF) inhibitors disclosed herein or known in the art). The two or more agents can optionally be administered simultaneously (as a single or separate composition) or sequentially (as separate compositions). The therapeutic agents can be administered in effective amounts. The therapeutic agents can be administered in therapeutically effective amounts. In some embodiments, the effective amount of one or more therapeutic agents can be less when used in combination therapy than the therapeutic amount of the same therapeutic agent when used as a monotherapy, due to the additive or synergistic effect of combining two or more therapeutic agents.

[0129] As used herein, the term "cyano" refers to a -CN group.

[0130] As used herein, the term "cycloalkyl" refers to a monovalent saturated cyclic hydrocarbon group, which, unless otherwise specified, may be bridged, fused, or spirocyclic having 3 to 8 carbons, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0131] As used herein, the term "cycloalkenyl" refers to a monovalent non-aromatic saturated cyclic hydrocarbon group, which, unless otherwise specified, may be bridged, fused, or spirocyclic having 3 to 8 carbons and containing one or more carbon-carbon double bonds.

[0132] As used herein, the term "diastereomers" means stereoisomers that are not mirror images of each other and are not superimposable with respect to one another.

[0133] As used herein, the term "dosage form" refers to a physically discrete unit of a compound (e.g., a compound of the invention) for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, such amount is a unit dose (or a whole fraction thereof) appropriate for administration according to a dosing regimen (i.e., using a therapeutic dosing regimen) that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population. Those skilled in the art will understand that the total amount of a therapeutic composition or compound administered to a particular subject will be determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0134] As used herein, the term "dosing regimen" refers to a collection of unit doses (usually two or more) administered individually to a subject, usually separated by a period of time. In some embodiments, a given therapeutic compound (e.g., a compound of the present disclosure) has a recommended dosing regimen, which may have one or more doses. In some embodiments, a dosing regimen includes multiple doses, each separated from the other by the same length of time period; in some embodiments, a dosing regimen includes multiple doses and at least two different time periods separating the individual doses. In some embodiments, all doses within a dosing regimen are the same unit dose. In some embodiments, different doses within a dosing regimen are different amounts. In some embodiments, a dosing regimen includes a first dose at a first dosage amount, followed by one or more additional doses at a second dosage amount that is different from the first dosage amount. In some embodiments, a dosing regimen includes a first dose at a first dosage amount, followed by one or more additional doses at a second dosage amount that is the same as the first dosage amount. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered across relevant populations (ie, is a therapeutic dosing regimen).

[0135] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0136] As used herein, "enantiomer" means each individual optically active form of a compound of the invention having an optical purity or enantiomeric excess (as measured by standard methods in the art) of at least 80% (i.e., at least 90% of one enantiomer and up to 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98%.

[0137] The term "guanidyl" means a compound having the structure [ka] wherein each R is independently any chemically suitable substituent described herein.

[0138] As used herein, the term "guanidinoalkylalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more guanidyl moieties.

[0139] As used herein, the term "haloacetyl" means an acetyl group in which at least one hydrogen has been replaced by a halogen.

[0140] As used herein, the term "haloalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more of the same or different halogen moieties.

[0141] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0142] As used herein, the term "heteroalkyl" refers to an "alkyl" group (as defined herein) in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom). The heteroatom can occur at the center or end of the radical.

[0143] As used herein, the term "heteroaryl" refers to a monovalent monocyclic or polycyclic ring system containing at least one fully aromatic ring, i.e., they contain 4n+2 pi electrons in the monocyclic or polycyclic ring system and at least one ring heteroatom selected from N, O, or S in the aromatic ring. Exemplary unsubstituted heteroaryl groups are those of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heteroaryl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings are fused to one or more aryl or carbocyclic rings, such as phenyl or cyclohexane rings. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl. A heteroaryl ring can be attached to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any ring atom can be optionally substituted. In some embodiments, a heteroaryl is substituted with 1, 2, 3, or 4 substituents.

[0144] As used herein, the term "heterocycloalkyl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system, which may be bridged, fused, or spirocyclic, in which at least one ring is non-aromatic and the non-aromatic ring contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Five-membered rings have 0 to 2 double bonds, and six- and seven-membered rings have 0 to 3 double bonds. Exemplary unsubstituted heterocycloalkyl groups are those of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heterocycloalkyl" also refers to heterocyclic compounds having bridged polycyclic structures in which one or more carbons or heteroatoms bridge two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group. The term "heterocycloalkyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, such as an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, a pyridine ring, or a pyrrolidine ring. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphthyridinyl. A heterocycloalkyl ring can be attached to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms can be optionally substituted.

[0145] As used herein, the term "hydroxy" refers to an --OH group.

[0146] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more --OH moieties.

[0147] As used herein, the term "inhibitor" refers to a compound that prevents a biomolecule (e.g., a protein, a nucleic acid) from completing or initiating a reaction. An inhibitor can inhibit a reaction, for example, by competitive, uncompetitive, or noncompetitive means. With respect to its binding mechanism, an inhibitor can be an irreversible inhibitor or a reversible inhibitor. Exemplary inhibitors include, but are not limited to, nucleic acids; DNA; RNA; shRNA; siRNA; proteins; protein mimetics; peptides; peptidomimetics; antibodies; small molecules; chemicals; and analogs that mimic the binding site of an enzyme, receptor, or protein. In some embodiments, the inhibitor is a small molecule, e.g., a low molecular weight organic compound, e.g., an organic compound having a molecular weight (Mw) of less than 1200 daltons (Da). In some embodiments, the MW is less than 1100 Da. In some embodiments, the MW is less than 1000 Da. In some embodiments, the MW is less than 900 Da. In some embodiments, the MW of the small molecule ranges from 800 Da to 1200 Da. Small molecule inhibitors include cyclic and acyclic compounds. Small molecule inhibitors include natural products and their derivatives and analogs. Small molecule inhibitors can include, for example, covalent cross-linking groups that can form covalent cross-links with amino acid side chains of target proteins.

[0148] As used herein, "isomer" refers to any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention can have one or more chiral centers or double bonds and therefore exist as stereoisomers, e.g., double bond isomers (i.e., geometric E / Z isomers), or diastereomers (e.g., enantiomers (i.e., (+) or (-), or cis / trans isomers)). In accordance with the present invention, the chemical structures depicted herein, and therefore the compounds of the invention, may be present in all their corresponding stereoisomers, i.e., in stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomeric pure), as well as in their corresponding stereoisomers. Both enantiomeric and stereoisomeric mixtures (e.g., racemates) are encompassed. Enantiomeric and stereoisomeric mixtures of the compounds of the invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0149] As used herein, the term "linker" means a divalent organic moiety that connects a first moiety (e.g., the macrocyclic moiety or B) to a second moiety (e.g., W) in a compound of Formula AI, Formula BI, Formula CI, Formula DIA, Formula EI, Formula FI, Formula FIII, or any one of these subformulas, such that the resulting compound is capable of achieving an IC50 of 2 uM or less in the Ras-RAF disruption assay procedure provided herein.

[0150] The purpose of this biochemical assay is to measure the ability of a test compound to facilitate ternary complex formation between a nucleotide-loaded Ras isoform and cyclophilin A, and the resulting ternary complex is a BRAF RBD disrupting binding to the construct and inhibiting Ras signaling through RAF effectors.

[0151] In an assay buffer containing 25 mM HEPES (pH 7.3), 0.002% Tween 20, 0.1% BSA, 100 mM NaCl, and 5 mM MgCl, untagged cyclophilin A, His6-K-RasGMPPNP (or other Ras variants), and GST-BRAF RBD are combined in a 384-well assay plate at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. Compounds are present in the plate wells as a 10-point, 3-fold dilution series starting at a final concentration of 30 μM. After 3 hours of incubation at 25°C, a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reactions were incubated for an additional 1.5 hours. TR-FRET signals were read in a microplate reader (excitation 320 nm, emission 665 / 615 nm). Compounds that promote disruption of the Ras:RAF complex are identified as those that induce a decrease in the TR-FRET ratio relative to DMSO control wells.

[0152] In some embodiments, the linker comprises 20 or fewer linear chain atoms. In some embodiments, the linker comprises 15 or fewer linear chain atoms. In some embodiments, the linker comprises 10 or fewer linear chain atoms. In some embodiments, the linker has a molecular weight of less than 500 g / mol. In some embodiments, the linker has a molecular weight of less than 400 g / mol. In some embodiments, the linker has a molecular weight of less than 300 g / mol. In some embodiments, the linker has a molecular weight of less than 200 g / mol. In some embodiments, the linker has a molecular weight of less than 100 g / mol. In some embodiments, the linker has a molecular weight of less than 50 g / mol.

[0153] As used herein, a "monovalent organic moiety" is less than 500 kDa. In some embodiments, a "monovalent organic moiety" is less than 400 kDa. In some embodiments, a "monovalent organic moiety" is less than 300 kDa. In some embodiments, a "monovalent organic moiety" is less than 200 kDa. In some embodiments, a "monovalent organic moiety" is less than 100 kDa. In some embodiments, a "monovalent organic moiety" is less than 50 kDa. In some embodiments, a "monovalent organic moiety" is less than 25 kDa. In some embodiments, a "monovalent organic moiety" is less than 20 kDa. In some embodiments, a "monovalent organic moiety" is less than 15 kDa. In some embodiments, a "monovalent organic moiety" is less than 10 kDa. In some embodiments, a "monovalent organic moiety" is less than 1 kDa. In some embodiments, a "monovalent organic moiety" is less than 500 g / mol. In some embodiments, the "monovalent organic moiety" is in the range of 500 g / mol to 500 kDa.

[0154] As used herein, the term "mutation" refers to any modification of a nucleic acid or polypeptide that results in a change in the nucleic acid or polypeptide. The term "mutation" can include, for example, point mutations, deletions, or insertions of single or multiple residues in a polynucleotide, and includes changes that occur within the protein-coding region of a gene, as well as changes in regions outside the protein-coding region, such as, but not limited to, regulatory or promoter sequences, as well as amplification, or chromosomal disruption or translocation. In certain embodiments, the mutation results in an amino acid substitution in the encoded protein.

[0155] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., a monkey, chimpanzee, baboon, or rhesus monkey.

[0156] The term "prevent" or "prevention" in relation to a subject refers to preventing the subject from suffering from a disease or disorder. Prevention includes prophylactic treatment. For example, prevention can include administering a compound disclosed herein to a subject before the subject suffers from a disease, which administration prevents the subject from suffering from the disease.

[0157] As used herein, the term "preventing acquired resistance" means avoiding the development of acquired, or adaptive, resistance. For example, the use of a RAS(ON) inhibitor as described herein in preventing acquired resistance / immune escape to a RAS(OFF) inhibitor means that the RAS(ON) inhibitor is administered before any detectable resistance to the RAS(OFF) inhibitor occurs, and that such administration of the RAS(ON) inhibitor does not result in resistance to the RAS(OFF) inhibitor.

[0158] As used herein, the term "pharmaceutical composition" means a compound, such as a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, formulated together with a pharmaceutically acceptable excipient.

