Compositions Comprising a First RAS Inhibitor, a Second RAS Inhibitor, and an SHP2 Inhibitor for Use in the Treatment of Cancer

Abstract

This disclosure features methods for treating cancer (e.g., immunorefractory cancer) using RAS inhibitors. This disclosure also features combination therapies including one or more RAS inhibitors for treating cancer.

Description

[Technical Field]

[0001] The present disclosure relates to compositions, uses and methods for treating cancer (e.g., immunorefractory cancers, examples of which include immunorefractory lung cancer). [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] The development of immune checkpoint inhibitors (ICIs) has dramatically improved the treatment of various solid tumors. However, initial or acquired resistance to ICI treatment is often an obstacle to sustained antitumor activity. Current response biomarkers for anti-PD-1 or anti-PD-L1 treatment include tumor mutation burden, programmed death-ligand-1 (PD-L1) expression, and T cell density. ICI-induced antitumor immunity depends on lymphocyte infiltration into the tumor core, with "T cell-inflammed" tumors demonstrating the best response. In contrast, "cold tumors," also known as immunorefractory or immune-evasive tumors, can be defined in part by a lack of T cell infiltration and a low IFN-g gene signature and are poorly responsive to immune checkpoint inhibition (Non-Patent Document 1). New compositions, uses, and methods for treating immunorefractory tumors are needed. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Bonaventura et al.al,Front. Immunol. 2019 Summary of the Invention

[0005] The present disclosure provides compositions, uses, and methods for treating cancer (e.g., immunorefractory cancer, an example of which is immunorefractory lung cancer). The present disclosure is based, at least in part, on the observation that immunorefractory cancer can be treated with a combination of (i) a first RAS inhibitor, (ii) a second RAS inhibitor, and (iii) an SHP2 inhibitor, optionally in combination with (iv) an immune checkpoint inhibitor. In some embodiments, the first RAS inhibitor inhibits a RAS harboring an oncogenic G12C mutation. In some embodiments, the RAS inhibitor is a covalent inhibitor, e.g., capable of forming a covalent bond with an oncogenic mutant form of RAS G12C at the G12C position. In some embodiments, the second RAS inhibitor is a RAS(MULTI) inhibitor. In some embodiments, treatment with a RAS inhibitor sensitizes the cancer to treatment with an immune checkpoint inhibitor or an SHP2 inhibitor. In some embodiments, a compound or combination of compounds described herein is administered to a subject who has previously failed immunotherapy treatment, such as immunotherapy treatment with an immune checkpoint inhibitor.

[0006] In a first aspect, the present disclosure provides a method of treating cancer in a subject. The method comprises administering to the subject: a) a first RAS inhibitor, or a pharmaceutically acceptable salt thereof; b) a second RAS inhibitor, or a pharmaceutically acceptable salt thereof; and c) an SHP2 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is an immunorefractory cancer.

[0007] In another aspect, the disclosure provides use of a) a first RAS inhibitor, or a pharmaceutically acceptable salt thereof, b) a second RAS inhibitor, or a pharmaceutically acceptable salt thereof, and c) an SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, in treating cancer in a subject. In some embodiments, the cancer is an immunorefractory cancer.

[0008] In another aspect, the disclosure provides use of a) a first RAS inhibitor, or a pharmaceutically acceptable salt thereof, b) a second RAS inhibitor, or a pharmaceutically acceptable salt thereof, and c) an SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject. In some embodiments, the cancer is an immunorefractory cancer.

[0009] In another aspect, the disclosure provides a method of sensitizing immunorefractory lung cancer in a subject, the method comprising administering to the subject a combination of (i) a first RAS inhibitor, (ii) a second RAS inhibitor, and (iii) an SHP2 inhibitor, optionally in combination with (iv) an immune checkpoint inhibitor.

[0010] In another aspect, the present disclosure provides use of a combination of (i) a first RAS inhibitor, (ii) a second RAS inhibitor, and (iii) an SHP2 inhibitor, and optionally (iv) an immune checkpoint inhibitor, to sensitize immunorefractory lung cancer in a subject.

[0011] In another aspect, the disclosure provides for the use of (i) a first RAS inhibitor, (ii) a second RAS inhibitor, and (iii) an SHP2 inhibitor, optionally in combination with (iv) an immune checkpoint inhibitor, in the manufacture of a medicament for sensitizing immunorefractory lung cancer in a subject.

[0012] In some embodiments of the methods or uses described herein, the subject has previously been administered an immune checkpoint inhibitor. In some embodiments, the subject is resistant to treatment with the immune checkpoint inhibitor. In some embodiments, the subject has acquired resistance to treatment with the immune checkpoint inhibitor.

[0013] In some embodiments, administration of the first RAS inhibitor or the second RAS inhibitor sensitizes the cancer to treatment with an immune checkpoint inhibitor.

