How to Inhibit the RAS

Abstract

The disclosure features methods of inhibiting RAS proteins, for example, RAS proteins that have acquired resistance to one or more RAS inhibitors. The disclosure also provides methods of treating cancer.

Description

[Technical Field]

[0001] Priority claims This application claims priority to U.S. Provisional Patent Application Serial Nos. 63 / 170,292, filed April 2, 2021, and 63 / 192,843, filed May 25, 2021, the entire contents of which are incorporated herein by reference. The present disclosure relates to methods for inhibiting RAS. [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 because it can lead to overactivation of RAS pathway signaling through a number of mechanisms, including, for example, pathway reactivation due to removal of negative feedback mechanisms that naturally operate in these pathways. As a result, cells initially sensitive to such inhibitors can become resistant. Therefore, there is a need for methods to effectively inhibit RAS pathway signaling while minimizing or mitigating the activation of resistance mechanisms. 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.

[0006] Therefore, in a first aspect, the present disclosure provides a method for treating cancer in a subject in need thereof, wherein the cancer comprises a mutation in RAS, and the cancer is resistant to treatment with a RAS(OFF) inhibitor, and the method comprises administering a RAS(ON) inhibitor to the subject.In some embodiments, the RAS mutation is an amino acid substitution at Y96.In some embodiments, the amino acid substitution is Y96D.

[0007] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, wherein the cancer comprises an amino acid substitution at RAS Y96, and the method comprises administering to the subject a RAS(ON) inhibitor. In some embodiments, the amino acid substitution is Y96D.

[0008] In some embodiments, the method further comprises administering a RAS(OFF) inhibitor to the subject (e.g., a RAS(OFF) inhibitor is administered to the subject in combination with a RAS(ON) inhibitor). The RAS(ON) inhibitor and the RAS(OFF) inhibitor can be administered simultaneously or sequentially. The RAS(ON) inhibitor and the RAS(OFF) inhibitor can be administered as a single formulation or as separate formulations. In some embodiments, 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, wherein the first period of time and the second period of time do not overlap and the first period of time precedes the second period of time. In some embodiments, 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, wherein the first period of time and the second period of time do not overlap and the first period of time precedes the second period of time. In some embodiments, the first period of time is sufficient to acquire a mutation (e.g., a RAS mutation) that confers resistance to treatment with a RAS(OFF) inhibitor. In some embodiments, the first period of time is 1 week to 1 month, 1 week to 6 months, 1 week to 1 year, 1 month to 6 months, 1 month to 1 year, 1 month to 2 years, 1 month to 5 years, at least 1 week, at least 1 month, at least 6 months, or at least 1 year. In some embodiments, the second period of time is 1 week to 1 month, 1 week to 6 months, 1 week to 1 year, 1 month to 6 months, 1 month to 1 year, 1 month to 2 years, 1 month to 5 years, at least 1 week, at least 1 month, at least 6 months, or at least 1 year.

[0009] In some embodiments, the subject's cancer progresses with a RAS(OFF) inhibitor (eg, when the subject is administered a RAS(OFF) inhibitor in the absence of a RAS(ON) inhibitor).

[0010] In some embodiments, the subject has been treated with a RAS(OFF) inhibitor (e.g., the subject has previously been treated with a RAS(OFF) inhibitor, e.g., prior to administration of the RAS(ON) inhibitor). In some embodiments, the subject has acquired resistance to a RAS(OFF) inhibitor (e.g., prior to administration of the RAS(ON) inhibitor, the subject has acquired a mutation that confers resistance to the RAS(OFF) inhibitor).

[0011] In another aspect, the present disclosure provides a method for inhibiting RAS in a cell, wherein the RAS comprises an amino acid substitution at Y96, and the method comprises contacting the cell with a RAS(ON) inhibitor. In some embodiments, the amino acid substitution is Y96D.

[0012] In some embodiments, the RAS comprises or further comprises an amino acid substitution at G12, G13, Q61, or a combination thereof. In some embodiments, the amino acid substitution is selected from G12C, G12D, G12V, G13C, G13D, or Q61L. In some embodiments, the amino acid substitution is G12C.

[0013] In some embodiments, RAS is KRAS. In some embodiments, RAS comprises or further comprises an amino acid substitution at G12, G13, Q61, or a combination thereof. In some embodiments, KRAS amino acid substitution is 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.

[0014] In some embodiments, RAS is NRAS. In some embodiments, NRAS comprises or further comprises amino acid substitutions at G12, G13, Q61, P185, A146, G60, A59, E132, E49, T50, or a combination thereof. In some embodiments, NRAS amino acid substitutions are 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.

[0015] In some embodiments, the RAS is HRAS. In some embodiments, the HRAS comprises or further comprises an amino acid substitution at G12, G13, Q61, K117, A59, A18, D119, A66, A146, or a combination thereof. In some embodiments, the HRAS amino acid substitution is 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.

[0016] In some embodiments, the RAS(ON) inhibitor is an inhibitor selective for RAS G12C, G13D, or G12D. In some embodiments, the RAS(ON) inhibitor is an inhibitor selective for RAS(ON). MULTI It is an inhibitor.

[0017] In some embodiments, the RAS(ON) inhibitor is a compound described by 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 (e.g., methyl).

[0018] In some embodiments, the RAS(ON) inhibitor is a compound of any one of formula AIa, formula AIb, formula AIc, formula AId, formula AIe, formula AIf, formula AIg, formula AIh, or formula AIi described herein, or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the RAS(ON) inhibitor is selected from a compound set forth in Table A1 or Table A2, or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, 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)-, 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(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 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 2is 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, 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 10is 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.

[0021] In some embodiments, the RAS(ON) inhibitor is a compound of any one of formula BIa, formula BIb, formula BIc, formula BId, formula BIe, formula BIf, formula BIg, formula BVI, formula BVia, formula BVIb, or formula BVic described herein, or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the RAS(ON) inhibitor is selected from the compounds set forth in Table B1 or Table B2, or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the RAS(ON) inhibitor is a compound described by formula CI: [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 -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 R2 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 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 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.

[0024] In some embodiments, the RAS(ON) inhibitor is a compound of any one of formula CIa, CIb, CIc, CId, CIe, CIf, CVI, CVIa, VIb, or CVII described herein, or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the RAS(ON) inhibitor is selected from a compound set forth in Table C1 or Table C2, or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the RAS(ON) inhibitor is a compound described by 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 1is 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.