[0159] As used herein, "pharmaceutically acceptable excipient" refers to any inert ingredient (e.g., a vehicle capable of suspending or dissolving an active compound) that is toxic and non-inflammatory in a subject. Typical excipients include, for example, anti-adhesives, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydration water. Excipients include, but are not limited to, optionally substituted butylated hydroxyl toluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxyl propyl cellulose, optionally substituted hydroxyl propyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those skilled in the art are familiar with the variety of agents and materials useful as excipients.See, e.g., Ansel, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients.

[0160] As used herein, the term "pharmaceutically acceptable salt" refers to those salts of the compounds described herein that are suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, etc., within the normal scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable organic acid.

[0161] The terms "RAS inhibitor" and "inhibitor of RAS" are used interchangeably and refer to any inhibitor that targets, i.e., selectively binds to or inhibits, a RAS protein. In various embodiments, these terms include RAS(OFF) and RAS(ON) inhibitors.

[0162] As used herein, the term "RAS(ON) inhibitor" refers to an inhibitor that targets, i.e., selectively binds to, or inhibits, the GTP-bound, activated state of RAS (e.g., more selectively than the GDP-bound, inactive state of RAS). Inhibition of the GTP-bound, activated state of RAS includes, for example, inhibition of oncogenic signaling from the GTP-bound, activated state of RAS. In some embodiments, a RAS(ON) inhibitor is an inhibitor that selectively binds to and inhibits the GTP-bound, activated state of RAS. In certain embodiments, a RAS(ON) inhibitor can also bind to or inhibit the GDP-bound, inactive state of RAS (e.g., with a lower affinity or inhibition constant than the GTP-bound, activated state of RAS). RAS(ON) inhibitors described herein include compounds of Formula AI, Formula BI, Formula CI, Formula DIa, Formula EI, Formula FI, Formula FIII, and subformulas thereof, as well as compounds of Table A1, Table A2, Table B1, Table B2, Table C1, Table C2, Table D1a, Table D1b, Table D2, Table D3, Table E1, Table F1, Table F3, Table F4, Table F5, and Table F6, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof. In some embodiments, the RAS(ON) inhibitor is a tri-complex RAS(ON) inhibitor, as that term is defined herein.

[0163] As used herein, the term "RAS(OFF) inhibitor" refers to an inhibitor that targets, i.e., selectively binds to, or inhibits, the GDP-bound, inactive state of RAS (e.g., selective for the GTP-bound, active state of RAS). Inhibition of the GDP-bound, inactive state of RAS includes, for example, preventing the adoption of an active conformation of RAS by sequestering the inactive state by inhibiting the exchange of GDP for GTP. In certain embodiments, a RAS(OFF) inhibitor can also bind to or inhibit the GTP-bound, activated state of RAS (e.g., with a lower affinity or inhibition constant than the GDP-bound, inactive state of RAS).

[0164] As used herein, the term "RAS MULTI By "RAS(ON) inhibitor" is meant a RAS(ON) inhibitor of at least three RAS variants having a missense mutation at one of the following positions: 12, 13, 59, 61, or 146. In some embodiments, a RAS(ON) inhibitor is used. MULTI (ON) inhibitors are RAS inhibitors of at least three RAS variants with missense mutations at one of the following positions: 12, 13, and 61. MULTI In some embodiments, RAS (ON) inhibitors are MULTI (ON) inhibitors are tri-complex RAS MULTI (ON) inhibitor.

[0165] The terms "RAS pathway" and "RAS / MAPK pathway" are used interchangeably herein to refer to the signal transduction cascade downstream of various cell surface growth factor receptors, in which activation of RAS (and its various isoforms and allotypes) is a central event driving various cellular effector events that determine cell proliferation, activation, differentiation, mobilization, and other functional properties. SHP2 delivers positive signals from growth factor receptors to the RAS activation / deactivation cycle, which is regulated by guanine nucleotide exchange factors (GEFs, such as SOS1) that load GTP onto RAS to produce functionally active, GTP-bound RAS, as well as GTP accelerator proteins (GAPs, such as NF1) that promote signal termination by converting GTP to GDP. The GTP-bound RAS produced by this cycle delivers essential positive signals to a series of serine / threonine kinases, including RAFs and MAP kinases, from which further signals propagate to various cellular effector functions.

[0166] As used herein, the term "resistance to therapy" refers to the treatment of a disorder with a therapeutic agent when the therapeutic agent is ineffective or when the therapeutic agent was previously effective but becomes less effective over time. Resistance to therapy includes acquired resistance to therapy, which refers to a decrease in the effectiveness of therapy over a period of time when the therapeutic agent is administered to a subject. Acquired resistance to therapy can result from the acquisition of mutations in the target protein that render the therapy ineffective or less effective. Thus, resistance to therapy can persist even after the administration of the therapeutic agent has ceased. In particular, cancers can become resistant to treatment with RAS(OFF) inhibitors due to the acquisition of mutations (e.g., in RAS proteins) that reduce the effectiveness of the RAS(OFF) inhibitor. Measuring the decrease in therapeutic effectiveness depends on the disorder being treated, and such methods are known to those skilled in the art. For example, the effectiveness of cancer therapy can be measured by disease progression. Effective therapy can slow or halt disease progression. Cancers that are resistant to treatment with therapeutic agents, such as RAS(OFF) inhibitors, may fail to slow or halt disease progression.

[0167] As used herein, the term "stereoisomer" refers to all possible different isomeric forms and structural forms that a compound (e.g., a compound of any formula described herein) may possess, in particular all possible stereochemical and structural isomeric forms of the basic molecular structure, including atropisomers, all diastereomers, enantiomers, or conformational isomers. Some compounds of the present invention can exist in different tautomeric forms, all of the latter being within the scope of the present invention.

[0168] As used herein, the term "sulfonyl" refers to the group -S(O)2-.

[0169] A "therapeutic agent" is any substance, e.g., a compound or composition, capable of treating a disease or disorder. In some embodiments, therapeutic agents useful in combination with the present disclosure include RAS inhibitors and cancer chemotherapy. Many such therapeutic agents are known in the art and are disclosed herein.

[0170] The term "therapeutically effective amount" refers to an amount sufficient to treat a disease, disorder, or condition when administered to a population afflicted with or suspected of having the disease, disorder, or condition in accordance with a therapeutic dosing regimen. In some embodiments, a therapeutically effective amount is an amount that reduces the occurrence or severity of one or more symptoms of the disease, disorder, or condition, or delays the onset of one or more symptoms of the disease, disorder, or condition. Those skilled in the art will appreciate that the term "therapeutically effective amount" does not, in fact, require that successful treatment be achieved in any particular individual. Rather, a therapeutically effective amount can be an amount that, when administered to subjects in need of such treatment, results in a specific, desired pharmacological response in a significant number of subjects. It is specifically understood that certain subjects may, in fact, be "refractory" to a "therapeutically effective amount." In some embodiments, reference to a therapeutically effective amount can be a reference to the amount measured in one or more specific tissues (e.g., tissues affected by a disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will appreciate that in some embodiments, a therapeutically effective amount can be formulated or administered in a single dose, hi some embodiments, a therapeutically effective amount can be formulated or administered in multiple doses, for example, as part of a dosing regimen.

[0171] By "therapeutic regimen" is meant a dosing regimen in which administration across a relevant population correlates with a desired or beneficial therapeutic outcome.

[0172] As used herein, the term "thiocarbonyl" refers to a -C(S)- group. The term "treatment" (plus "treat" or "treating"), in its broadest sense, refers to any administration of a substance (e.g., a compound of the present disclosure) that partially or completely ameliorates, alleviates, reduces, or inhibits a particular disease, disorder, or condition; partially or completely delays the onset of a particular disease, disorder, or condition; partially or completely reduces the severity of a particular disease, disorder, or condition; or partially or completely reduces the occurrence of one or more symptoms, characteristics, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment can be administered to a subject who does not exhibit signs of the associated disease, disorder, or condition, or who exhibits only early signs of a disease, disorder, or condition. Alternatively, or in addition, in some embodiments, such treatment can be administered to a subject who exhibits established signs of one or more of the associated diseases, disorders, or conditions. In some embodiments, treatment can be in a subject diagnosed with the associated disease, disorder, or condition. In some embodiments, treatment may be in a subject known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the relevant disease, disorder or condition.

[0173] The term "treatment" (plus "treat" or "treating"), in its broadest sense, refers to any administration of a substance (e.g., a compound of the present disclosure) that partially or completely ameliorates, alleviates, reduces, or inhibits a particular disease, disorder, or condition; partially or completely delays the onset of a particular disease, disorder, or condition; partially or completely reduces the severity of a particular disease, disorder, or condition; or partially or completely reduces the occurrence of one or more symptoms, characteristics, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment can be administered to a subject who does not exhibit signs of the associated disease, disorder, or condition, or who exhibits only early signs of a disease, disorder, or condition. Alternatively, or in addition, in some embodiments, such treatment can be administered to a subject who exhibits established signs of one or more of the associated diseases, disorders, or conditions. In some embodiments, treatment can be in a subject who has been diagnosed as suffering from the associated disease, disorder, or condition. In some embodiments, treatment may be in a subject known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the relevant disease, disorder or condition.

[0174] As used herein, the term "vinyl ketone" refers to a group containing a carbonyl group attached directly to a carbon-carbon double bond.

[0175] As used herein, the term "vinyl sulfone" refers to a group containing a sulfonyl group attached directly to a carbon-carbon double bond. The term "wild-type" refers to an entity having a structure or activity that is found in nature in a "normal" (as opposed to a mutant, disease, alteration, etc.) state or context. Those skilled in the art will understand that wild-type genes and polypeptides often exist in multiple alternative forms (e.g., alleles).

[0176] As used herein, the term "ynone" refers to a compound having the structure [ka] wherein R is any suitable optional substituent as described herein.

[0177] RAS inhibitors Provided herein are compounds that inhibit RAS, and uses thereof. Also provided are pharmaceutical compositions comprising one or more RAS inhibitor compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient. RAS inhibitor compounds can be used in the methods of inhibiting RAS (e.g., in a subject or cell) and treating cancer described herein. In some embodiments, the compounds of the present disclosure are or act as prodrugs, e.g., for administration to a cell or a subject in need thereof.

[0178] RAS(ON) inhibitors RAS(ON) inhibitors are provided herein. RAS(ON) inhibitors target, i.e., selectively bind to, or inhibit, the GTP-bound, activated state of RAS, i.e., are selective for the GDP-bound, inactive state of RAS. Inhibition of the GTP-bound, activated state of RAS includes, for example, inhibition of oncogenic signaling from the GTP-bound, activated state of RAS. In some embodiments, the RAS(ON) inhibitor selectively binds to and inhibits the GTP-bound, activated state of RAS. In certain embodiments, the RAS(ON) inhibitor can also bind to or inhibit the GDP-bound, inactive state of RAS (e.g., with a lower affinity or inhibition constant than the GTP-bound, activated state of RAS).