[0014] In some embodiments, the method or use further comprises administering to the subject an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor.

[0015] In some embodiments, the inhibitors are administered simultaneously or sequentially, hi some embodiments, the inhibitors are administered as a single formulation or as separate formulations.

[0016] In some embodiments, the subject has one or more tumors with a low tumor mutational burden. In some embodiments, the subject has one or more tumors that are microsatellite stable. In some embodiments, the subject has one or more tumors with low microsatellite instability. In some embodiments, the subject has one or more tumors with a low tumor immune infiltrate.

[0017] In some embodiments, administering a combination of (i) a first RAS inhibitor, (ii) a second RAS inhibitor, (iii) an SHP2 inhibitor, and optionally (iv) an immune checkpoint inhibitor alters the tumor immune infiltrate. In some embodiments, the tumor immune infiltrate comprises antigen-presenting cells, myeloid cells, or lymphoid cells. In some embodiments, administering a combination of (i) a first RAS inhibitor, (ii) a second RAS inhibitor, (iii) an SHP2 inhibitor, and optionally (iv) an immune checkpoint inhibitor alters the anti-tumor immune response. In some embodiments, administering a combination of (i) a first RAS inhibitor, (ii) a second RAS inhibitor, (iii) an SHP2 inhibitor, and optionally (iv) an immune checkpoint inhibitor alters the tumor microenvironment. In some embodiments, administering a combination of (i) a first RAS inhibitor, (ii) a second RAS inhibitor, (iii) an SHP2 inhibitor, and optionally (iv) an immune checkpoint inhibitor converts an immunologically cold tumor to an immunologically hot tumor. In some embodiments, the method or use reduces the size of the tumor or inhibits tumor growth.

[0018] In some embodiments, the first RAS inhibitor is a RAS G12C inhibitor. In some embodiments, the second RAS inhibitor is a RAS(MULTI) inhibitor. In some embodiments, the first RAS inhibitor is a RAS G12C inhibitor and the second RAS inhibitor is a RAS(MULTI) inhibitor.

[0019] In some embodiments, the SHP2 inhibitor is RMC-4550, or a pharmaceutically acceptable salt thereof. In some embodiments, the SHP2 inhibitor is RMC-4630, or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the second RAS inhibitor has the structure of formula AI: [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 )- 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 C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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)2R', 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, 3- to 11-membered heterocycloalkyl optionally substituted with C0-C4 alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; 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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is 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 5is 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; R 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R7 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; 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 3-6 membered cycloalkyl, or an optionally substituted 3-7 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 form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; 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 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.

[0021] In some embodiments, the second RAS inhibitor is a compound selected from Table A1 or Table A2.

[0022] In some embodiments, the first RAS inhibitor has the structure of formula BI, i.e., [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)—; 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 C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’is independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N; Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 1 and R 2 combine with the atom to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; 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; 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 3-6 membered cycloalkyl, or an optionally substituted 3-7 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 form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; 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, combined with the atom to which they are attached, 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).

[0023] In some embodiments, the first RAS inhibitor is a compound selected from Table B1 or Table B2.

[0024] In some embodiments, the second RAS inhibitor is a compound having the structure of formula DIa, i.e., [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, an optionally substituted 5- to 6-membered heteroarylene, an optionally substituted C2-C4 alkylene, or an optionally substituted C2-C4 alkenylene; Y is [ka] and W is hydrogen, C1-C4 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted 3-10 membered cycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; X 1 and X 4 are each independently CH or NH, R 1 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; 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; R 10is hydrogen, hydroxy, optionally substituted C1-C3 alkyl, or optionally substituted C1-C6 heteroalkyl.

[0025] In some embodiments, the second RAS inhibitor is a compound selected from Table DIa, Table DIb, Table D2, or Table D3.

[0026] In some embodiments of the methods or uses described herein, the cancer is lung cancer. In some embodiments, the cancer is immunorefractory lung cancer. In some embodiments, the immunorefractory lung cancer is non-small cell lung cancer or small cell lung cancer. In some embodiments, the immunorefractory lung cancer comprises a Ras mutation. In some embodiments, the Ras mutation is K-Ras G12C, H-Ras C12C, or N-Ras G12C. In some embodiments, the Ras mutation is K-Ras G12C.