[0027] In some embodiments, the RAS(ON) inhibitor is a compound represented by formula DII (e.g., formula DII-1, DII-2, DII-3, DII-4, DII-5, DII-6, DII-7, DII-8, or DII-9), formula DIII (e.g., formula DIII-1, DIII-2, DIII-3, DIII-4, DIII-5, DIII-6, DIII-7, DIII-8, or DIII-9), formula DIV (e.g., formula DIV-1, DIV-2, DIV-3, DIV-4, DIV-5, DIV-6, DIV-7, DIV-8, or DIV-9), formula DV (e.g., formula DV-1, DV-2, DV-3, DV-4, or D DIX (e.g., formula DIX-1, DIX-2, DIX-3, DIX-4, or DIX-5), formula DVI (e.g., formula DVI-1, DVI-2, DVI-3, DVI-4, or DVI-5), formula DVII (e.g., formula DVII-1, DVII-2, DVII-3, DVII-4, or DVII-5), formula DVIII (e.g., formula DVIII-1, DVIII-2, DVIII-3, DVIII-4, or DVIII-5), formula DIX (e.g., formula DIX-1, DIX-2, DIX-3, DIX-4, or DIX-5), or formula DX (e.g., formula DX-1, DX-2, DX-3, DX-4, or DX-5), or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the RAS(ON) inhibitor is selected from a compound set forth in Table D1a or Table D1b, or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the RAS(ON) inhibitor is a compound described by a formula in WO 2020132597, e.g., a compound of formula (I) therein, or a pharmaceutically acceptable salt thereof, or a compound of Figure 1 therein, or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the RAS(OFF) inhibitor selectively targets RAS G12C. In some embodiments, the RAS(OFF) inhibitor selectively targets RAS G12D.

[0031] In some embodiments, the RAS inhibitor is selected from the group consisting of AMG510 (sotorasib), MRTX849 (adagrasib), MRTX1257, JNJ-74699157 (ARS-3248), LY3537982, ARS-853, ARS-1620, GDC-6036, BPI-421286, JDQ443, JAB-21000, JAB-22000, and JAB-23000. In some embodiments, the RAS(OFF) inhibitor is an inhibitor of K-Ras G12D, such as MRTX1133 or JAB-22000. In some embodiments, the RAS(OFF) inhibitor is a K-Ras G12V inhibitor, such as JAB-23000.

[0032] In some embodiments, the RAS(OFF) inhibitor is a compound described in the following patent publications: WO 2022052895, WO 2022048545, WO 2022047093, WO 2022042630, WO 2022040469, WO 2022037631, WO 2022037560, WO 2022031678, WO 2022028492, WO 2022028346, WO 2022026726, WO 2022026723, WO 2022015375, WO 2022002102, WO 2022002018, WO 2021259331, WO 2021257828, WO 2021252339, WO 2021248095, WO 2021248090, WO 2021248083, WO 2021248082, WO 2021248079, WO 2021248055, WO 2021245051, WO 2021244603, WO 2021239058, WO 2021231526, WO 2021228161, WO 2021219090, WO 2021219090, WO 2021219072, WO 2021218939, WO 2021217019, WO 2021216770, WO 2021215545, WO 2021215544, WO 2021211864, WO 2021190467, WO 2021185233, WO 2021180181, WO 2021175199, 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO 2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO 2021147965, WO 2021143693, WO 2021142252, WO 2021141628, WO 2021139748, WO 2021139678, WO 2021129824, WO 2021129820, WO 2021127404, WO 2021126816, WO 2021126799, WO 2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO2021055728、WO 2021031952、WO 2021027911、WO 2021023247、WO 2020259513、WO 2020259432、WO 2020234103、WO 2020233592、WO 2020216190、WO 2020178282、WO 2020146613、WO 2020118066、WO 2020113071、WO 2020106647、WO 2020102730、WO 2020101736、WO 2020097537、WO 2020086739、WO 2020081282、WO 2020050890、WO 2020047192、WO 2020035031、WO 2020028706、WO 2019241157、WO 2019232419、WO 2019217691、WO 2019217307、WO 2019215203、WO 2019213526、WO 2019213516、WO 2019155399、WO 2019150305、WO 2019110751、WO 2019099524、WO 2019051291、WO 2018218070、WO 2018218071、WO 2018218069、WO 2018217651、WO 2018206539、WO 2018143315、WO 2018140600、WO 2018140599、WO 2018140598、WO 2018140514、WO 2018140513、WO 2018140512、WO 2018119183、WO 2018112420、WO 2018068017、WO 2018064510、WO 2017201161、WO 2017172979、WO 2017100546、WO 2017087528、WO 2017058807、WO 2017058805、WO 2017058728、WO 2017058902、WO 2017058792、WO 2017058768、WO 2017058915、WO 2017015562、WO 2016168540、WO 2016164675、WO 2016049568、WO 2016049524、WO 2015054572、WO 2014152588、WO 2014143659、WO 2013155223、CN114195788, CN 114057776, CN 114057744, CN 114057743, CN 113999226, CN 113980032, CN 113980014, CN 113960193, CN 113929676, CN 113754653, CN 113683616, CN 113563323, CN 113527299, CN 113527294, CN 113527293, CN 113493440, CN 113429405, CN 113248521, CN 113087700,CN 113024544,CN and CN 109574871.

[0033] In any of the embodiments herein relating to a RAS(OFF) inhibitor, the RAS(OFF) inhibitor can be replaced with a RAS inhibitor disclosed in the following patent publication: WO 2021041671, which is incorporated herein by reference in its entirety. In some embodiments, such a replacement RAS inhibitor is MRTX1133.

[0034] In some embodiments, the cancer is selected from colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, 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, appendiceal cancer, endometrial cancer, and melanoma. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is pancreatic cancer.