[0179] In some embodiments, the RAS(ON) inhibitor is selected from the tri-complex inhibitors disclosed in WO 202132597, WO 2021091956, WO 2021091982, or WO 2021091967, or the compounds disclosed in Table A1, Table A2, Table B1, Table B2, Table C1, Table C2, Table D1a, Table D1b, Table D2, Table D3, Table E1, Table F1, Table F2, Table F3, Table F4, Table F5, Table F6, or compounds of Formula AI, Formula BI, Formula CI, Formula DIa, Formula EI, Formula FI, Formula FIII, and subformulas thereof. In some embodiments, the RAS(ON) inhibitor is a compound described by a formula in WO 2020132597, e.g., the compound of Figure 1 therein, or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the RAS(ON) inhibitor is selective for a RAS comprising an amino acid substitution at G12, G13, Q61, or a combination thereof. In some embodiments, the RAS(ON) inhibitor is selective for a RAS comprising an amino acid substitution selected from G12C, G12D, G12V, G13C, G13D, Q61L, or a combination thereof. In some embodiments, the RAS(ON) inhibitor is selective for a RAS comprising a G12C amino acid substitution.

[0181] In some embodiments, the RAS(ON) inhibitor is a KRAS(ON) inhibitor, which refers to an inhibitor that targets, i.e., selectively binds to, or selectively inhibits, the GTP-bound, activated state of KRAS (e.g., more selectively than the GDP-bound, inactive state of KRAS). In some embodiments, the KRAS(ON) inhibitor is selective for KRAS containing an amino acid substitution at G12, G13, Q61, A146, K117, L19, Q22, V14, A59, or a combination thereof. In some embodiments, the KRAS(ON) inhibitor is selective for KRAS that contains an amino acid substitution selected from G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, G13V, or a combination thereof.

[0182] In some embodiments, the RAS(ON) inhibitor is an NRAS(ON) inhibitor, which refers to an inhibitor that targets, i.e., selectively binds to, or selectively inhibits, the GTP-bound, activated state of NRAS (e.g., more selectively than the GDP-bound, inactive state of NRAS). In some embodiments, the NRAS(ON) inhibitor is selective for NRAS containing an amino acid substitution at G12, G13, Q61, P185, A146, G60, A59, E132, E49, T50, or a combination thereof. In some embodiments, the NRAS(ON) inhibitor is selective for NRAS containing an amino acid substitution selected from Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, A59T, or a combination thereof.

[0183] In some embodiments, the RAS(ON) inhibitor is an HRAS(ON) inhibitor, which refers to an inhibitor that targets, i.e., selectively binds to, or selectively inhibits, the GTP-bound, activated state of HRAS (e.g., more selectively than the GDP-bound, inactive state of HRAS). In some embodiments, the HRAS(ON) inhibitor is selective for HRAS containing an amino acid substitution at G12, G13, Q61, K117, A59, A18, D119, A66, A146, or a combination thereof. In some embodiments, the HRAS(ON) inhibitor is selective for NRAS containing an amino acid substitution selected from Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, G12R, or a combination thereof.

[0184] In some embodiments, the RAS(ON) inhibitor is a RAS(ON) MULTI It is an inhibitor.

[0185] In some embodiments, the RAS(ON) inhibitors described herein require the formation of a high-affinity ternary complex ("tri-complex") between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the protein of interest (e.g., RAS) and a cytosolic chaperone (presenter protein) (e.g., cyclophilin A) that is ubiquitously expressed in the cell. More specifically, in some embodiments, the RAS(ON) inhibitors described herein comprise a novel cytosolic binding pocket in RAS by driving the formation of a high-affinity tri-complex between the RAS protein and the ubiquitously expressed cytosolic chaperone cyclophilin A (CYPA). Without being bound by theory, one way in which the inhibitory effects at Ras are affected by the compounds and complexes of the present invention is by the formation of steric occlusion of the interaction site between Ras and downstream effector molecules, such as RAF and PI3K, which is necessary for the propagation of oncogenic signals. In some embodiments, the RAS(ON) inhibitors inhibit the tri-complex RAS G12C In some embodiments, the RAS(ON) inhibitor is a tri-complex RAS(ON) inhibitor. G12D In some embodiments, the RAS(ON) inhibitor is a tri-complex RAS(ON) inhibitor. MULTI Such tri-complex RAS(ON) inhibitors may inhibit KRAS, HRAS, or NRAS, or a combination thereof.

[0186] In some embodiments, the RAS(ON) inhibitor is a compound having the structure of formula A00, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; swIp (switch I / P-loop) refers to an organic moiety that non-covalently binds to both the switch I binding pocket and residues 12 or 13 of the P-loop of a Ras protein (see, e.g., Johnson et al., 292:12981-12993 (2017), incorporated herein by reference); X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 1 and R 2 combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, and R 16 is hydrogen or C1-C3 alkyl (e.g., methyl). In some embodiments, the resulting compound is capable of achieving an IC50 of 2 uM or less (e.g., 1.5 uM, 1 uM, 500 nM, or 100 nM or less) in the Ras-RAF disruption assay protocol described herein.

[0187] In some embodiments, the present disclosure relates to a compound of structural formula AI, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; B is absent or -CH(R 9 )- or >C=CR 9 R 9 ' [wherein carbon is -N(R 11 )C(O)—, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is hydrogen, cyano, S(O)R', optionally substituted amino, optionally substituted amido, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, CO-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 1is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 1 and R 2 combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, R 11 is hydrogen or C1-C3 alkyl, R 16 is hydrogen or C1-C3 alkyl (e.g., methyl).

[0188] In some embodiments, the present disclosure relates to a compound of structural formula AIa, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; B is -CH(R 9 )- or >C=CR 9 R 9 ' [wherein carbon is -N(R 11)C(O)—, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, CO-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) nand X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 1 and R 2 combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8aare independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, and R 11 is hydrogen or C1-C3 alkyl].

[0189] In some embodiments, the present disclosure relates to a compound of structural formula AIb, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-[wherein the carbon is -N(R 11 )C(O)—, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, CO-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8'; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 is hydrogen or C1-C3 alkyl.

[0190] In some embodiments of formula AI and subformulas thereof, G is an optionally substituted C1-C4 heteroalkylene.

[0191] In some embodiments, the RAS(ON) inhibitor has the structure of formula AIc, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-[wherein the carbon is -N(R 11 )C(O)—, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, CO-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 is hydrogen or C1-C3 alkyl.

[0192] In some embodiments of formula AI and its subformulas, X 2 In some embodiments of formula AI and its subformulas, X 3 is CH.

[0193] In some embodiments of formula AI and its subformulas, R 11 is hydrogen. In some embodiments of formula AI and subformulas thereof, R 11 is C1-C3 alkyl. In some embodiments of formula AI and subformulas thereof, R 11 is methyl.

[0194] In some embodiments, the RAS(ON) inhibitor has the structure of formula AId, or a pharmaceutically acceptable salt thereof. [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, CO-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl, and R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl.

[0195] In some embodiments of the compounds of the present invention, X 1 is an optionally substituted C1-C2 alkylene. In some embodiments, X 1 is methylene. In some embodiments, X 1 is methylene substituted with a C1-C6 alkyl group or a halogen. 1 is —CH(Br)—. In some embodiments, X 1 is -CH(CH3)-.

[0196] In some embodiments of formula AI and its subformulas, R 3 does not exist.

[0197] In some embodiments of formula AI and its subformulas, R 4 is hydrogen.

[0198] In some embodiments of formula AI and its subformulas, R 5 is hydrogen. In some embodiments of formula AI and subformulas thereof, R 5 is C1-C4 alkyl optionally substituted with halogen. In some embodiments of formula AI and subformulas thereof, R 5 is methyl.

[0199] In some embodiments of formula AI and its subformulas, Y 4 is C. In some embodiments of formula AI and its subformulas, Y 5 In some embodiments of formula AI and its subformulas, Y 6 In some embodiments of formula AI and its subformulas, Y 1 is C. In some embodiments of formula AI and its subformulas, Y 2 is C. In some embodiments of formula AI and its subformulas, Y 3 is N. In some embodiments of formula AI and its subformulas, Y 7 is C.

[0200] In some embodiments, the RAS(ON) inhibitor has the structure of formula AIe, or a pharmaceutically acceptable salt thereof: [ka] wherein A is —N(H or CH3)C(O)—(CH2)—; wherein the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, CO-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl, and R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl.

[0201] In some embodiments of formula AI and its subformulas, R 6 is hydrogen.

[0202] In some embodiments of formula AI and its subformulas, R 2 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments of formula AI and its subformulas, R 2 is optionally substituted C1-C6 alkyl, for example, ethyl. In some embodiments of formula AI and its subformulas, R 2 is fluoroC1-C6 alkyl, for example, —CH2CH2F, —CH2CHF2, or —CH2CF3.

[0203] In some embodiments of formula AI and its subformulas, R 7 is an optionally substituted C1-C3 alkyl. In some embodiments of formula AI and subformulas thereof, R 7 is C1-C3 alkyl.

[0204] In some embodiments of formula AI and its subformulas, R 8 is an optionally substituted C1-C3 alkyl. In some embodiments of formula AI and subformulas thereof, R 8 is C1-C3 alkyl, for example methyl.

[0205] In some embodiments, the RAS(ON) inhibitor has the structure of formula AIf, or a pharmaceutically acceptable salt thereof: [ka] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, CO-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R 7 is C1-C3 alkyl, R 8 is C1-C3 alkyl, and R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0206] In some embodiments of formula AI and its subformulas, R 1 is a 5-10 membered heteroaryl. In some embodiments, R 1 is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl.

[0207] In some embodiments of formula AI and subformulas thereof, R1 is [ka] or a stereoisomer thereof. In some embodiments, R is [ka] or a stereoisomer thereof. In some embodiments, R is [ka] In some embodiments, R is [ka] or a stereoisomer thereof. In some embodiments, R is [ka] is.

[0208] In some embodiments, the RAS(ON) inhibitor has the structure of formula AIg, or a pharmaceutically acceptable salt thereof: [ka] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, CO-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R 2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R 7 is C1-C3 alkyl, R 8 is C1-C3 alkyl, R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; or X e is N, CH, or CR 17 and X f is N or CH, R 12 is hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, and R 17is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, an optionally substituted 3- to 6-membered cycloalkenyl, an optionally substituted 3- to 6-membered heterocycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl.

[0209] In some embodiments of formula AI and its subformulas, X e is N and X f is CH. In some embodiments, X e is CH and X f is N. In some embodiments, X e is CR 17 and X f is N.

[0210] In some embodiments of formula AI and its subformulas, R 12 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R 12 teeth, [ka] is.

[0211] In some embodiments, the RAS(ON) inhibitor has the structure of formula AIh, or a pharmaceutically acceptable salt thereof: [ka] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, CO-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R 2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R 7 is C1-C3 alkyl, R 8 is C1-C3 alkyl, R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; or X e is CH, or CR 17 and R 17 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, an optionally substituted 3- to 6-membered cycloalkenyl, an optionally substituted 3- to 6-membered heterocycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl.