[0027] 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 or any use of the present disclosure, and any method or any use of the present disclosure may be used to produce or utilize any compound or composition of the present disclosure. [Brief explanation of the drawings]

[0028] [Figure 1A] The reduction in tumor volume over a 120 day period immediately following treatment with vehicle control is shown. [Figure 1B] 1 shows the reduction in tumor volume over a 120 day period immediately following treatment with Compound A. [Figure 1C] 1 shows the reduction in tumor volume over a 120 day period immediately following treatment with Compound B. [Figure 1D] 1 shows the reduction in tumor volume over a 120 day period immediately following treatment with RMC-4550. [Figure 1E] 1 shows the reduction in tumor volume over a 120 day period immediately following treatment with a combination of Compound A and RMC-4550. [Figure 1F] 1 shows the reduction in tumor volume over a 120 day period immediately following treatment with a combination of Compound A and Compound B. [Figure 1G] 1 shows the reduction in tumor volume over a 120 day period immediately following treatment with the triple combination of Compound A, Compound B and RMC-4550. [Figure 2A] Figure 1 shows that various combination treatments result in increased reduction of myeloid-derived suppressor cells (MDSCs). Data points, from left to right, represent treatment with vehicle control, Compound A, Compound B, RMC-4550, Compound A combined with RMC-4550, Compound A combined with Compound B, and the triple combination of Compound A, Compound B, and RMC-4550. [Figure 2B] 1 shows that various combination treatments result in increased T cell expansion. Data points, from left to right, represent treatment with vehicle control, Compound A, Compound B, RMC-4550, Compound A in combination with RMC-4550, Compound A in combination with Compound B, and the triple combination of Compound A, Compound B, and RMC-4550. [Figure 2C] 1 shows that various combination treatments result in increased T cell activity. Data points, from left to right, represent treatment with vehicle control, Compound A, Compound B, RMC-4550, Compound A combined with RMC-4550, Compound A combined with Compound B, and the triple combination of Compound A, Compound B, and RMC-4550. DETAILED DESCRIPTION OF THE INVENTION

[0029] The present disclosure generally relates to compositions and methods for treating cancer (e.g., immunorefractory cancer). The disclosure is based, at least in part, on the observation that immunorefractory cancer can be treated with a combination of (i) a first RAS inhibitor, (ii) a second RAS inhibitor, and (iii) an SHP2 inhibitor. In some embodiments, the first RAS inhibitor inhibits a RAS harboring an oncogenic G12C mutation. In some embodiments, the first RAS inhibitor is a covalent inhibitor, e.g., capable of forming a covalent bond with an oncogenic mutant form of RAS G12C at the G12C position. In some embodiments, the second RAS inhibitor is a RAS(MULTI) inhibitor. In some embodiments, treatment with a RAS inhibitor sensitizes the cancer to treatment with an immune checkpoint inhibitor or an SHP2 inhibitor. In some embodiments, a compound, or combination of compounds, described herein is administered to a subject who has previously failed immunotherapy treatment (e.g., treatment with an immune checkpoint inhibitor).

[0030] Overall Method The practice of the present disclosure 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 (RIFreshney), ed., 1987); 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.

[0031] 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.

[0032] 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 employed to determine the value. In certain embodiments, the term "about" refers to a range of values ​​that is included within 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) of the stated value, unless otherwise specified or otherwise clear from the context (e.g., where such number may exceed 100% of the possible values).

[0033] As used herein, the term "adjacent" in the context of describing adjacent atoms means divalent atoms that are directly joined by a covalent bond.

[0034] As used herein, "compounds of the invention" and similar terms refer to the Ras inhibitors described herein, including compounds of Formula I and subformulas thereof, and compounds in Table 1 and Table 2, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof, whether or not explicitly stated.

[0035] 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., where one or more atoms are 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.

[0036] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. 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 are known in the art, for example, by resolution of racemic mixtures or stereoselective synthesis. 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 disclosure. 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.

[0037] In some embodiments, one or more compounds described herein can exist in different tautomeric forms. Unless explicitly excluded, as is clear from the context, reference to such a compound encompasses all such tautomeric forms. In some embodiments, a tautomeric form results from the exchange of a single bond with an adjacent double bond and the accompanying migration of a proton. In certain embodiments, a tautomeric form can be a prototropic tautomer, which is an isomeric protonation state having the same empirical formula and total charge as the referenced form. Examples of moieties having prototropic tautomeric forms are ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position in a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. In some embodiments, the tautomeric forms are in equilibrium or can be sterically locked into one form by appropriate substitution. In certain embodiments, the tautomeric forms arise from acetal interconversion.

[0038] 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 are: 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 result in 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.

[0039] Non-limiting examples of moieties that may contain one or more deuterium substitutions (any position "R" can also be deuterium (D)) in the compounds of the present invention are: [ka] Additional examples include moieties, examples of which include: [ka] and similar R 1 There is deuteration of the type part, R 1The definition of is described herein. Deuteration of moieties within the substituent W in the compounds of the invention is also contemplated, where W is defined herein (e.g., Formula I and subformulas thereof, as well as specific examples of W described herein, such as [ka] Additionally, deuteration of any available position in the A moiety of compounds of the formulae described herein is contemplated, examples of which include: [ka] Furthermore, deuterium substitution also [ka] may occur in the compounds of the present invention at linker positions such as:

[0040] In further embodiments, silylated substitutions are also contemplated, such as in linkers such as: [ka]

[0041] As is known in the art, many chemical compounds can exist 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.