[0035] 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. [Brief explanation of the drawings]

[0036] [Figure 1A] Serial computed tomography (CT) images of axillary lymph node metastases in subjects at baseline, during response to the RAS(OFF) inhibitor MRTX849, and at the time of progression on MRTX849. [Figure 1B] Western blot analysis of MIA PaCa-2 cells (stably expressing BRAF(V600E)-V5) treated with the RAS(OFF) inhibitor MRTX849 at the indicated concentrations for 4 hours. [Figure 1C] FIG. 1 shows alterations detected in post-MRTX849 cfDNA, including acquired mutations in KRAS, as well as multiple components of the MAPK signaling cascade. [Figure 2A] This is an overlap of sequence reads of KRASG13D occurring in trans with KRASG12C. [Figure 2B] This is an overlap of the sequence reads of KRASG12V occurring in cis with KRASG12C. [Figure 3] A series of model crystal structures of the RAS(OFF) inhibitors MRTX849 (6UT0), AMG 510 (6OIM), and ARS-1620 (5V9U) bound to KRASG12C (top panel) and KRASG12C / Y96D (bottom panel). [Figure 4A] 1 is a series of plots of cell viability assays performed with NCI-H358, MIA PaCa-2, and Ba / F3 cells infected with retroviruses packaging KRAS (G12C or G12C / Y96D) in the presence of RAS(OFF) inhibitors. [Figure 4B]Western blot analysis of MIA PaCa-2 cells stably expressing KRASG12C or KRASG12C / Y96D treated with the RAS(OFF) inhibitor MRTX849 for 4 hours. [Figure 4C] Western blot of MGH1138-1 cells expressing KRASG12C or KRASG12C / Y96D after treatment with the RAS(OFF) inhibitor MRTX849 for 4 hours. Cell viability data for MGH1138-1 cells after treatment with the indicated concentrations of MRTX849 for 72 hours are plotted on the right. [Figure 4D] Western blot of HEK293T cells transiently expressing mutant KRAS after treatment with the RAS(OFF) inhibitor MRTX849 for 4 hours. [Figure 4E] 1 is a bar graph showing densitometry analysis of KRAS-GTP levels in untreated HEK293T cells stably expressing KRASG12C and KRASG12C / Y96D. [Figure 4F] Western blot analysis of HEK293T cells stably expressing KRAS mutants treated with the indicated inhibitors for 4 hours. [Figure 4G] RAS-GTP pull-down assay performed after treating HEK293T cells stably expressing KRAS mutants for 4 hours in the presence of the RAS(OFF) inhibitor MRTX849. [Figure 4H] Western blot of LU-65 cells transiently expressing KRASG12C or KRASG12C / Y96D after treatment with MRTX849 for 4 hours. [Figure 5A] 1 shows the mechanism of action of the RAS(ON) inhibitor RM-018, a RAS(ON)G12C inhibitor compound of formula BI herein, also a compound of Table B1 herein, and also found in WO 2021 / 091982. [Figure 5B] 1 is a graph of cell viability of cells with various mutations in the presence of the RAS(ON) inhibitor RM-018. [Figure 5C-1]1 is a series of cell viability plots performed on NCI-H358, MIA PaCa-2, Ba / F3, and MGH1138-1 cells stably infected with KRASG12C or KRASG12C / Y96D treated with the RAS(ON) inhibitor RM-018 for 72 hours. [Figure 5C-2] Same as above. [Figure 5D] Western blot analysis performed on MIA PaCa-2 stably expressing KRASG12C or KRASG12C / Y96D after 4 hours of treatment with the RAS(ON) inhibitor RM-018. [Figure 5E] Western blot analysis of HEK293T cells transiently expressing the indicated KRAS mutants after treatment with the RAS(ON) inhibitor RM-018 for 4 hours. [Figure 5F] Western blot analysis of MGH1138-1 cells transiently expressing KRASG12C or KRASG12C / Y96D after treatment with the RAS(ON) inhibitor RM-018 for 4 hours. [Figure 5G] Western blot performed on HEK293T cells transiently expressing mutant KRAS after treatment with 100 nmol / L of each of the indicated drugs for 4 hours. [Figure 6] 1 is a graph showing that compound AA, a KRASG12C(ON) inhibitor, which is a RAS(ON)G12C inhibitor compound of formula BI herein, which is also a compound of Table 1 herein, and which is also found in WO 2021 / 091982, inhibits KRASG12C / Y96D in cells. [Figure 7] 1 is a graph showing the pERK potency of Compound AA, a KRASG12C(ON) inhibitor, in KRASG12C / Y96D cells. DETAILED DESCRIPTION OF THE INVENTION

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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).

[0041] As used herein, the term "adjacent" in the context of describing adjacent atoms means divalent atoms that are directly joined by a covalent bond.

[0042] 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.

[0043] 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 methods, 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.

[0044] 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-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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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 o;-C(NCN)NR°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)2R°;-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, where each R° may be optionally substituted as defined below and is independently hydrogen, -C1-6 aliphatic, -CH2Ph, -O(CH2)0-1Ph, -CH2- (5-6 membered heteroaryl ring), or nitrogen, oxygen, or or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from 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.

[0051] 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 l , -(Haro R l), -(CH2)0-2OH, -(CH2)0-2OR l , -(CH2)0-2CH(OR l )2, -O(HaloR l ), -CN, -N3, -(CH2)0-2C(O)R l , -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR l , -(CH2)0-2SR l , -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR l , -(CH2)0-2NR l 2, -NO2, -SiR l 3. -OSiR l 3. -C(O)SR l , -(C1-4 straight or branched chain alkylene)C(O)OR l , or -SSR l wherein each R l 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.

[0052] 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.

[0053] R * Suitable substituents on the aliphatic group include -R l , (Halo R l ), -OH, -OR l , -OR l , -O(HaloR l ), -CN, -C(O)OH, -C(O)OR l , -NH2, -NHR l , —NR2, or —NO2, where each R l 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.

[0054] 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, a 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 above definition, 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.

[0055] R † Suitable substituents on the aliphatic group are independently halogen, —R l ,-(Halo R l ), -OH, -OR l , -O(HaloR l ), -CN, -C(O)OH, -C(O)OR l , -NH2, -NHR l , -NR l 2, or -NO2, where each R l 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.

[0056] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0057] 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.

[0058] As used herein, the term "alkoxy" refers to an -O-C 20 It means that the alkyl and alkoxy groups are attached to the remainder of the compound through an oxygen atom.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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.

[0064] As used herein, the term "amino" refers to -N(R†)2, e.g., -NH2 and -N(CH3)2.

[0065] As used herein, the term "aminoalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more amino moieties.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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)-.

[0070] 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.

[0071] As used herein, the term "carbonyl" refers to a C(O) group, which can also be represented as C=O.

[0072] As used herein, the term "carboxyl" refers to -CO2H, (C=O)(OH), COOH, or C(O)OH, or the unprotonated corresponding groups.