[0212] In some embodiments, the RAS(ON) inhibitor has the structure of formula AIi, or a pharmaceutically acceptable salt thereof: [ka] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, CO-C4 alkyl, optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; R 2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R 7 is C1-C3 alkyl, R 8 is C1-C3 alkyl, and R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl.

[0213] In some embodiments of formula AI and subformulas thereof, A is an optionally substituted 6-membered arylene. In some embodiments, A is a group represented by the structure [ka] wherein R 13 is hydrogen, hydroxy, amino, cyano, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is hydroxy. In some embodiments, A is an optionally substituted 5-10 membered heteroarylene. In some embodiments, A is [ka] In some embodiments, A is an optionally substituted 5-6 membered heteroarylene. In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0214] In some embodiments of formula AI and subformulas thereof, B is —CHR 9 In some embodiments, R 9 is an optionally substituted C1-C6 alkyl or an optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, R 9 teeth, [ka] In some embodiments, R 9 teeth, [ka] In some embodiments, R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0215] In some embodiments of formula AI and subformulas thereof, B is an optionally substituted 6-membered arylene.

[0216] In some embodiments, B is a 6-membered arylene. [ka] In some embodiments, B is absent.

[0217] In some embodiments of formula AI and its subformulas, R 7 is methyl.

[0218] In some embodiments of formula AI and its subformulas, R 8 is methyl.

[0219] In some embodiments of formula AI and its subformulas, R 16 is hydrogen.

[0220] In some embodiments of Formula AI and subformulas thereof, the linker has the structure of Formula AII: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 formula AII [In the formula, A 1is the bond between the linker and B; A 2 is the bond between W and the linker; B 1 , B 2 , B 3 , and B 4 are each independently an optionally substituted C1-C2 alkylene, an optionally substituted C1-C3 heteroalkylene, O, S, and NR N Selected from;R N is hydrogen, optionally substituted C1-4 alkyl, optionally substituted C1-C3 cycloalkyl, optionally substituted C 2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted C1-C7 heteroalkyl; C 1 and C 2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; D 1 is an optionally substituted C1-C 10 Alkylene, optionally substituted C-C 10 Alkenylene, optionally substituted C-C 10 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-C 10 Polyethylene glycolene or optionally substituted C1-C 10 heteroalkylene, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2In some embodiments, the linker is acyclic. In some embodiments, the linker has the structure of Formula AIIa: [ka] [In the formula, X a is absent or is N, R 14 is absent or is hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C3 cycloalkyl, and L 2 is absent, -C(O)-, -SO2-, optionally substituted C1-C4 alkylene, or optionally substituted C1-C4 heteroalkylene; and X a , R 14 , or L 2 In some embodiments, at least one of the following is present: [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, the linker is or includes a cyclic group. In some embodiments of Formula AI and its subformulas, the linker has the structure of Formula AIIb: [ka] wherein o is 0 or 1; X b is C(O) or SO2, R 15is hydrogen or optionally substituted C1-C6 alkyl, Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heterocycloalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene, and L 3 is absent, —C(O)—, —SO—, an optionally substituted C-C alkylene, or an optionally substituted C-C heteroalkylene. In some embodiments, the linker has the following structure: [ka] [ka]

[0221] In some embodiments of formula AI and subformulas thereof, W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, C0-C4 alkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted 3-8 membered cycloalkyl, or 3-8 membered heteroaryl.

[0222] In some embodiments of Formula AI and its subformulas, W is hydrogen. In some embodiments of Formula AI and its subformulas, W is optionally substituted amino. In some embodiments of Formula AI and its subformulas, W is -NHCH3 or -N(CH3)2. In some embodiments of Formula AI and its subformulas, W is optionally substituted C1-C4 alkoxy. In some embodiments, W is methoxy or isopropoxy. In some embodiments of Formula AI and its subformulas, W is optionally substituted C1-C4 alkyl. In some embodiments, W is methyl, ethyl, isopropyl, tert-butyl, or benzyl. In some embodiments of Formula AI and its subformulas, W is optionally substituted amido. In some embodiments, W is [ka] In some embodiments, W is [ka] In some embodiments of formula AI and subformulas thereof, W is optionally substituted C1-C4 hydroxyalkyl. In some embodiments, W is [ka] In some embodiments of formula AI and subformulas thereof, W is an optionally substituted C1-C4 aminoalkyl. In some embodiments, W is [ka] In some embodiments of formula AI and subformulas thereof, W is an optionally substituted C1-C4 haloalkyl. In some embodiments, W is [ka] In some embodiments of formula AI and subformulas thereof, W is optionally substituted C1-C4 guanidinoalkyl. In some embodiments, W is [ka] In some embodiments of formula AI and subformulas thereof, W is C0-C4 alkyl, optionally substituted 3-11 membered heterocycloalkyl. In some embodiments, W is [ka] [ka] [ka] [ka] [ka] In some embodiments of formula AI and subformulas thereof, W is an optionally substituted 3-8 membered cycloalkyl. In some embodiments, W is [ka] In some embodiments of formula AI and subformulas thereof, W is an optionally substituted 3-8 membered heteroaryl. In some embodiments, W is [ka] In some embodiments of formula AI and subformulas thereof, W is an optionally substituted 6-10 membered aryl (e.g., phenyl, 4-hydroxy-phenyl, or 2,4-methoxy-phenyl).

[0223] In some embodiments, the RAS(ON) inhibitor is selected from Table A1, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the RAS(ON) inhibitor is selected from Table A1, or a pharmaceutically acceptable salt or atropisomer thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-79

Table 1-80

Table 1-81

[0224] In some embodiments, a compound of Table A2, or a pharmaceutically acceptable salt thereof, is provided. In some embodiments, the RAS(ON) inhibitor is selected from Table A2, or a pharmaceutically acceptable salt or atropisomer thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

[0225] The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic, or enzymatic processes.

[0226] The compounds of the present invention can be prepared by a number of methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods shown in the following schemes and WO 2021 / 091956, along with synthetic methods known in the art of organic synthetic chemistry, or variations thereof as would be understood by those skilled in the art. These methods include, but are not limited to, the following schemes and the methods described in WO 2021 / 091956.

[0227] The compounds in Table A1 herein were prepared using the methods disclosed herein or prepared using the methods disclosed herein in combination with the knowledge of those skilled in the art. The compounds in Table A2 can be prepared using the methods disclosed herein or prepared using the methods disclosed herein in combination with the knowledge of those skilled in the art.

[0228] Scheme A1. General synthesis of macrocyclic esters [ka]

[0229] The general synthesis of macrocyclic esters is outlined in Scheme A1. The appropriately substituted arylindole intermediate (1) can be prepared in three steps, starting from protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol and an appropriately substituted boronic acid, including palladium-mediated coupling, alkylation, and deprotection reactions.

[0230] Methyl-amino-hexahydropyridazine-3-carboxylate-boronic ester (2) can be prepared in three steps including protection, iridium catalyst-mediated borylation, and methyl (S)-hexahydropyridazine-3-carboxylate.

[0231] Methyl-L-valinate can be coupled with protected (S)-pyrrolidine-3-carboxylic acid, followed by deprotection and coupling with an appropriately substituted carboxylic acid, followed by a hydrolysis step to generate the appropriately substituted acetylpyrrolidine-3-carbonyl-N-methyl-L-valine (4).

[0232] The final macrocyclic ester is prepared by coupling methyl-amino-hexahydropyridazine-3-carboxylate-boronic ester (2) with intermediate (1) in the presence of a Pd catalyst, followed by hydrolysis and macrolactonization steps to afford the appropriately protected macrocyclic intermediate (5). Deprotection and coupling with appropriately substituted acetylpyrrolidine-3-carbonyl-N-methyl-L-valine (4) affords the macrocyclic product. Additional deprotection or functionalization steps are required to prepare the final compound. For example, one skilled in the art could introduce the desired -BLW group (where B, L, and W are as defined herein) of a compound of formula (AI) into the macrocyclic ester by using the methods exemplified in the Examples section of this specification.

[0233] Scheme A2. Alternative general synthesis of macrocyclic esters [ka]

[0234] Alternatively, macrocyclic esters can be prepared as described in Scheme 2. A suitably protected bromo-indolyl (6) can be coupled with a boronate ester (3) in the presence of a Pd catalyst, followed by iodination, deprotection, and ester hydrolysis. Coupling with methyl (S)-hexahydropyridazine-3-carboxylate, followed by hydrolysis and macrolactonization, affords the iodo intermediate (7). Coupling with an appropriately substituted boronate ester in the presence of a Pd catalyst and alkylation affords the fully protected macrocyclic compound (5). Additional deprotection or functionalization steps are required to generate the final compound. For example, one skilled in the art could use the methods illustrated in the Examples section of this specification to introduce the desired -BLW group (where B, L, and W are as defined herein) of a compound of formula (AI) into the macrocyclic ester.

[0235] Scheme A3. General synthesis of macrocyclic esters [ka]

[0236] Alternatively, the fully protected macrocycle (5) can be deprotected, coupled with an appropriately substituted coupling partner, and deprotected to provide the macrocyclic product. Additional deprotection or functionalization steps are required to generate the final compound. For example, one skilled in the art could use the methods illustrated in the Examples section of this specification to introduce the desired -BLW group (where B, L, and W are as defined herein) of a compound of formula (AI) into the macrocyclic ester.

[0237] Scheme A4. General synthesis of macrocyclic esters [ka]

[0238] An alternative general synthesis of macrocyclic esters is outlined in Scheme A4. Appropriately substituted indolylboronic esters (8) can be prepared in four steps starting from protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol and an appropriately substituted boronic acid, including palladium-mediated coupling, alkylation, deprotection, and palladium-mediated borylation.

[0239] Methyl-amino-3-(4-bromothiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (10) can be prepared by coupling of (S)-2-amino-3-(4-bromothiazol-2-yl)propanoic acid (9) with methyl (S)-hexahydropyridazine-3-carboxylate.

[0240] The final macrocyclic ester is prepared by coupling methyl-amino-3-(4-bromothiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (10) and an appropriately substituted indolylboronic ester (8) in the presence of a Pd catalyst, followed by hydrolysis and macrolactonization steps to afford the appropriately protected macrocyclic intermediate (11). Deprotection and coupling with an appropriately substituted carboxylic acid (or other coupling partner) or intermediate 4 can provide the macrocyclic product. Additional deprotection or functionalization steps may be required to generate the final compounds 13 or 14.

[0241] Furthermore, the compounds of the present disclosure can be synthesized using methods known in the art of synthetic organic chemistry, or variations thereof as understood by those skilled in the art, as well as the methods described in the following examples. These methods include, but are not limited to, those described in WO2021 / 091956. For example, one skilled in the art could use the methods exemplified in the Examples section of this specification to introduce the desired -BLW group (wherein B, L, and W are as defined herein) of a compound of formula (AI) into a macrocyclic ester.