[0042] 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 includes multiple positions where a substituent is disclosed in a group or range, unless otherwise specified, the disclosure is intended to encompass individual compounds and groups (e.g., genera and subgenera) of compounds including each and every individual subcombination of the members at each position.

[0043] 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 that it is optional. As described herein, certain compounds of interest may contain one or more "optionally substituted" moieties. In general, "substituted," whether preceded by the term "substituted" or not, means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent, e.g., any of the substituents or groups described herein. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents are either the same or different at all positions. For example, in the term "optionally substituted C1-C6 alkyl-C2-C9 heteroaryl," the alkyl portion, the heteroaryl portion, or both can be optionally substituted. Combinations of substituents contemplated by the present disclosure preferably result in the formation of stable or chemically suitable compounds. The term "stable," as used herein, refers to a compound that remains substantially unchanged when subjected to conditions that foresee the production, detection, and, in certain embodiments, recovery, purification, and use of the compounds for one or more purposes disclosed herein.

[0044] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently deuterium, halogen, -(CH) 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, -(CH2) 0-4Ph [may be substituted with R°], -(CH2) 0-4 O(CH2)0-1Ph [may be substituted with R°], -CH=CHPh [may be substituted with R°], -(CH2) 0-4 O(CH2) 0-1 -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) 0-4 N(R°)2, -(CH2) 0-4 N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(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) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 -C(O)-N(R°)2;-(CH2) 0-4 -C(O)-N(R°)-S(O)2-R°;-C(NCN)NR°2;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2)0-4 S(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 alkylene)ON(R°)2; or -(C 1-4 straight or branched chain alkylene)C(O)ON(R°), where each R° may be optionally substituted as defined below and independently represents hydrogen, —C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, notwithstanding the above definitions, two independently occurring R° may be taken together with the atom(s) between them to 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.

[0045] Suitable monovalent substituents on R° (or the ring formed by two independently occurring R° taken together with the atoms between which they intervene) are independently halogen, —(CH) 0-2 R λ ,-(Halo R λ ), -(CH2) 0-2 OH, -(CH2) 0-2 OR λ , -(CH2) 0-2 CH(OR λ )2;-O(HaloR λ ), -CN, -N3, -(CH2) 0-2 C(O)R λ , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR λ , -(CH2) 0-2 SR λ , -(CH2)0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR λ , -(CH2) 0-2 NR λ 2, -NO2, -SiR λ 3. -OSiR λ 3. -C(O)SR λ 、 -(C 1-4 Straight or branched chain alkylene)C(O)OR λ , or -SSR λ wherein each R λ is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently represents C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 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.

[0046] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═O, ═S, ═NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S- [wherein each independently occurring 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 adjacent substitutable carbons of an "optionally substituted" group are -O(CR * 2) 2-3O—, wherein each independently occurring R * is hydrogen, C which may be substituted as defined below 1-6 aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0047] R * Suitable substituents on the aliphatic groups are halogen, -R λ ,-(Halo R λ ), -OH, -OR λ , -O(HaloR λ ), -CN, -C(O)OH, -C(O)OR λ , -NH2, -NHR λ , -NR λ 2, or -NO2, wherein each R λ is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently represents C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0048] A suitable substituent on a substitutable nitrogen of an "optionally substituted" group is -R † , including -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † ;In the formula, each R † are independently hydrogen, optionally substituted as defined below, C 1-6may be an aliphatic, unsubstituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, may be any of two independently occurring R † together with the atom(s) they intervene to 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.

[0049] R † Suitable substituents on the aliphatic group are independently halogen, —R λ ,-(Halo R λ ), -OH, -OR λ , -O(HaloR λ ), -CN, -C(O)OH, -C(O)OR λ , -NH2, -NHR λ , -NR λ 2, or -NO2, where each R λ is unsubstituted or, if preceded by "halo", is substituted only by one or more halogens, independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2) 0-1 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 include ═O and ═S.

[0050] 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 the 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 the compound from a racemic mixture of the compound, a particular salt of a compound may be considered a different form from another salt form of the 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 the 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.

[0051] 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.

[0052] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0053] 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.

[0054] 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-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and neopentyl.

[0055] 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 The term "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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] As used herein, the term “amino” refers to —N(R † )2, for example, -NH2 and -N(CH3)2.

[0060] As used herein, the term "aminoalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more amino moieties.

[0061] 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. "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.

[0062] As used herein, "amino acid substitution" refers to the replacement of a wild-type amino acid in a protein with a non-wild-type amino acid. Amino acid substitutions can occur through genetic mutation and can alter one or more properties of a protein (e.g., can confer altered binding affinity or specificity, altered enzymatic activity, altered structure, or altered function).