[0073] The term "combination therapy" refers to a therapeutic method that includes administering to a subject at least two therapeutic agents, optionally as one or more pharmaceutical compositions, as part of a therapeutic regimen. For example, combination therapy can include the administration of a single pharmaceutical composition that includes at least two therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. Combination therapy can also include the administration of two or more pharmaceutical compositions, each of which includes 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 RAS(ON) inhibitors (e.g., 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 RAS(OFF) inhibitors (e.g., 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 therapies.

[0074] As used herein, the term "cyano" refers to a -CN group.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] As used herein, the term "dosage form" refers to a physically discrete unit of a compound (e.g., a compound of the present disclosure) 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.

[0079] 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).

[0080] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0081] 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%.

[0082] The term "guanidyl" means a compound having the structure [ka] wherein each R is independently any chemically suitable substituent described herein.

[0083] As used herein, the term "guanidinoalkylalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more guanidyl moieties.

[0084] As used herein, the term "haloacetyl" means an acetyl group in which at least one hydrogen has been replaced by a halogen.

[0085] As used herein, the term "haloalkyl" refers to an alkyl moiety having one or more carbon atoms substituted with one or more of the same or different halogen moieties.

[0086] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] As used herein, the term "hydroxy" refers to an --OH group.

[0091] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more --OH moieties.

[0092] 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.

[0093] 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., stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomeric pure), as well as mirror image isomers. This includes both isomeric and stereoisomeric mixtures (e.g., racemates). Enantiomeric and stereoisomeric mixtures of the compounds of the invention can usually 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.

[0094] 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, 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] As used herein, the term "subject" refers to any member of the animal kingdom. In some embodiments, "subject" refers to a human at any stage of development. In some embodiments, "subject" refers to a human patient. In some embodiments, "subject" refers to a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, or pig). In some embodiments, the subject includes, but is not limited to, a mammal, bird, reptile, amphibian, fish, or worm. In some embodiments, the subject can be a transgenic animal, a genetically modified animal, or a clone.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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, 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, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof.

[0108] 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).

[0109] As used herein, the term "RAS(ON) 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) MULTI By inhibitor is meant a RAS(ON) inhibitor of at least three RAS variants that have a missense mutation at one of the following positions: 12, 13, and 61.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] As used herein, the term "sulfonyl" refers to the group -S(O)2-.

[0114] 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.

[0115] 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.

[0116] By "therapeutic regimen" is meant a dosing regimen in which administration across a relevant population correlates with a desired or beneficial therapeutic outcome.

[0117] 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 subjects known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the relevant disease, disorder or condition.

[0118] As used herein, the term "vinyl ketone" refers to a group containing a carbonyl group attached directly to a carbon-carbon double bond.

[0119] As used herein, the term "vinyl sulfone" refers to a group containing a sulfonyl group attached directly to a carbon-carbon double bond.

[0120] The term "wild-type" refers to an entity having a structure or activity that is found in a "normal" (as opposed to a mutant, diseased, altered, etc.) state or context in nature. Those skilled in the art will understand that wild-type genes and polypeptides often exist in multiple alternative forms (e.g., alleles).

[0121] As used herein, the term "ynone" refers to a compound having the structure [ka] wherein R is any suitable optional substituent as described herein.

[0122] 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.

[0123] 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).

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] In some embodiments, the RAS(ON) inhibitor is a RAS(ON) MULTI It is an inhibitor.

[0129] 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 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 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 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.

[0130] In some embodiments, the disclosure features 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, R1 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 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).

[0131] In some embodiments, the disclosure features 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] teeth- 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.

[0132] In some embodiments, the disclosure features 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; 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; R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 is hydrogen or C1-C3 alkyl.

[0133] In some embodiments of formula AI and subformulas thereof, G is an optionally substituted C1-C4 heteroalkylene.

[0134] 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.

[0135] In some embodiments of formula AI and its subformulas, X 2 In some embodiments of formula AI and its subformulas, X 3 is CH.

[0136] 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.

[0137] 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.

[0138] 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)-.

[0139] In some embodiments of formula AI and its subformulas, R 3 does not exist.

[0140] In some embodiments of formula AI and its subformulas, R 4 is hydrogen.

[0141] 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.

[0142] In some embodiments of formula AI and its subformulas, Y 4 is C. In some embodiments of formula AI and its subformulas, X 5 In some embodiments of formula AI and its subformulas, X 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.

[0143] 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.

[0144] In some embodiments of formula AI and its subformulas, R 6 is hydrogen.

[0145] 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 an optionally substituted C1-C6 alkyl, such as ethyl. In some embodiments of formula AI and subformulas thereof, R 2 is fluoroC1-C6 alkyl, such as -CH2CH2F, -CH2CHF2, or -CH2CF3.

[0146] 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.

[0147] 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 a C1-C3 alkyl such as methyl.

[0148] 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 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] In some embodiments of formula AI and subformulas thereof, B is an optionally substituted 6-membered arylene.

[0159] In some embodiments, B is a 6-membered arylene. [ka] In some embodiments, B is absent.

[0160] In some embodiments of formula AI and its subformulas, R 7 is methyl.

[0161] In some embodiments of formula AI and its subformulas, R 8 is methyl.

[0162] In some embodiments of formula AI and its subformulas, R 16 is hydrogen.

[0163] 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] [where, 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]

[0164] 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.

[0165] 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).

[0166] 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 A, or a pharmaceutically acceptable salt or atropisomer thereof.

[0167] [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

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-108

Table 1-109

Table 1-110

Table 1-111

Table 1-112

Table 1-113

Table 1-114

Table 1-115

Table 1-116

Table 1-117

Table 1-118

Table 1-119

Table 1-120

Table 1-121

Table 1-123

Table 1-124

Table 1-125

Table 1-126

Table 1-127

Table 1-129

Table 1-131

Table 1-133

Table 1-136

Table 1-137

Table 1-138

Table 1-139

Table 1-141

Table 1-145

Table 1-147

Table 1-149

Table 1-150

Table 1-151

Table 1-152

Table 1-153

Table 1-155

Table 1-156

Table 1-157

Table 1-158

Table 1-159

Table 1-161

Table 1-166

Table 1-171

Table 1-176

Table 1-177

Table 1-178

Table 1-179

Table 1-186

Table 1-191

Table 1-193

Table 1-196

Table 1-197

Table 1-199

Table 1-200

Table 1-201

Table 1-202

Table 1-203

Table 1-205

Table 1-207

Table 1-209

Table 1-211

Table 1-212

Table 1-213

Table 1-216

Table 1-217

Table 1-219

Table 1-220

Table 1-221

Table 1-222

Table 1-223

Table 1-224

Table 1-225

Table 1-226

Table 1-227

Table 1-228

Table 1-229

Table 1-231

[0168] 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.