[0242] In some embodiments, the RAS(ON) inhibitor is a compound having the structure of formula BI, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; B is absent or -CH(R 9 )-,>C=CR 9 R 9 ', or >CR 9 R 9 ' [wherein carbon is -N(R 11 )C(O)—, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a vinyl ketone, vinyl sulfone, ynone, haloacetyl, or alkynyl sulfone; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 1 and R 2 combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, or R 9 and R 9’ combine with the atom to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, R 11 is hydrogen or C1-C3 alkyl, and R 21 is hydrogen or C1-C3 alkyl (e.g., methyl).

[0243] In some embodiments of Formula BI, R 9 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0244] In some embodiments of Formula BI, R 21 is hydrogen.

[0245] In some embodiments, provided herein are compounds having the structure of Formula BIa, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; B is -CH(R 9 )- or >C=CR 9 R 9 ' [wherein carbon is -N(R 11 )C(O)—, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8)-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a vinyl ketone, vinyl sulfone, ynone, haloacetyl, or alkynyl sulfone; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 1 and R 2combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, and R 11 is hydrogen or C1-C3 alkyl].

[0246] In some embodiments, the present disclosure relates to a compound of structural formula BIb, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-[wherein the carbon is -N(R 11 )C(O)—, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a vinyl ketone, vinyl sulfone, ynone, haloacetyl, or alkynyl sulfone; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 and Y 6 are independently CH or N; R 1is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11is hydrogen or C1-C3 alkyl.

[0247] In some embodiments of formula BI and subformulas thereof, G is an optionally substituted C1-C4 heteroalkylene.

[0248] In some embodiments, provided are compounds having the structure of Formula BIc, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-[wherein the carbon is -N(R 11 )C(O)—, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone; X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7 'R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 is hydrogen or C1-C3 alkyl.

[0249] In some embodiments of formula B1 and its subformulas, X 2 In some embodiments of formula BI and its subformulas, X 3 In some embodiments of formula BI and its subformulas, R 11 is hydrogen. In some embodiments of Formula BI and its subformulas, R 11 is C1-C3 alkyl. In some embodiments of Formula BI and its subformulas, R 11 is methyl.

[0250] In some embodiments, the RAS(ON) inhibitor has the structure of Formula BId, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7’ R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl, and R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl.

[0251] In some embodiments of formula B1 and its subformulas, X 1 is an optionally substituted C1-C2 alkylene. In some embodiments, X 1 is methylene. In some embodiments of formula BI and its subformulas, X 1 is methylene substituted with a C1-C6 alkyl group or a halogen. 1 is —CH(Br)—. In some embodiments, X 1 is —CH(CH)—. In some embodiments of Formula BI and its subformulas, R 5 is hydrogen. In some embodiments of Formula BI and its subformulas, R 5 is C-C alkyl optionally substituted with halogen. In some embodiments, R 5 is methyl. In some embodiments of formula BI and its subformulas, Y 4 is C. In some embodiments of formula BI and its subformulas, R4 is hydrogen. In some embodiments of formula BI and its subformulas, Y 5 is CH.

[0252] In some embodiments of formula B1 and its subformulas, Y 6 In some embodiments of formula BI and its subformulas, Y 1 is C. In some embodiments of formula BI and its subformulas, Y 2 is C. In some embodiments of formula BI and its subformulas, Y 3 is N. In some embodiments of formula BI and its subformulas, R 3 In some embodiments of formula BI and its subformulas, Y 7 is C.

[0253] In some embodiments, the RAS(ON) inhibitor has the structure of Formula BIe, or a pharmaceutically acceptable salt thereof: [ka] wherein A is —N(H or CH3)C(O)—(CH2)—; wherein the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone; R 1is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7’ R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl, and R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl.

[0254] In some embodiments of formula B1 and its subformulas, R 6 is hydrogen. In some embodiments, R 2 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl. In some embodiments, R 2is an optionally substituted C1-C6 alkyl. In some embodiments, R2 is fluoroalkyl. In some embodiments, R 2 is ethyl. In some embodiments, R2 is -CH2CF3. In some embodiments, R2 is C2-C6 alkynyl. In some embodiments, R2 is -CHC≡CH. In some embodiments, R2 is -CH2C≡CCH3. In some embodiments, R 7 is an optionally substituted C1-C3 alkyl. In some embodiments, R 7 is C1-C3 alkyl. In some embodiments, R 8 is an optionally substituted C1-C3 alkyl. In some embodiments, R 8 is C1-C3 alkyl.

[0255] In some embodiments, the RAS(ON) inhibitor has the structure of formula BIf, or a pharmaceutically acceptable salt thereof: [ka] wherein A is —N(H or CH3)C(O)—(CH2)—; wherein the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone; R 1is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R 7 is C1-C3 alkyl, R 8 is C1-C3 alkyl, and R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0256] In some embodiments of formula B1 and its subformulas, R 1 is an optionally substituted 6-10 membered aryl, an optionally substituted 3-6 membered cycloalkenyl, or an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 1 is an optionally substituted 6-membered aryl, an optionally substituted 6-membered cycloalkenyl, or an optionally substituted 6-membered heteroaryl.

[0257] In some embodiments of Formula B1 and subformulas thereof, R1 is [ka] In some embodiments of formula BI and its subformulas, R 12 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R 12 teeth, [ka] In some embodiments, R 12 teeth [ka] is.

[0258] In some embodiments, the RAS(ON) inhibitor has the structure of formula BVI, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 10-membered heteroarylene; B is absent or -CH(R 9 )-,>C=CR 9 R 9 ', or >CR 9 R 9 ' [wherein carbon is -N(R 11 )C(O)—, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a vinyl ketone, vinyl sulfone, ynone, haloacetyl, or alkynyl sulfone; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR7’ R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, or R 9 and R 9’ combine with the atom to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, R 11 is hydrogen or C1-C3 alkyl, R 21 is hydrogen or C1-C3 alkyl (e.g., methyl), and X e and X f are independently N or CH].

[0259] In some embodiments, the RAS(ON) inhibitor has the structure of formula BVIa, or a pharmaceutically acceptable salt thereof: [ka] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; R 2 is C1-C6 alkyl, C1-C6 fluoroalkyl, or 3- to 6-membered cycloalkyl; R 7 is C1-C3 alkyl, R 8 is C1-C3 alkyl, and R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; or X e and X f are independently N or CH; R 11 is hydrogen or C1-C3 alkyl, and R 21 is hydrogen or C1-C3 alkyl].

[0260] In some embodiments of formula B1 and its subformulas, X e is N and X f is CH. In some embodiments, X e is CH and X f is N.

[0261] In some embodiments, the RAS(ON) inhibitor has the structure of formula BVIb, or a pharmaceutically acceptable salt thereof: [ka] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; or L is absent or a linker, and W is a bridging group comprising a vinyl ketone, vinyl sulfone, ynone, or alkynyl sulfone].

[0262] In some embodiments of Formula BI or subformulas thereof, A is an optionally substituted 6-membered arylene.

[0263] In some embodiments, the RAS(ON) inhibitor has the structure of formula BVIc, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 10-membered heteroarylene; B is absent or -CH(R 9 )-,>C=CR 9 R 9 ', or >CR 9 R 9 ' [wherein carbon is -N(R 11 )C(O)—, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a vinyl ketone, vinyl sulfone, ynone, haloacetyl, or alkynyl sulfone; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7’ R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, or R 9 and R 9’ combine with the atom to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, R 11 is hydrogen or C1-C3 alkyl, and R 21 is hydrogen or C1-C3 alkyl (e.g., methyl).

[0264] In some embodiments of formula BI and subformulas thereof, A has the following structure: [ka] wherein R 13 is hydrogen, halo, hydroxy, amino, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 13a is hydrogen or halo. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 andR13a are each hydrogen. In some embodiments, R 13 is hydroxy, methyl, fluoro, or difluoromethyl.

[0265] In some embodiments of formula BI and subformulas thereof, A is an optionally substituted 5- to 6-membered heteroarylene. [ka] is.

[0266] In some embodiments of formula BI and subformulas thereof, A is an optionally substituted C1-C4 heteroalkylene. [ka] In some embodiments of formula BI and subformulas thereof, A is an optionally substituted 3- to 6-membered heterocycloalkylene. In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0267] In some embodiments of formula B1 and subformulas thereof, B is -CHR 9 In some embodiments of formula BI and its subformulas, R 9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. 9 teeth, [ka] In some embodiments, R 9 teeth, [ka] In some embodiments, R 9 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0268] In some embodiments of formula B1 and subformulas thereof, B is an optionally substituted 6-membered arylene. In some embodiments, B is a 6-membered arylene. In some embodiments, B is [ka] is.

[0269] In some embodiments of formula B1 and its subformulas, R 7 is methyl.

[0270] In some embodiments of formula B1 and its subformulas, R 8 is methyl.

[0271] In some embodiments of formula B1 and its subformulas, R 21 is hydrogen.

[0272] In some embodiments of Formula BI and subformulas thereof, the linker has the structure of Formula BII: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C2 ) j -(B 4 ) k -A 2 Formula BII [In the formula, A 1 is the bond between the linker and B; A 2 is the bond between W and the linker; B 1 , B 2 , B 3 , and B 4 are each independently an optionally substituted C1-C2 alkylene, an optionally substituted C1-C3 heteroalkylene, O, S, and NR N Selected from;R N is hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted C1-C7 heteroalkyl; C 1 and C 2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; D 1 is an optionally substituted C1-C 10 Alkylene, optionally substituted C-C 10 Alkenylene, optionally substituted C-C 10 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-C 10 Polyethylene glycolene or optionally substituted C1-C 10 heteroalkylene, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C2 ) j -(B 4 ) k -A 2 In some embodiments, the linker is acyclic. In some embodiments, the linker has the structure of Formula BIIa: [ka] [In the formula, X a is absent or is N, R 14 is absent, hydrogen, or optionally substituted C1-C6 alkyl, and L 2 is absent, -SO2-, an optionally substituted C1-C4 alkylene, or an optionally substituted C1-C4 heteroalkylene; and X a , R 14 , or L 2 In some embodiments, the linker has the following structure: [ka]

[0273] In some embodiments of Formula B1 and its subformulas, the linker is or includes a cyclic moiety. In some embodiments, the linker has the structure of Formula B1b: [ka] wherein o is 0 or 1; R 15 is hydrogen, or optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; X 4 is absent, optionally substituted C1-C4 alkylene, O, NCH3, or optionally substituted C1-C4 heteroalkylene; Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heterocycloalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene, and L 3 is absent, -SO2-, an optionally substituted C1-C4 alkylene, or an optionally substituted C1-C4 heteroalkylene.

[0274] In some embodiments of Formula B1 and subformulas thereof, the linker has the structure of Formula BIIb-1: [ka] wherein o is 0 or 1; R 15 is hydrogen, or optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heterocycloalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene, and L 3 is absent, -SO2-, an optionally substituted C1-C4 alkylene, or an optionally substituted C1-C4 heteroalkylene.

[0275] In some embodiments of Formula BI and subformulas thereof, the linker has the structure of Formula BIIc: [ka] [In the formula, R 15 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene, and R 15a , R 15b , R 15c , R15d , R 15e , R 15f , and R 15g are independently hydrogen, halo, hydroxy, cyano, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or 15b and R 15d combine with the carbons to which they are attached to form an optionally substituted 3- to 8-membered cycloalkylene or an optionally substituted 3- to 8-membered heterocycloalkylene.