[0063] 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.

[0064] 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)-.

[0065] 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 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.

[0066] As used herein, the term "carbonyl" refers to a C(O) group, which can also be represented as C=O.

[0067] As used herein, the term "carboxyl" refers to -CO2H, (C=O)(OH), COOH, or C(O)OH, or the unprotonated corresponding groups.

[0068] The term "combination therapy" refers to a method of treatment that includes administering to a subject at least two therapeutic agents, optionally in one or more pharmaceutical compositions, as part of a treatment regimen. For example, combination therapy can include administration of a single pharmaceutical composition containing at least two therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. Combination therapy can include administration of two or more pharmaceutical compositions, each containing one or more therapeutic agents and one or more pharmaceutically acceptable carriers, excipients, diluents, or surfactants. 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, for example, due to an additive or synergistic effect of combining two or more therapeutic agents.

[0069] As used herein, the term "cyano" refers to a -CN group.

[0070] 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 ring carbons, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0071] 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 ring carbons and containing one or more carbon-carbon double bonds.

[0072] 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.

[0073] As used herein, the term "dosage form" means 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 an appropriate 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.

[0074] 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).

[0075] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0076] 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%.

[0077] The term "guanidyl" means a compound having the structure [ka] wherein each R is independently any chemically suitable substituent described herein.

[0078] As used herein, the term "guanidinoalkylalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more guanidyl moieties.

[0079] As used herein, the term "haloacetyl" means an acetyl group in which at least one hydrogen has been replaced by a halogen.

[0080] As used herein, the term "haloalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more of the same or different halogen moieties.

[0081] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0082] 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 may occur at the center or at the end of the group.

[0083] As used herein, the term "heteroaryl" refers to a monovalent, monocyclic or polycyclic ring system containing at least one fully aromatic ring. That is, they contain 4n+2 pi-electrons within the monocyclic or polycyclic ring system and at least one ring heteroatom selected from N, O, or S within 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 of the ring atoms can be optionally substituted. In some embodiments, a heteroaryl is substituted with 1, 2, 3, or 4 substituents.

[0084] 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.

[0085] As used herein, the term "hydroxy" refers to an --OH group.

[0086] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more --OH moieties.

[0087] As used herein, the term "isomer" refers to any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the present invention. It is recognized that the compounds of the present invention may 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, i.e., the compounds of the present invention, may be expressed in all corresponding stereoisomers, i.e., stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomeric pure forms), and enantiomers. The present invention encompasses both mixtures of enantiomers and stereoisomers, e.g., racemates. Mixtures of enantiomers and stereoisomers of the compounds of the present invention can typically be expanded into the constituent 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.

[0088] As used interchangeably herein, the terms "immunorefractory," "immune escape," or "cold tumor" refer to tumors, cancers, or patients with tumors or cancers for which prior immunotherapy, such as immune checkpoint inhibitors, has proven ineffective or intolerable. For example, patients with immunorefractory cancer include patients who have previously been treated with immunotherapy, such as immune checkpoint inhibitors, but the immunotherapy has proven ineffective or not sufficiently effective in slowing or stopping disease progression or alleviating symptoms associated with disease progression. Immunorefractory cancers include cancers that have become resistant to or have reduced sensitivity to immunotherapy treatment (e.g., the effectiveness of immunotherapy, such as immune checkpoint inhibitors, previously administered to the patient has diminished over time). Immunorefractory cancers can be identified by methods known to those skilled in the art or described herein. For example, immunorefractory cancers can be characterized by low immune cell infiltration in one or more tumors. Low immune cell infiltration can include a reduction or absence of lymphocytes, tumor-infiltrating lymphocytes (TILs), dendritic cells, myeloid cells, natural killer (NK) cells, macrophages, CD8+ T cells, CD4+ T cells, or CD4+ / CD8+ T cells. See, e.g., Chen and Mellman, Nature, 541:321 (2017). In contrast, in some embodiments, a "hot tumor" refers to a tumor, cancer, or a patient with a tumor or cancer that is not immunorefractory. Cells with a low number of cytotoxic T cells are characterized as "immune desert." In some embodiments, cells with cytotoxic T cells representing less than 1% of viable cells are considered "immune desert." In some embodiments, cells with cytotoxic T cells representing less than 0.5% of viable cells are considered "immune desert." In some embodiments, cells in which the number of cytotoxic T cells is less than 0.25% of viable cells are considered to be in an "immune desert."

[0089] 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 other 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 small molecules ranges from 800 Da to 1200 Da. Small molecule inhibitors include cyclic and acyclic compounds. Small molecule inhibitors include natural products, as well as derivatives and analogs thereof. Small molecule inhibitors can, for example, contain covalent cross-linking groups capable of forming covalent cross-links with amino acid side chains of target proteins.