[0169] [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

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

Table 2-43

[0170] The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic, or enzymatic processes.

[0171] 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.

[0172] 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.

[0173] Scheme A1. General synthesis of macrocyclic esters [ka]

[0174] 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.

[0175] 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.

[0176] 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).

[0177] 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.

[0178] Scheme A2. Alternative general synthesis of macrocyclic esters [ka]

[0179] 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.

[0180] Scheme A3. General synthesis of macrocyclic esters [ka]

[0181] 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.

[0182] Scheme A4. General synthesis of macrocyclic esters [ka]

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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 Examples below. These methods include, but are not limited to, those described in WO 2021 / 091956. For example, one skilled in the art would be able 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 by using the methods exemplified in the Examples section of this specification.

[0187] 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 )-, 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(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 )-to bonded to the ring; 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 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).

[0188] 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.

[0189] In some embodiments of Formula BI, R 21 is hydrogen.

[0190] 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.

[0191] In some embodiments, the disclosure features 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.

[0192] In some embodiments of formula BI and subformulas thereof, G is an optionally substituted C1-C4 heteroalkylene.

[0193] 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.

[0194] 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.

[0195] In some embodiments, the RAS(ON) inhibitor has the structure of Formula BId, or a pharmaceutically acceptable salt thereof.

[0196] [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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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 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.

[0202] 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.

[0203] In some embodiments of Formula B1 and subformulas thereof, R1 is [ka] or a stereoisomer (e.g., atropisomer) thereof. In some embodiments of Formula BI and subformulas thereof, R1 is [ka] or a stereoisomer (e.g., atropisomer) thereof. In some embodiments of Formula BI and subformulas thereof, R1 is [ka] is.

[0204] In some embodiments, the RAS(ON) inhibitor has the structure of formula BIg, 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 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; X e and X fare independently N or CH, and R 12 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, or an optionally substituted 3- to 6-membered heterocycloalkylene. 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.

[0205] In some embodiments of formula B1 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.

[0206] 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 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol), or 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, R 21 is hydrogen or C1-C3 alkyl (e.g., methyl), and X e and X f are independently N or CH.

[0207] 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.

[0208] 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.

[0209] 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; W is a bridging group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone. In some embodiments of Formula BI or subformulas thereof, A is an optionally substituted 6-membered arylene.

[0210] 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 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol), or 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 2is 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, 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 10is 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).

[0211] In some embodiments of formula BI and subformulas thereof, A has the 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 and R13a are each hydrogen. In some embodiments, R 13 is hydroxy, methyl, fluoro, or difluoromethyl.

[0212] In some embodiments of formula BI and subformulas thereof, A is an optionally substituted 5- to 6-membered heteroarylene. [ka] is.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] In some embodiments of formula B1 and its subformulas, R 7 is methyl.

[0217] In some embodiments of formula B1 and its subformulas, R 8 is methyl.

[0218] In some embodiments of formula B1 and its subformulas, R 21 is hydrogen.

[0219] 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 -(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 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 1-4alkyl, 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-C 7 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; D1 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 -(B1) f -(C1) g -(B2) h -(B3) i -(C2) j -(B4) k -A2 is a chemical bond that connects the linker to A2. In some embodiments, the linker is acyclic. In some embodiments, the linker has the structure of Formula BIIa: [ka] [where, 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, at least one of the following is present: [ka]

[0220] 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.

[0221] 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 15is 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.

[0222] 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 , R 15d , 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.

[0223] In some embodiments of Formula BI and subformulas thereof, the linker has the structure: [ka] [ka]

[0224] In some embodiments of Formula BI and subformulas thereof, the linker has the structure: [ka] [ka] [ka] [ka]

[0225] In some embodiments of formula BI and subformulas thereof, the linker has the structure [ka] It has.

[0226] In some embodiments of formula BI and subformulas thereof, the linker has the structure [ka] 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.

[0227] 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 , R18b , 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] In some embodiments of formula BI and subformulas thereof, W has the structure of formula BIIIe: [ka] [where, X e is a halogen, and R 20is 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 haloacetyl. In some embodiments of Formula BI and subformulas thereof, W is not haloacetyl.

[0228] 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.

[0229] [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

Table 3-89

Table 3-90

Table 3-91

Table 3-92

Table 3-93

Table 3-94

Table 3-95

Table 3-96

Table 3-97

Table 3-98

Table 3-99

Table 3-100

Table 3-101

Table 3-102

Table 3-103

Table 3-104

Table 3-105

Table 3-106

Table 3-107

Table 3-108

Table 3-109

Table 3-110

Table 3-111

Table 3-112

Table 3-113

Table 3-114

Table 3-115

Table 3-116

Table 3-117

Table 3-118

Table 3-119

Table 3-120

Table 3-121

Table 3-122

Table 3-123

Table 3-124

Table 3-125

Table 3-126

Table 3-127

Table 3-128

Table 3-129

Table 3-130

Table 3-131

Table 3-132

Table 3-133

Table 3-134

Table 3-135

Table 3-136

Table 3-137

Table 3-138

Table 3-139

Table 3-140

Table 3-141

Table 3-142

Table 3-143

Table 3-144

Table 3-145

Table 3-146

Table 3-147

Table 3-148

Table 3-149

Table 3-150

Table 3-151

Table 3-152

Table 3-153

Table 3-154

Table 3-155

Table 3-156

Table 3-157

Table 3-158

Table 3-159

Table 3-160

Table 3-161

Table 3-162

Table 3-163

Table 3-164

Table 3-165

Table 3-166

Table 3-167

Table 3-168

Table 3-169

Table 3-170

Table 3-171

Table 3-172

Table 3-173

[0230] 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.