[0276] In some embodiments of Formula BI and subformulas thereof, the linker has the structure: [ka] [ka]

[0277] In some embodiments of Formula BI and subformulas thereof, the linker has the structure: [ka] [ka] [ka] [ka]

[0278] In some embodiments of formula BI and subformulas thereof, the linker has the structure [ka] It has.

[0279] In some embodiments of formula BI and subformulas thereof, the linker has the structure [ka] In some embodiments of Formula B1 and its subformulas, W is a bridging group comprising a vinyl ketone. In some embodiments, W has the structure of Formula BIIIa: [ka] [In the formula, R 16a , R 16b , and R 16c are independently hydrogen, —CN, halogen, or —OH, —O—C1-C3 alkyl, In some embodiments, W is -NH, -NH(C-C alkyl), -N(C-C alkyl), or -C-C alkyl optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl. [ka] In some embodiments of Formula B1 and its subformulas, W is a bridging group comprising an ynone. In some embodiments, W has the structure of Formula BIIIb: [ka] [In the formula, R 17 is hydrogen; -C1-C3 alkyl optionally substituted with one or more substituents independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or 4- to 7-membered saturated heterocycloalkyl; or 4- to 7-membered saturated heterocycloalkyl. In some embodiments, W is [ka] [ka] In some embodiments, W is [ka] is.

[0280] In some embodiments of Formula B1 and its subformulas, W is a bridging group comprising a vinyl sulfone. In some embodiments, W has the structure of Formula BIIIc: [ka] [In the formula, R 18a , R 18b , and R 18c are independently hydrogen, —CN, or —OH, —O—C1-C3 alkyl, In some embodiments, W is -NH, -NH(C-C alkyl), -N(C-C alkyl), or -C-C alkyl optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl. [ka] In some embodiments of Formula B1 and its subformulas, W is a bridging group comprising an alkynyl sulfone. In some embodiments, W has the structure of Formula BIIId: [ka] [In the formula, R 19 is hydrogen; -C1-C3 alkyl optionally substituted with one or more substituents independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or 4- to 7-membered saturated heterocycloalkyl; or 4- to 7-membered saturated heterocycloalkyl. In some embodiments, W is [ka] is.

[0281] In some embodiments of Formula B1 and its subformulas, W has the structure of Formula BIIIe: [ka] [In the formula, X e is a halogen, and R 20 is hydrogen; -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or -C1-C3 alkyl optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl. In some embodiments of Formula BI and subformulas thereof, W is: In some embodiments of Formula BI and subformulas thereof, W is not haloacetyl.

[0282] In some embodiments, the RAS(ON) inhibitor is selected from Table B1, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the RAS(ON) inhibitor is selected from Table B1, or a pharmaceutically acceptable salt or atropisomer thereof. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5]

Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 3-10

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Table 3-24

Table 3-25

Table 3-26

Table 3-27

Table 3-28

Table 3-29

Table 3-30

Table 3-31

Table 3-32

Table 3-33

Table 3-34

Table 3-35

Table 3-36

Table 3-37

Table 3-38

Table 3-39

Table 3-40

Table 3-41

Table 3-42

Table 3-43

Table 3-44

Table 3-45

Table 3-46

Table 3-47

Table 3-48

Table 3-49

Table 3-50

Table 3-51

Table 3-52

Table 3-53

Table 3-54

Table 3-55

Table 3-56

Table 3-57

Table 3-58

Table 3-59

Table 3-60

Table 3-61

Table 3-62

Table 3-63

Table 3-64

Table 3-65

Table 3-66

Table 3-67

Table 3-68

Table 3-69

Table 3-70

Table 3-71

Table 3-72

Table 3-73

Table 3-74

Table 3-75

Table 3-76

Table 3-77

Table 3-78

Table 3-79

Table 3-80

Table 3-81

Table 3-82

Table 3-83

Table 3-84

Table 3-85

Table 3-86

Table 3-87

Table 3-88

[0283] In some embodiments, a compound of Table B2, or a pharmaceutically acceptable salt thereof, is provided. In some embodiments, the RAS(ON) inhibitor is selected from Table B2, or a pharmaceutically acceptable salt or atropisomer thereof. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7]

Table 4-8

Table 4-9

Table 4-10

Table 4-11

Table 4-12

Table 4-13

Table 4-14

Table 4-15

Table 4-16

Table 4-17

Table 4-18

Table 4-19

Table 4-20

Table 4-21

Table 4-22

Table 4-23

Table 4-24

Table 4-25

Table 4-26

Table 4-27

Table 4-28

Table 4-29

Table 4-30

Table 4-31

Table 4-32

Table 4-33

Table 4-34

Table 4-35

[0284] In some embodiments, the RAS(ON) inhibitor is or functions as a prodrug, for example, for administration to a cell or subject in need thereof.

[0285] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0286] In some embodiments, the RAS(ON) inhibitor is provided as a conjugate comprising the structure of formula BIV, or a salt thereof: MLP formula BIV wherein L is a linker; P is a monovalent organic moiety; M has the structure of formula BVa. [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is absent or -CH(R 9 )-,>C=CR 9 R 9 ', or >CR 9 R 9 ' [wherein carbon is -N(R 11 )C(O)—, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 1 and R 2 combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7’R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, or R 9 and R 9’ combine with the atom to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl; R 10is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, and R 11 is hydrogen or C1-C3 alkyl.

[0287] In some embodiments, the conjugate, or a salt thereof, comprises the structure of formula BIV: MLP formula BIV wherein L is a linker; P is a monovalent organic moiety; M has the structure of formula BVb. [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )- or >C=CR 9 R 9 ' [wherein carbon is -N(R 11 )C(O)—, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 1is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 1 and R 2 combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7’ R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, and R 11 is hydrogen or C1-C3 alkyl.

[0288] In some embodiments, the conjugate has the structure of formula BIV: MLP formula BIV wherein L is a linker; P is a monovalent organic moiety; M has the structure of formula BVc. [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-[wherein the carbon is -N(R 11)C(O)—, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7’ R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 is hydrogen or C1-C3 alkyl].

[0289] In some embodiments, the RAS(ON) inhibitor has the structure of formula BIV: MLP formula BIV wherein L is a linker; P is a monovalent organic moiety; M has the structure of formula BVd. [ka] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; R 2 is C1-C6 alkyl, C1-C6 fluoroalkyl, or 3- to 6-membered cycloalkyl; R 7 is C1-C3 alkyl, R 8 is C1-C3 alkyl, and R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; or X e and X f are independently N or CH; R 11 is hydrogen or C1-C3 alkyl, and R 21 is hydrogen or C1-C3 alkyl].

[0290] In some embodiments of formula B1 and its subformulas, X e is N and X f is CH. In some embodiments, X e is CH and X f is N.

[0291] In some embodiments, the RAS(ON) inhibitor has the structure of formula BIV: MLP formula BIV wherein L is a linker; P is a monovalent organic moiety; M has the structure of formula BVe. [ka] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; and R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0292] In some embodiments of the conjugate of Formula BIV, the linker has the structure of Formula BII: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Formula BII [In the formula, A 1 is the bond between the linker and B; A 2 is the bond between P and the linker; B 1 , B 2 , B 3 , and B 4 are each independently an optionally substituted C1-C2 alkylene, an optionally substituted C1-C3 heteroalkylene, O, S, and NRN Selected from;R N is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted C1-C7 heteroalkyl; C 1 and C 2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; D 1 is an optionally substituted C1-C 10 Alkylene, optionally substituted C-C 10 Alkenylene, optionally substituted C-C 10 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-C 10 Polyethylene glycolene or optionally substituted C1-C 10 heteroalkylene, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 [This is a chemical bond that connects the two molecules together.]

[0293] In some embodiments of the conjugate of formula BIV, the monovalent organic moiety is a protein, such as a Ras protein. In some embodiments, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras proteins are described herein. In some embodiments, the linker is attached to the monovalent organic moiety via a bond to a sulfhydryl group of an amino acid residue of the monovalent organic moiety. In some embodiments, the linker is attached to the monovalent organic moiety via a bond to a carboxyl group of an amino acid residue of the monovalent organic moiety.

[0294] The compounds described in Tables B1 and B2 can be made from commercially available starting materials or can be synthesized using known organic, inorganic, or enzymatic processes.

[0295] The compounds of the present invention can be prepared by a number of methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods shown in the following schemes, along with synthetic methods known in the field of organic synthetic chemistry, or variations thereof as would be understood by those skilled in the art. These methods include, but are not limited to, the following schemes and the methods described in WO 2021 / 091982.

[0296] Scheme B1. General synthesis of macrocyclic esters [ka]

[0297] The general synthesis of macrocyclic esters is outlined in Scheme B1. Appropriately substituted aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (1) can be prepared in three steps starting from protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol and an appropriately substituted boronic acid, including palladium-mediated coupling, alkylation, and deprotection reactions.

[0298] Methyl-amino-hexahydropyridazine-3-carboxylate-boronic ester (2) can be prepared in three steps including protection, iridium catalyst-mediated borylation, and methyl(S)-hexahydropyridazine-3-carboxylate.

[0299] Coupling of methyl-L-valinate with protected (S)-pyrrolidine-3-carboxylic acid, followed by deprotection, coupling with a carboxylic acid containing an appropriately substituted Michael acceptor, and a hydrolysis step can generate appropriately substituted acetylpyrrolidine-3-carbonyl-N-methyl-L-valine (or alternative amino acid derivative (4)).

[0300] The final macrocyclic ester can be prepared by coupling methyl-amino-hexahydropyridazine-3-carboxylate-boronic ester (2) with aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (1) in the presence of a Pd catalyst, followed by hydrolysis and macrolactonization steps to afford the appropriately protected macrocyclic intermediate (5). Deprotection and coupling with appropriately substituted intermediate 4 affords the macrocyclic product. Further deprotection and / or functionalization steps may be required to generate the final compound.

[0301] Scheme B2. Alternative general synthesis of macrocyclic esters [ka]

[0302] Alternatively, macrocyclic esters can be prepared as described in Scheme B2. A suitably protected bromo-indolyl (6) is coupled with a boronate ester (3) in the presence of a Pd catalyst, followed by iodination, deprotection, and ester hydrolysis. Coupling with methyl (S)-hexahydropyridazine-3-carboxylate, followed by hydrolysis and macrolactonization, affords the iodo intermediate (7). Coupling with an appropriately substituted boronate ester in the presence of a Pd catalyst and alkylation affords the fully protected macrocycle (5). Additional deprotection or functionalization steps are required to generate the final compound.

[0303] Furthermore, compounds of the present disclosure can be synthesized using methods known in the art of synthetic organic chemistry, or variations thereof as understood by those skilled in the art, as described in the Examples below or in WO2021 / 091982. These methods include, but are not limited to, those described in the Examples below. For example, one skilled in the art would be able to introduce the desired -BLW group of a compound of formula (BI) (wherein B, L, and W are as defined herein) into a macrocyclic ester by using the methods exemplified in the Examples section of this specification and in WO2021 / 091982.