[0090] As used herein, the term "linker" refers to a divalent organic moiety that connects a first moiety (e.g., a macrocyclic moiety) to a second moiety (e.g., a bridging group). In some embodiments, the linker results in compounds that are capable of achieving an IC50 of 2 uM or less in the Examples below and in the Ras-RAF disruption assay protocol provided herein.

[0091] 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 RBDdisrupting binding to the construct and inhibiting Ras signaling through RAF effectors.

[0092] Untagged cyclophilin A, His6-K-RasGMPPNP (or other Ras variants), and GST-BRAF were incubated 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. 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 is added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reactions are incubated for an additional 1.5 hours. TR-FRET signals are 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, e.g., a monkey, chimpanzee, baboon, or rhesus monkey.

[0097] 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.

[0098] 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.

[0099] 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-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water for hydration. Excipients include, but are not limited to, optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropylcellulose, optionally substituted hydroxypropylmethylcellulose, 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.

[0100] 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. PH Stahl and CG 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.

[0101] The terms "RAS inhibitor" and "inhibitor of RAS" are used interchangeably and refer to any inhibitor that targets, i.e., selectively binds to or selectively inhibits, a RAS protein.

[0102] As used herein, "RAS" MULTI The term "RAS (MULTI) inhibitor" or "RAS (MULTI) inhibitor" refers to a RAS inhibitor of at least three RAS variants with missense mutations at one of the following positions: 12, 13, 59, 61, or 146. In some embodiments, a RAS MULTI The inhibitor refers to a RAS inhibitor of at least three RAS variants that have a missense mutation at one of the following positions: 12, 13 and 61.

[0103] 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, active state of RAS includes, for example, inhibition of oncogenic signaling from the GTP-bound, active state of RAS. In some embodiments, a RAS(ON) inhibitor is an inhibitor that selectively binds to and inhibits the GTP-bound, active state of RAS. In certain embodiments, a RAS(ON) inhibitor may 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, active state of RAS). The RAS inhibitors of Formula 0 and Formula I, and their sub-formulas herein, are RAS(ON) inhibitors.

[0104] The terms "RAS pathway" and "RAS / MAPK pathway" are used interchangeably herein to refer to the signaling cascade downstream of various cell surface growth factor receptors. Here, activation of RAS (and its various isoforms and allotypes) is a central event that drives 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.

[0105] As used herein, the term "resistant 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 a treatment over a period of time when the therapeutic agent is administered to a subject. Acquired resistance to therapy may result from the acquisition of mutations in the target protein that render the treatment ineffective or less effective. Thus, resistance to therapy may persist even after the administration of a therapeutic agent has ceased. In particular, cancers may become resistant to immune checkpoint inhibitor treatment after treatment with an immune checkpoint inhibitor. Such cancers are also referred to herein as "immune refractory." 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 treatment can be measured by disease progression. Effective treatment can slow or halt disease progression. Cancers that are resistant to treatment with therapeutic agents, such as immune checkpoint inhibitors, may fail to slow or halt the progression of the disease.

[0106] As used herein, the term "stereoisomer" refers to all possible different isomeric and conformational forms that a compound (e.g., a compound of any formula described herein) may possess, in particular all possible stereochemical and conformational isomeric forms, all diastereomers, enantiomers, or conformational isomers of a basic molecular structure, e.g., atropisomers. Some compounds of the present invention can exist in different tautomeric forms, all of the latter being included within the scope of the present invention.

[0107] As used herein, the term "sulfonyl" refers to the group -S(O)2-.

[0108] 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.

[0109] 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 actually require that successful treatment be achieved in particular individuals. 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 may be formulated or administered in a single dose, hi some embodiments, a therapeutically effective amount may be formulated or administered in multiple doses, e.g., as part of a dosing regimen.

[0110] As used herein, the term "thiocarbonyl" refers to a -C(S)- group.

[0111] 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 alleviates, improves, reduces, or inhibits a particular disease, disorder, or condition; partially or completely delays the onset of a particular disease, disorder, or condition; partially or completely reduces the severity of a particular disease, disorder, or condition; or partially or completely reduces the occurrence of one or more symptoms, characteristics, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment can be administered to a subject who does not exhibit signs of the associated disease, disorder, or condition, or who exhibits only early signs of a disease, disorder, or condition. Alternatively, or in addition, in some embodiments, such treatment can be administered to a subject who exhibits established signs of one or more of the associated diseases, disorders, or conditions. In some embodiments, treatment can be in a subject who has been diagnosed as suffering from the associated disease, disorder, or condition. In some embodiments, treatment may be in a subject known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the relevant disease, disorder or condition.

[0112] As used herein, the term "vinyl ketone" refers to a group containing a carbonyl group attached directly to a carbon-carbon double bond.