[0231]

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

Table 4-36

Table 4-37

Table 4-38

Table 4-39

Table 4-40

Table 4-41

Table 4-42

Table 4-43

Table 4-44

Table 4-45

Table 4-46

Table 4-47

Table 4-48

Table 4-49

Table 4-50

Table 4-51

Table 4-52

Table 4-53

Table 4-54

Table 4-55

Table 4-56

Table 4-57

Table 4-58

Table 4-59

Table 4-60

Table 4-61

Table 4-62

Table 4-63

Table 4-64

Table 4-65

Table 4-66

Table 4-67

Table 4-68

Table 4-69

Table 4-70

Table 4-71

Table 4-72

Table 4-73

Table 4-74

Table 4-75

Table 4-76

Table 4-77

Table 4-78

Table 4-79

Table 4-80

Table 4-81

Table 4-82

Table 4-83

[0232] 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.

[0233] 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.

[0234] 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=CR9 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 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 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 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.

[0235] 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 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.

[0236] 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 R8 )-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 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.

[0237] 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; R7 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.

[0238] In some embodiments of the compounds of the present invention, X e is N and X f is CH. In some embodiments, X e is CH and X f is N.

[0239] 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 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.

[0240] 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 NR N 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 2are 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 It is a chemical bond that connects to .

[0241] 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.

[0242] 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.

[0243] 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.

[0244] Scheme B1. General synthesis of macrocyclic esters [ka]

[0245] 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.

[0246] 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.

[0247] 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)).

[0248] 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.

[0249] Scheme B2. Alternative general synthesis of macrocyclic esters [ka]

[0250] 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.

[0251] Additionally, compounds of the present disclosure can be synthesized using methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art, as described in the Examples below or in WO 2021 / 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 (wherein B, L, and W are as defined herein) of a compound of formula (BI) into a macrocyclic ester by using the methods exemplified in the Examples section of this specification and in WO 2021 / 091982.

[0252] 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.

[0253] Scheme B3. General synthesis of macrocyclic esters [ka]

[0254] 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.

[0255] 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.

[0256] 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.

[0257] Scheme B4. General synthesis of macrocyclic esters [ka]

[0258] 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.

[0259] 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.

[0260] Scheme B5. General synthesis of macrocyclic esters [ka]

[0261] 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.

[0262] 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.

[0263] Additionally, 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 incorporate the desired -BLW group of a compound of formula (BI) (wherein B, L, and W are as defined herein) into a macrocyclic ester using the methods exemplified in WO 2021 / 091982.

[0264] 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 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 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 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, and R 11 is hydrogen or C1-C3 alkyl, and R 34 is hydrogen or C1-C3 alkyl (e.g., methyl).

[0265] 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.

[0266] In some embodiments of formula CI and subformulas thereof, R 34 is hydrogen.

[0267] In some embodiments of formula CI and subformulas thereof, G is an optionally substituted C1-C4 heteroalkylene.

[0268] 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 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; 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 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 11is hydrogen or C1-C3 alkyl.

[0269] In some embodiments of formula CI and subformulas thereof, X 2 is NH. In some embodiments, X 3 is CH.

[0270] 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.

[0271] 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 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 R2 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.

[0272] 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.

[0273] In some embodiments of formula CI and subformulas thereof, R 4 is hydrogen.

[0274] In some embodiments of formula CI and subformulas thereof, R 5 is hydrogen. In some embodiments, R 5 is C-C alkyl optionally substituted with halogen. In some embodiments, R 5 is methyl.

[0275] In some embodiments of formula CI and its subformulas, Y 4 is C. In some embodiments of formula CI and its subformulas, R4 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.

[0276] 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 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.

[0277] In some embodiments of formula CI and subformulas thereof, R 6 is hydrogen.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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(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 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.

[0282] 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.

[0283] 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.

[0284] In some embodiments of formula CI and subformulas thereof, X e is N. In some embodiments, X e is CH.

[0285] 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.

[0286] 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.

[0287] 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 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol), or 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.

[0288] 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.

[0289] 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.

[0290] 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 option...

Claims

1. 1. A pharmaceutical composition for the treatment of cancer in a subject in need thereof, comprising a RAS(ON) inhibitor, The pharmaceutical composition, wherein the cancer comprises a mutation in RAS, and the cancer is resistant to treatment with a RAS(OFF) inhibitor.

2. The pharmaceutical composition of claim 1 , wherein the subject is further administered a RAS(OFF) inhibitor.

3. 2. The pharmaceutical composition of claim 1, wherein the subject's cancer has progressed on a RAS(OFF) inhibitor prior to treatment with the RAS(ON) inhibitor.

4. The pharmaceutical composition of claim 1 , wherein the RAS mutation is an amino acid substitution at Y96.

5. The pharmaceutical composition of claim 4, wherein the amino acid substitution is Y96D.

6. The method of claim 1 , wherein the subject has previously been treated with a RAS(OFF) inhibitor.

7. 1. A pharmaceutical composition for the treatment of cancer in a subject in need thereof, comprising a RAS(ON) inhibitor, The pharmaceutical composition, wherein the cancer comprises an amino acid substitution in RAS Y96.

8. 8. The pharmaceutical composition of claim 7, wherein the amino acid substitution is Y96D.

9. The method of claim 7, wherein the subject has previously been treated with a RAS(OFF) inhibitor.

10. The pharmaceutical composition of claim 7, wherein the cancer is resistant to treatment with a RAS(OFF) inhibitor.

11. 10. The pharmaceutical composition of claim 9, wherein the subject's cancer has progressed on a RAS(OFF) inhibitor prior to treatment with the RAS(ON) inhibitor.

12. 1. A pharmaceutical composition for use in inhibiting a RAS in a cell, comprising a RAS(ON) inhibitor, The pharmaceutical composition, wherein the RAS comprises an amino acid substitution at Y96.

13. 13. The pharmaceutical composition of claim 12, wherein the amino acid substitution is Y96D.

14. 2. The pharmaceutical composition of claim 1, wherein the RAS comprises, or further comprises, an amino acid substitution at G12, G13, Q61, or a combination thereof.

15. 15. The pharmaceutical composition of claim 14, wherein the amino acid substitution is selected from G12C, G12D, G12V, G13C, G13D, or Q61L.

16. 16. The pharmaceutical composition of claim 15, wherein the amino acid substitution is G12C.

17. The pharmaceutical composition of claim 1 , wherein the RAS is KRAS.

18. 18. The pharmaceutical composition of claim 17, wherein the KRAS comprises, or further comprises, amino acid substitutions at G12, G13, Q61, A146, K117, L19, Q22, V14, A59, or combinations thereof.