[0304] The compounds in Table B1 herein were prepared using the methods disclosed herein or prepared using the methods disclosed herein in combination with the knowledge of those skilled in the art. The compounds in Table B2 can be prepared using the methods disclosed herein or prepared using the methods disclosed herein in combination with the knowledge of those skilled in the art.

[0305] Scheme B3. General synthesis of macrocyclic esters [ka]

[0306] An alternative general synthesis of macrocyclic esters is outlined in Scheme B3. Appropriately substituted indolylboronic esters (8) can be prepared in four steps starting from protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol and an appropriately substituted boronic acid, including palladium-mediated coupling, alkylation, deprotection, and palladium-mediated borylation.

[0307] Methyl-amino-3-(4-bromothiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (10) can be prepared by coupling of (S)-2-amino-3-(4-bromothiazol-2-yl)propanoic acid (9) with methyl (S)-hexahydropyridazine-3-carboxylate.

[0308] The final macrocyclic ester is prepared by coupling methyl-amino-3-(4-bromothiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (10) and an appropriately substituted indolylboronic ester (8) in the presence of a Pd catalyst, followed by hydrolysis and macrolactonization steps to afford the appropriately protected macrocyclic intermediate (11). Deprotection and coupling with an appropriately substituted intermediate 4 can provide the macrocyclic product. Additional deprotection or functionalization steps may be required to generate the final compounds 13 or 14.

[0309] Scheme B4. General synthesis of macrocyclic esters [ka]

[0310] An alternative general synthesis of macrocyclic esters is outlined in Scheme B4. A suitably substituted morpholine or alternative heterocyclic intermediate (15) can be coupled with a suitably protected intermediate 1 via palladium-mediated coupling. Subsequent ester hydrolysis and coupling with a piperazine ester provides intermediate 16.

[0311] The macrocyclic ester can be prepared by a hydrolysis, deprotection, and macrocyclization sequence. Subsequent deprotection and coupling with intermediate 4 (or an analog) affords the appropriately substituted final macrocyclic product. Additional deprotection or functionalization steps may be required to prepare the final compound 17.

[0312] Scheme B5. General synthesis of macrocyclic esters [ka]

[0313] An alternative general synthesis of macrocyclic esters is outlined in Scheme B5. Starting from an appropriately protected boronic ester 18 and a bromoindolyl intermediate (19), the appropriately substituted macrocycle (20) can be prepared, involving palladium-mediated coupling, hydrolysis, coupling with a piperazine ester, hydrolysis, deprotection, and macrocyclization steps. Subsequent coupling with an appropriately substituted protected amino acid, followed by palladium-mediated coupling, affords intermediate 21. Additional deprotection and derivatization steps, including alkylation, may be required at this point.

[0314] The final macrocyclic ester can be prepared by coupling intermediate 22 with an appropriately substituted carboxylic acid intermediate 23. Additional deprotection or functionalization steps may be required to prepare the final compound 24.

[0315] Furthermore, compounds of the present disclosure can be synthesized using methods known in the art of synthetic organic chemistry, or variations thereof as understood by those skilled in the art, including, but not limited to, the methods described in the Examples below and in WO 2021 / 091982. For example, one skilled in the art could use the methods exemplified in WO 2021 / 091982 to introduce the desired -BLW group of a compound of formula (BI) into a macrocyclic ester, where B, L, and W are as defined herein.

[0316] In some embodiments, the RAS(ON) inhibitor is a compound having the structure of formula CI, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; B is -CH(R 9 )- or >C=CR 9 R 9 ' [wherein carbon is -N(R 11 )C(O)—, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethylcarbamate, a chloroethylthiocarbamate, an aziridine, a trifluoromethylketone, a boronic acid, a boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an isoEEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 1 and R 2 combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7’ R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, and R 11 is hydrogen or C1-C3 alkyl, and R 34 is hydrogen or C1-C3 alkyl (e.g., methyl).

[0317] In some embodiments of formula CI and subformulas thereof, R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0318] In some embodiments of formula CI and subformulas thereof, R 34 is hydrogen.

[0319] In some embodiments of formula CI and subformulas thereof, G is an optionally substituted C1-C4 heteroalkylene.

[0320] In some embodiments, the RAS(ON) inhibitor has the structure of Formula CIa, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-[wherein the carbon is -N(R 11 )C(O)—, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethylcarbamate, a chloroethylthiocarbamate, an aziridine, a trifluoromethylketone, a boronic acid, a boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an isoEEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal; X 2 is O or NH, X 3is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7’ R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 is hydrogen or C1-C3 alkyl.

[0321] In some embodiments of formula CI and subformulas thereof, X 2 is NH. In some embodiments, X 3 is CH.

[0322] In some embodiments of formula CI and subformulas thereof, R 11 is hydrogen. In some embodiments, R 11 is a C1-C3 alkyl such as methyl.

[0323] In some embodiments, the RAS(ON) inhibitor has the structure of formula CIb, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethylcarbamate, a chloroethylthiocarbamate, an aziridine, a trifluoromethylketone, a boronic acid, a boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an isoEEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7’ R 8'; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl, and R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl.

[0324] In some embodiments of formula CI and subformulas thereof, X 1 is an optionally substituted C1-C2 alkylene. In some embodiments, X 1 is methylene.

[0325] In some embodiments of formula CI and subformulas thereof, R 4 is hydrogen.

[0326] In some embodiments of formula CI and subformulas thereof, R 5 is hydrogen. In some embodiments, R 5is C-C alkyl optionally substituted with halogen. In some embodiments, R 5 is methyl.

[0327] In some embodiments of formula CI and its subformulas, Y 4 is C. In some embodiments of formula CI and its subformulas, R 4 is hydrogen. In some embodiments of formula CI and its subformulas, Y 5 In some embodiments of formula CI and subformulas thereof, Y 6 In some embodiments of formula CI and subformulas thereof, Y 1 is C. In some embodiments of formula CI and its subformulas, Y 2 is C. In some embodiments of formula CI and its subformulas, Y 3 is N. In some embodiments of formula CI and subformulas thereof, R 3 In some embodiments of formula CI and its subformulas, Y 7 is C.

[0328] In some embodiments, the RAS(ON) inhibitor has the structure of formula CIc, or a pharmaceutically acceptable salt thereof: [ka] wherein A is —N(H or CH3)C(O)—(CH2)—; wherein the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethylcarbamate, a chloroethylthiocarbamate, an aziridine, a trifluoromethylketone, a boronic acid, a boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an isoEEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7’ R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl, and R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl].

[0329] In some embodiments of formula CI and subformulas thereof, R 6 is hydrogen.

[0330] In some embodiments of formula CI and subformulas thereof, R 2 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-6 membered heterocycloalkyl. In some embodiments, R 2 is an optionally substituted C1-C6 alkyl, such as ethyl.

[0331] In some embodiments of formula CI and subformulas thereof, R 7 is an optionally substituted C1-C3 alkyl. In some embodiments, R 7 is C1-C3 alkyl.

[0332] In some embodiments of formula CI and subformulas thereof, R 8 is an optionally substituted C1-C3 alkyl. In some embodiments, R 8 is C1-C3 alkyl.

[0333] In some embodiments, the RAS(ON) inhibitor has the structure of Formula CId, or a pharmaceutically acceptable salt thereof: [ka] wherein A is —N(H or CH3)C(O)—(CH2)—; wherein the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethylcarbamate, a chloroethylthiocarbamate, an aziridine, a trifluoromethylketone, a boronic acid, a boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an isoEEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R 7 is C1-C3 alkyl, R 8 is C1-C3 alkyl, and R 9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl.

[0334] In some embodiments of formula CI and subformulas thereof, R 1 is a 5-10 membered heteroaryl. In some embodiments, R 1 is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl.

[0335] In some embodiments, the RAS(ON) inhibitor has the structure of Formula CIe, or a pharmaceutically acceptable salt thereof: [ka] wherein A is —N(H or CH3)C(O)—(CH2)—; wherein the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethylcarbamate, a chloroethylthiocarbamate, an aziridine, a trifluoromethylketone, a boronic acid, a boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an isoEEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal; R 2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R 7 is C1-C3 alkyl, R 8 is C1-C3 alkyl, and R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; Xe is N or CH, and R 12 is an optionally substituted C1-C6 alkyl, or an optionally substituted C1-C6 heteroalkyl.

[0336] In some embodiments of formula CI and subformulas thereof, X e is N. In some embodiments, X e is CH.

[0337] In some embodiments of formula CI and subformulas thereof, R 12 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R 12 teeth [ka] In some embodiments, R 12 teeth [ka] is.

[0338] In some embodiments, the RAS(ON) inhibitor has the structure of formula CIf, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-[wherein the carbon is -N(R 11)C(O)—, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethylcarbamate, a chloroethylthiocarbamate, an aziridine, a trifluoromethylketone, a boronic acid, a boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an isoEEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7’ R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 is hydrogen or C1-C3 alkyl].

[0339] In some embodiments, the RAS(ON) inhibitor has the structure of formula CVI, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 10-membered heteroarylene; B is -CH(R 9 )- or >C=CR9 R 9 ' [wherein carbon is -N(R 11 )C(O)—, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene; [ka] [In the formula, [ka] -C(R 7 R 8 )-bonded to ], [ka] [In the formula, [ka] -C(R 7 R 8 )-; optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethylcarbamate, a chloroethylthiocarbamate, an aziridine, a trifluoromethylketone, a boronic acid, a boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an isoEEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O)n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl, and R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 combine with the carbon atom to which they are attached, forming C=CR 7’ R 8 '; forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or combined with the carbon to which they are attached to form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl, R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, R 11 is hydrogen or C1-C3 alkyl, R 34 is hydrogen or C1-C3 alkyl, and X e and X f are independently N or CH].

[0340] In some embodiments, the RAS(ON) inhibitor has the structure of formula CVIa, or a pharmaceutically acceptable salt thereof: [ka] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethylurea, a chloroethylthiourea, a chloroethylcarbamate, a chloroethylthiocarbamate, an aziridine, a trifluoromethylketone, a boronic acid, a boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an isoEEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal; X 1 is an optionally substituted C1-C2 alkylene, NR, O, or S(O) n and X 2 is O or NH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2; Each R ’ are independently H or optionally substituted C1-C4 alkyl; R 2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R 7 is C1-C3 alkyl, R8 is C1-C3 alkyl, and R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; or X e and X f are independently N or CH; R 11 is hydrogen or C1-C3 alkyl, and R 21 is hydrogen or C1-C3 alkyl.

[0341] In some embodiments of formula CI and subformulas thereof, X e is N and X f is CH. In some embodiments, X e is CH and X f is N.

[0342] In some embodiments, the RAS(ON) inhibitor has the structure of formula CVIb, or a pharmaceutically acceptable salt thereof: [ka] wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or a linker; W is a bridging group comprising a carbodiimide, an oxazoline, a thiazoline,...