[0113] As used herein, the term "vinyl sulfone" refers to a group containing a sulfonyl group attached directly to a carbon-carbon double bond.

[0114] 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).

[0115] As used herein, the term "ynone" refers to a compound having the structure [ka] wherein R is any suitable optional substituent as described herein.

[0116] RAS inhibitors Compounds that inhibit RAS and uses thereof are provided herein. Pharmaceutical compositions comprising one or more RAS inhibitor compounds, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient are also provided. RAS inhibitor compounds may be used in methods of inhibiting RAS (e.g., in a subject or cell) and treating cancer, as described herein. In some embodiments, the compounds of the present disclosure are or act as prodrugs, for example, for administration to a cell or a subject in need thereof.

[0117] 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 due to activating mutations, overexpression, or upstream activating genes 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. This 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. Additionally, 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 (e.g., G13D) and codon 61 (e.g., Q61K) of RAS also contribute to oncogenic activity in some cancers.

[0118] Oncogenic pathways such as KRAS and the presence of immunosuppressive cell populations such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) have emerged as biological mechanisms of T cell elimination (Liu et al., Theranostics 2021).

[0119] KRAS mutations are prevalent in lung, pancreatic, and colon cancers, determining the immunosuppressive tumor microenvironment (TME) in these tumors (Gu et al., Cancers 2021). Oncogenic KRAS mutations mediate autocrine effects and crosstalk with the TME by inducing several inflammatory cytokines, chemokines, and signaling pathways that promote carcinogenesis and resistance to immunotherapy (Hamarsheh et al., Nat. Commun. 2020).

[0120] The RAS inhibitors described herein can enhance the sensitivity of immunorefractory lung cancer to immunotherapy. As described herein, treatment using the RAS inhibitors described herein can alter tumor immune infiltrates consisting of T cells, B cells, APCs, monocytes, MDSCs, TAMs, neutrophils, other monocyte-derived cells, tumor-associated stroma, cancer stem cells, or mesenchymal stem cells, resulting in enhanced anti-tumor therapeutic effects. In some embodiments, the RAS inhibitors described herein can enhance the sensitivity of subjects to immunotherapy, such as checkpoint inhibitor therapy.

[0121] The disclosed RAS inhibitors can form high-affinity ternary complexes or conjugates between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the protein of interest (e.g., RAS) and a cytosolic chaperone (presenter protein) (e.g., cyclophilin A) that is widely expressed in cells. More specifically, in some embodiments, the RAS inhibitors described herein induce a novel binding pocket in RAS by driving the formation of a high-affinity tri-complex or conjugate between the RAS protein and the widely expressed cytosolic chaperone cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one manner in which the inhibitory effects on RAS are affected by the compounds of the present invention and the complexes or conjugates they form is through steric occlusion of the interaction site between RAS and downstream effector molecules (e.g., RAFs) that are required to propagate oncogenic signals. See, for example, WO2021 / 091982, the contents of which are incorporated herein by reference in their entirety.

[0122] In some embodiments of the combination therapy described herein, the second RAS inhibitor is a RAS(MULTI) inhibitor (e.g., a compound of formula AI or a subformula thereof, or a compound of Table A1 or Table A2). RAS(MULTI) inhibitors of formula AI are described in WO 2021 / 091956, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the RAS inhibitor is a compound having the structure of formula A00, or a pharmaceutically acceptable salt thereof, i.e., [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; G is an optionally substituted C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is independently H or optionally substituted C-C alkyl; Y 1 is C, CH, or N; Y2 , 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 6is hydrogen or methyl; 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; 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 3-6 membered cycloalkyl, or an optionally substituted 3-7 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 form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; 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.

[0123] In some embodiments, the RAS inhibitor is a compound of 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 )-, 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 C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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, 3- to 11-membered heterocycloalkyl optionally substituted with C0-C4 alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; 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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is 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; 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; 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 3-6 membered cycloalkyl, or an optionally substituted 3-7 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 form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; 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 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).

[0124] In some embodiments, the RAS inhibitor is 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 )-, 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 C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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, 3- to 11-membered heterocycloalkyl optionally substituted with C0-C4 alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; 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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is 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; 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; 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 3-6 membered cycloalkyl, or an optionally substituted 3-7 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 form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; or R 9 and L, together with the atom to which they are attached, combine to form an optionally substituted 3- to 14-membered heterocycloalkyl; R 9’ is hydrogen or optionally substituted C1-C6 alkyl; R 10 is hydrogen, halo, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl; R 10a is hydrogen or halo, and R 11 is hydrogen or C1-C3 alkyl.

[0125] In some embodiments, the RAS inhibitor is 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 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-[wherein the 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 C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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, 3- to 11-membered heterocycloalkyl optionally substituted with C0-C4 alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; 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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N; Y2 , 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; 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; 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 C-C alkyl; R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ combine with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl; R 9is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; or R 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 is hydrogen or C1-C3 alkyl.