19. 19. The pharmaceutical composition of claim 18, wherein the KRAS amino acid substitutions are 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 combinations thereof.

20. The pharmaceutical composition of claim 1 , wherein the RAS is NRAS.

21. 21. The pharmaceutical composition of claim 20, wherein the NRAS comprises, or further comprises, amino acid substitutions at G12, G13, Q61, P185, A146, G60, A59, E132, E49, T50, or combinations thereof.

22. 22. The pharmaceutical composition of claim 21, wherein the NRAS amino acid substitutions are 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 combinations thereof.

23. The pharmaceutical composition of claim 1 , wherein the RAS is HRAS.

24. 24. The pharmaceutical composition of claim 23, wherein the HRAS comprises, or further comprises, amino acid substitutions at G12, G13, Q61, K117, A59, A18, D119, A66, A146, or combinations thereof.

25. 25. The pharmaceutical composition of claim 24, wherein the HRAS amino acid substitutions are 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.

26. 2. The pharmaceutical composition of claim 1, wherein the RAS(ON) inhibitor is an inhibitor that is selective for RAS G12C, G13D, G12D, or a combination thereof.

27. The RAS(ON) inhibitor is ＭＵＬＴＩ The pharmaceutical composition of claim 1 which is an inhibitor.

28. The RAS(ON) inhibitor is represented by the formula AI 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is -N(H or CH ３ )C(O)-(CH ２ )—[wherein the amino nitrogen is —CH(R １０ )-, 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(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 an optionally substituted C １ -C ４ Alkylene, optionally substituted C １ -C ４ Alkenylene, optionally substituted C １ -C ４ Heteroalkylene, 【Chemistry 2】 [In the formula, 【Chemistry 3】 HA -C(R ７ R ８ )-bonded to 【Chemistry 4】 [In the formula, 【Chemistry 5】 HA -C(R ７ R ８ )-.], optionally substituted C １ -C ４ heteroalkylene or 3- to 8-membered heteroarylene; L is absent or a linker; W is hydrogen, cyano, S(O) ２ R′, optionally substituted amino, optionally substituted amido, optionally substituted C １ -C ４ Alkoxy, optionally substituted C １ -C ４ Hydroxyalkyl, optionally substituted C １ -C ４ Aminoalkyl, optionally substituted C １ -C ４ Haloalkyl, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ４ Guanidinoalkyl, C ０ -C ４ an optionally substituted 3- to 11-membered heterocycloalkyl, an optionally substituted 3- to 8-membered cycloalkyl, or an optionally substituted 3- to 8-membered heteroaryl; X １ is an optionally substituted C １ -C ２ 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 C １ -C ４ Alkyl, optionally substituted C ２ -C ４ Alkenyl, optionally substituted C ２ -C ４ Alkynyl, C(O)R', C(O)OR', C(O)N(R') ２ , S(O)R', S(O) ２ R', or S(O) ２ N(R') ２ and Each R ’ are independently H or optionally substituted C １ -C ４ is alkyl, Y １ is C, CH, or N; Y ２ , Y ３ , Y ４ , and Y ７ are independently C or N; Y ５ , CH, CH ２ or N, Y ６ is C(O), CH, CH ２ or N, R １ is cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ 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 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, or optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ 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, C optionally substituted with halogen １ -C ４ Alkyl, cyano, hydroxy, or C １ -C ４ alkoxy, cyclopropyl, or cyclobutyl; R ６ is hydrogen or methyl; R ７ is hydrogen, halogen, or optionally substituted C １ -C ３ is 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 C １ -C ３ Alkoxy, optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ alkynyl, an optionally substituted 3- to 8-membered cycloalkyl, an optionally substituted 3- to 14-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heteroaryl, or an 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 C=CR ７ 'R ８ '; C=N(OH), C=N(OC １ -C ３ 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 C １ -C ３ alkyl or, when combined with the carbon to which they are attached, form a carbonyl; R ７’ is hydrogen, halogen, or optionally substituted C １ -C ３ alkyl, R ８’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C １ -C ３ Alkoxy, optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ alkynyl, an optionally substituted 3- to 8-membered cycloalkyl, an optionally substituted 3- to 14-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heteroaryl, or an 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 C １ -C ６ Alkyl, optionally substituted C １ -C ６ 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 an optionally substituted C １ -C ６ is alkyl, R １０ is hydrogen, halo, hydroxy, C １ -C ３ Alkoxy, or C １ -C ３ is alkyl, R １０ａ is hydrogen or halo, R １１ is hydrogen or C １ -C ３ is alkyl, R １６ is hydrogen or C １ -C ３ is alkyl, The pharmaceutical composition according to any one of claims 1 to 27.

29. 2. The pharmaceutical composition of claim 1, wherein the RAS(ON) inhibitor is selected from the compounds set forth in Table A1 or Table A2, or a pharma- ceutically acceptable salt thereof.

30. The RAS(ON) inhibitor is of formula BI 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof, wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is -N(H or CH ３ )C(O)-(CH ２ )—[wherein the amino nitrogen is —CH(R １０ )-, 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(R ９ )-, >C=CR ９ R ９ ', or >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 an optionally substituted C １ -C ４ Alkylene, optionally substituted C １ -C ４ Alkenylene, optionally substituted C １ -C ４ Heteroalkylene, 【Chemistry 7】 [In the formula, 【Chemistry 8】 HA -C(R ７ R ８ )-bonded to 【Chemistry 9】 [In the formula, 【Chemistry 10】 HA -C(R ７ R ８ )-.], optionally substituted C １ -C ４ 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 C １ -C ２ 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 C １ -C ４ Alkyl, optionally substituted C ２ -C ４ Alkenyl, optionally substituted C ２ -C ４ Alkynyl, C(O)R', C(O)OR', C(O)N(R') ２ , S(O)R', S(O) ２ R', or S(O) ２ N(R') ２ and Each R ’ are independently H or optionally substituted C １ -C ４ is alkyl, Y １ is C, CH, or N; Y ２ , Y ３ , Y ４ , and Y ７ are independently C or N; Y ５ , CH, CH ２ or N, Y ６ is C(O), CH, CH ２ or N, R １ is cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ 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 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, or optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ 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, C optionally substituted with halogen １ -C ４ Alkyl, cyano, hydroxy, or C １ -C ４ alkoxy, cyclopropyl, or cyclobutyl; R ６ is hydrogen or methyl; R ７ is hydrogen, halogen, or optionally substituted C １ -C ３ is 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 C １ -C ３ Alkoxy, optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ alkynyl, an optionally substituted 3- to 8-membered cycloalkyl, an optionally substituted 3- to 14-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heteroaryl, or an 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 C=CR ７ 'R ８ '; C=N(OH), C=N(OC １ -C ３ 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 C １ -C ３ alkyl or, when combined with the carbon to which they are attached, form a carbonyl; R ７’ is hydrogen, halogen, or optionally substituted C １ -C ３ alkyl, R ８’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C １ -C ３ Alkoxy, optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ alkynyl, an optionally substituted 3- to 8-membered cycloalkyl, an optionally substituted 3- to 14-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heteroaryl, or an 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 C １ -C ６ Alkyl, optionally substituted C １ -C ６ 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 an optionally substituted C １ -C ６ is 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, C １ -C ３ Alkoxy, or C １ -C ３ is alkyl, R １０ａ is hydrogen or halo, R １１ is hydrogen or C １ -C ３ is alkyl, and R ２１ is hydrogen or C １ -C ３ is alkyl, The pharmaceutical composition according to any one of claims 1 to 26.