Claims

1. A pharmaceutical composition for use in the treatment of cancer in a subject in need thereof, comprising a RAS(ON) inhibitor, wherein the cancer is (a) a first RAS mutation that is G12C and a second RAS mutation at a position selected from the group consisting of H95, R68, G13, and Q61, or a second RAS mutation selected from the group consisting of Y96C, Y96F, Y96H, Y96N, Y96S; or (b) a first RAS mutation at position G12 selected from the group consisting of G12H, G12I, G12K, G12M, G12N, G12P, G12Q, G12T, G12W, and G12Y, and the cancer is resistant to treatment with a RAS(OFF) inhibitor. A pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the cancer comprises a first RAS mutation that is G12C and a second RAS mutation at position H95 or R68.

3. The pharmaceutical composition according to claim 2, wherein the second RAS mutation is selected from the group consisting of H95D, H95L, H95N, H95P, H95Q, H95R, and H95Y.

4. The pharmaceutical composition according to claim 2, wherein the second RAS mutation is selected from the group consisting of R68G, R68K, R68M, R68S, R68T, and R68W.

5. The pharmaceutical composition according to claim 1, wherein any RAS mutation is selected from a KRAS mutation, anNRAS mutation, and an HRAS mutation.

6. The pharmaceutical composition according to claim 1, wherein the RAS(ON) inhibitor is an inhibitor that is selective for RAS G12C, G13D, or G12D.

7. The pharmaceutical composition according to claim 1, wherein the RAS(ON) inhibitor is a RAS(ON) MULTI inhibitor.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the RAS(ON) inhibitor is a trimeric complex RAS(ON) inhibitor.

9. The RAS(ON) inhibitor is a compound of formula AI: 【Chemical Formula 1】 or a pharmaceutically acceptable salt thereof, wherein the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH₃)C(O)-(CH₂)- [wherein the amino nitrogen is bonded to the carbon atom of -CH(R₁₀)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene, B is absent or -CH(R₉)- or >C=CR₉R₉' [wherein the carbon is bonded to the carbonyl carbon of -N(R₁₁)C(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, G is optionally substituted C₁-C₄ alkylene, optionally substituted C₁-C₄ alkenylene, optionally substituted C₁-C₄ heteroalkylene, [Chemical 2] [wherein, [Chemical Formula 3] is bonded to -C(R₇R₈)-. [Chemical Formula 4] [wherein, [Chemical Formula 5] is bonded to -C(R₇R₈)-, optionally substituted C₁-C₄ heteroalkylene, or 3- to 8-membered heteroarylene, L is absent or a linker, W is hydrogen, cyano, S(O)₂R', optionally substituted amino, optionally substituted amide, optionally substituted C₁-C₄ alkoxy, optionally substituted C₁-C₄ hydroxyalkyl, optionally substituted C₁-C₄ aminoalkyl, optionally substituted C₁-C₄ haloalkyl, optionally substituted C₁-C₄ alkyl, optionally substituted C₁-C₄ guanidinoalkyl, 3- to 11-membered heterocycloalkyl optionally substituted with C₀-C₄ alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl, X₁ is optionally substituted C₁-C₂ alkylene, NR, O, or S(O)ₙ, X₂ is O or NH, X₃ is N or CH, n is 0, 1, or 2, R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2, each R' is independently H or optionally substituted C1-C4 alkyl, Y1 is C, CH, or N, Y2, Y3, Y4, and Y7 are independently C or N, Y5 is CH, CH2, or N, Y6 is C(O), CH, CH2, or N, R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R1 and R2 combine with the atoms to which they are attached to form an optionally substituted 3-14 membered heterocycloalkyl, R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl, R3 is absent or R2 and R3 combine with the atoms to which they are attached to form an optionally substituted 3-8 membered cycloalkyl or optionally substituted 3-14 membered heterocycloalkyl, R4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl, R6 is hydrogen or methyl, R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7, in combination with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, and R8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8, in combination with the carbon atom to which they are attached, form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, R7a and R8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or, in combination with the carbon to which they are attached, form a carbonyl, R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R8' is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8', in combination with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, or R9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl, R9' is hydrogen or optionally substituted C1-C6 alkyl, R10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, R10a is hydrogen or halo, R11 is hydrogen or C1-C3 alkyl, R16 is hydrogen or C1-C3 alkyl, The pharmaceutical composition according to claim 1.

10. The RAS(ON) inhibitor is a compound of formula BI: 【Chemical Formula 6】 or a pharmaceutically acceptable salt thereof, wherein the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH3)C(O)-(CH2)- [wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene, B is absent or -CH(R9)-, >C=CR9R9', or >CR9R9' [wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, 【Chemical Formula 7】 wherein 【Chemical 8】 is bonded to -C(R7R8)-. 【Chemical Formula 9】 wherein 【Chemical 10】 is bonded to -C(R7R8)-, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene, L is absent or a linker, W is a crosslinking group containing vinyl ketone, vinyl sulfone, inone, haloacetyl, or alkynyl sulfone, X1 is optionally substituted C1-C2 alkylene, NR, O, or S(O)n, X2 is O or NH, X3 is N or CH, n is 0, 1, or 2, R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2, each R' is independently H or optionally substituted C1-C4 alkyl, Y1 is C, CH, or N, Y2, Y3, Y4, and Y7 are independently C or N, Y5 is CH, CH2, or N, Y6 is C(O), CH, CH2, or N, R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, or R1 and R2, together with the atoms to which they are attached, combine to form an optionally substituted 3-14 membered heterocycloalkyl, R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl, R3 is absent, or R2 and R3, together with the atoms to which they are attached, combine to form an optionally substituted 3-8 membered cycloalkyl or an optionally substituted 3-14 membered heterocycloalkyl, R4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl, R6 is hydrogen or methyl, R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R7, in combination with the carbon atom to which they are attached, form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl, and R8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8, in combination with the carbon atom to which they are attached, form C=CR7'R8'; C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, R7a and R8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or, in combination with the carbon to which they are attached, form carbonyl, R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R8' is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R9 is H, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, or R9 and L combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl, R9' is hydrogen or optionally substituted C1-C6 alkyl, or R9 and R9' combine with the atom to which they are attached to form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl, R10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, R10a is hydrogen or halo, R11 is hydrogen or C1-C3 alkyl, and R21 is hydrogen or C1-C3 alkyl, The pharmaceutical composition according to claim 1.

11. The RAS(ON) inhibitor is a compound of formula CI: 【Chemical 11】 or a pharmaceutically acceptable salt thereof, wherein the dotted line represents 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH3)C(O)-(CH2)- [wherein the amino nitrogen is attached to the carbon atom of -CH(R10)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene, B is -CH(R9)- or >C=CR9R9' [wherein the carbon is attached to the carbonyl carbon of -N(R11)C(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, G is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, 【Chemical 12】 wherein, 【Chemical 13】 is bonded to -C(R₇R₈)-.], 【Chemical 14】 [In the formula, 【Chemical Formula 15】 is bonded to -C(R₇R₈)-.], an optionally substituted C₁-C₄ heteroalkylene, or a 3- to 8-membered heteroarylene, L is absent or is a linker, W is a crosslinking group including carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethylcarbamate, chloroethylthiocarbamate, aziridine, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxide, oxazolium, or glycarl, X₁ is an optionally substituted C₁-C₂ alkylene, NR, O, or S(O)ₙ, X₂ is O or NH, X₃ is N or CH, n is 0, 1, or 2, R is hydrogen, cyano, an optionally substituted C₁-C₄ alkyl, an optionally substituted C₂-C₄ alkenyl, an optionally substituted C₂-C₄ alkynyl, C(O)R', C(O)OR', C(O)N(R')₂, S(O)R', S(O)₂R', or S(O)₂N(R')₂, each R' is independently H or an optionally substituted C₁-C₄ alkyl, Y₁ is C, CH, or N, Y₂, Y₃, Y₄, and Y₇ are independently C or N, Y₅ is CH, CH₂, or N, Y₆ is C(O), CH, CH₂, or N, R₁ is cyano, an optionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆ heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, an optionally substituted 3- to 6-membered cycloalkenyl, an optionally substituted 3- to 6-membered heterocycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl, or R₁ and R₂, together with the atoms to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl, R₂ is absent, hydrogen, optionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl, and R₃ is absent or R₂ and R₃, together with the atom to which they are attached, form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl, R₄ is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens, R₅ is hydrogen, C₁-C₄ alkyl optionally substituted with halogen, cyano, hydroxy, or C₁-C₄ alkoxy, cyclopropyl, or cyclobutyl, R₆ is hydrogen or methyl, and R₇ is hydrogen, halogen, or optionally substituted C₁-C₃ alkyl, or R₆ and R₇, together with the carbon atom to which they are attached, form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, and R₈ is hydrogen, halogen, hydroxy, cyano, optionally substituted C₁-C₃ alkoxyl, optionally substituted C₁-C₃ alkyl, optionally substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R₇ and R₈, together with the carbon atom to which they are attached, form C═CR₇′R₈′; C═N(OH), C═N(O-C₁-C₃ alkyl), C═O, C═S, C═NH, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl, R₇a and R₈a are independently hydrogen, halo, optionally substituted C₁-C₃ alkyl, or, together with the carbon to which they are attached, form a carbonyl, R7' is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R8' is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8', in combination with the carbon atom to which they are attached, form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl, R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, or R9 and L, in combination with the atom to which they are attached, form optionally substituted 3- to 14-membered heterocycloalkyl, R9' is hydrogen or optionally substituted C1-C6 alkyl, R10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, R10a is hydrogen or halo, and R11 is hydrogen or C1-C3 alkyl, and R34 is hydrogen or C1-C3 alkyl, The pharmaceutical composition according to claim 1.

12. The RAS(ON) inhibitor is a compound of formula D1a: 【Chemical 16】 or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C4 alkylene, or optionally substituted C2-C4 alkenylene, Y is 【Chemical 17】 as follows, W is hydrogen, C1-C4 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, X1 and X4 are each independently CH2 or NH, R1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, and R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, and R10 is hydrogen, hydroxy, optionally substituted C1-C3 alkyl, or optionally substituted C1-C6 heteroalkyl, The pharmaceutical composition according to claim 1.

13. The RAS(ON) inhibitor is a compound of formula EI: 【Chemical 18】 or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene, L1 is absent or is a linker, W is a crosslinking group containing vinyl ketone, vinyl sulfone, enone, or 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, The pharmaceutical composition according to claim 1.

14. The RAS(ON) inhibitor is a compound of formula FI: 【Chemical 19】 or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; W is a crosslinking group containing aziridine, epoxide, carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethylcarbamate, chloroethylthiocarbamate, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, oxazolium, or glycarl; X1 is CH2 or O; m is 1 or 2; n is 0 or 1; R1 is hydrogen or optionally substituted 3- to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is optionally substituted C1-C6 alkyl or optionally substituted 3- to 6-membered cycloalkyl, The pharmaceutical composition according to claim 1.

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