31. 2. The pharmaceutical composition of claim 1, wherein the RAS(ON) inhibitor is selected from the compounds set forth in Table B1 or Table B2, or a pharma- ceutically acceptable salt thereof.

32. The RAS(ON) inhibitor has the formula 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof, wherein the dotted lines represent 0, 1, 2, 3, or 4 non-adjacent double bonds; A is -N(H or CH ３ )C(O)-(CH ２ )—[wherein the amino nitrogen is —CH(R １０ )-, 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(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 an optionally substituted C １ -C ４ Alkylene, optionally substituted C １ -C ４ Alkenylene, optionally substituted C １ -C ４ Heteroalkylene, 【Chemistry 12】 [In the formula, 【Chemistry 13】 HA -C(R ７ R ８ )-bonded to 【Chemistry 14】 [In the formula, 【Chemistry 15】 HA -C(R ７ R ８ )-.], optionally substituted C １ -C ４ 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), isoEEDQ or other EEDQ derivatives, an epoxide, an oxazolium, or a glycal; X １ is an optionally substituted C １ -C ２ 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 C １ -C ４ Alkyl, optionally substituted C ２ -C ４ Alkenyl, optionally substituted C ２ -C ４ Alkynyl, C(O)R', C(O)OR', C(O)N(R') ２ , S(O)R', S(O) ２ R', or S(O) ２ N(R') ２ and Each R ’ are independently H or optionally substituted C １ -C ４ is alkyl, Y １ is C, CH, or N; Y ２ , Y ３ , Y ４ , and Y ７ are independently C or N; Y ５ , CH, CH ２ or N, Y ６ is C(O), CH, CH ２ or N, R １ is cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ 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 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, or optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ 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, C optionally substituted with halogen １ -C ４ Alkyl, cyano, hydroxy, or C １ -C ４ alkoxy, cyclopropyl, or cyclobutyl; R ６ is hydrogen or methyl; R ７ is hydrogen, halogen, or optionally substituted C １ -C ３ is 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 C １ -C ３ Alkoxyl, optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ alkynyl, an optionally substituted 3- to 8-membered cycloalkyl, an optionally substituted 3- to 14-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heteroaryl, or an 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 C=CR ７ 'R ８ '; C=N(OH), C=N(OC １ -C ３ 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 C １ -C ３ alkyl or, when combined with the carbon to which they are attached, form a carbonyl; R ７’ is hydrogen, halogen, or optionally substituted C １ -C ３ alkyl, R ８’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C １ -C ３ Alkoxyl, optionally substituted C １ -C ３ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ alkynyl, an optionally substituted 3- to 8-membered cycloalkyl, an optionally substituted 3- to 14-membered heterocycloalkyl, an optionally substituted 5- to 10-membered heteroaryl, or an 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 C １ -C ６ Alkyl, optionally substituted C １ -C ６ 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 an optionally substituted C １ -C ６ is alkyl, R １０ is hydrogen, halo, hydroxy, C １ -C ３ Alkoxy, or C １ -C ３ is alkyl, R １０ａ is hydrogen or halo, and R １１ is hydrogen or C １ -C ３ is alkyl, and R ３４ is hydrogen or C １ -C ３ is alkyl, The pharmaceutical composition according to any one of claims 1 to 26.

33. 2. The pharmaceutical composition of claim 1, wherein the RAS(ON) inhibitor is selected from the compounds set forth in Table C1 or Table C2, or a pharma- ceutically acceptable salt thereof.

34. The RAS(ON) inhibitor has the formula DIa 【Chemistry 16】 or a pharma- ceutically acceptable salt thereof, In the formula, 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 C ２ -C ４ Alkylene or optionally substituted C ２ -C ４ alkenylene, Y is, 【Chemistry 17】 and W is hydrogen, C １ -C ４ Alkyl, optionally substituted C １ -C ３ 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; X １ and X ４ are each independently CH ２ or NH, R １ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ 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 R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ 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 C １ -C ３ Alkyl or optionally substituted C １ -C ６ is heteroalkyl, The pharmaceutical composition according to any one of claims 1 to 27.

35. 2. The pharmaceutical composition of claim 1, wherein the RAS(ON) inhibitor is selected from the compounds set forth in Table D1a or Table D1b, or a pharma- ceutically acceptable salt thereof.

36. 2. The pharmaceutical composition of claim 1, wherein the RAS(OFF) inhibitor selectively targets KRAS G12C.

37. 2. The pharmaceutical composition of claim 1, wherein the RAS(OFF) inhibitor selectively targets KRAS G12D.

38. The pharmaceutical composition of claim 1, wherein the RAS(OFF) inhibitor selectively targets KRAS G12C, KRAS G12D, and KRAS G12V.

39. 2. The pharmaceutical composition of claim 1, 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, and JAB-21000.

40. 8. The pharmaceutical composition of claim 1 or 7, wherein the cancer is selected from colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small intestine cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, uterine cancer, esophageal cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, bladder cancer, appendiceal cancer, uterine cancer, and melanoma.

41. 41. The pharmaceutical composition of claim 40, wherein the cancer is non-small cell lung cancer.

42. 41. The pharmaceutical composition of claim 40, wherein the cancer is pancreatic cancer.

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