[0126] In some embodiments of formula AI and subformulas thereof, G is an optionally substituted C1-C4 heteroalkylene.

[0127] In some embodiments, the RAS inhibitor is a compound having the structure of formula AIc, or a pharmaceutically acceptable salt thereof, i.e., [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 6-membered heteroarylene; B is -CH(R 9 )-[wherein the 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; 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, 3- to 11-membered heterocycloalkyl optionally substituted with C0-C4 alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; 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-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N; Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 and Y 6 are independently CH or N; R 1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; R 2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; 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; R 7 and R 8combine 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 C-C alkyl; 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 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 is hydrogen or C1-C3 alkyl.

[0128] In some embodiments of formula AI and its subformulas, X 2 In some embodiments of formula AI and its subformulas, X 3 is CH.

[0129] In some embodiments of formula AI and its subformulas, R 11is hydrogen. In some embodiments of formula AI and its subformulas, R 11 is C1-C3 alkyl. In some embodiments of formula AI and subformulas thereof, R 11 is methyl.

[0130] In some embodiments, the RAS inhibitor is a compound having the structure of formula AId, or a pharmaceutically acceptable salt thereof, i.e., [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 6-membered heteroarylene; B is -CH(R 9 )-, 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; 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, 3- to 11-membered heterocycloalkyl optionally substituted with C0-C4 alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is independently H or optionally substituted C-C 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 5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; 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; 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 C-C alkyl; 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.

[0131] In some embodiments of formula AI and its subformulas, 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)-.

[0132] In some embodiments of formula AI and its subformulas, R 3 does not exist.

[0133] In some embodiments of formula AI and its subformulas, R 4 is hydrogen.

[0134] 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.

[0135] In some embodiments of formula AI and its subformulas, Y 4 is C. In some embodiments of formula AI and its subformulas, Y 5 In some embodiments of formula AI and its subformulas, Y 6 In some embodiments of formula AI and its subformulas, Y 1 is C. In some embodiments of formula AI and its subformulas, Y 2 is C. In some embodiments of formula AI and its subformulas, Y 3 is N. In some embodiments of formula AI and its subformulas, Y 7 is C.

[0136] In some embodiments, the RAS inhibitor is a compound having the structure of formula AIe, or a pharmaceutically acceptable salt thereof, i.e., [ka] wherein A is —N(H or CH3)C(O)—(CH2)—; 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 6-membered heteroarylene; B is -CH(R 9)-, 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; 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, 3- to 11-membered heterocycloalkyl optionally substituted with C0-C4 alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; 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; R6 is hydrogen or methyl; 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; 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 C-C alkyl; 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.

[0137] In some embodiments of formula AI and its subformulas, R 6 is hydrogen.

[0138] In some embodiments of formula AI and its subformulas, R 2 is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments of formula AI and its subformulas, R 2 is optionally substituted C1-C6 alkyl, for example, ethyl. In some embodiments of formula AI and subformulas thereof, R 2 is fluoroC1-C6 alkyl, for example, —CH2CH2F, —CH2CHF2, or —CH2CF3.

[0139] 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.

[0140] In some embodiments of formula AI and its subformulas, R 8 is an optionally substituted C1-C3 alkyl. In some embodiments of formula AI and subformulas thereof, R 8 is C1-C3 alkyl, for example methyl.

[0141] In some embodiments, the RAS inhibitor is a compound having the structure of formula AIf, or a pharmaceutically acceptable salt thereof, i.e., [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 )-, 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; 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, 3- to 11-membered heterocycloalkyl optionally substituted with C0-C4 alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; 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 3-6 membered cycloalkyl; R 7 is C1-C3 alkyl; R 8is 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.

[0142] 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.

[0143] 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.

[0144] In some embodiments, the RAS inhibitor is a compound having the structure of formula AIg, or a pharmaceutically acceptable salt thereof, i.e., [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 )-, 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; 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, 3- to 11-membered heterocycloalkyl optionally substituted with C0-C4 alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; 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; X e is N, CH, or CR 17 and; X f is N or CH; R 12is an optionally substituted C1-C6 alkyl or an optionally substituted C1-C6 heteroalkyl; 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.

[0145] 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.

[0146] 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.

[0147] In some embodiments, the RAS inhibitor is a compound having the structure of formula AIh, or a pharmaceutically acceptable salt thereof, i.e., [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)-, 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; 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, 3- to 11-membered heterocycloalkyl optionally substituted with C0-C4 alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; 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, 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.

[0148] In some embodiments, the RAS inhibitor is a compound having the structure of formula AIi, or a pharmaceutically acceptable salt thereof, i.e., [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 )-, 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; 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, 3- to 11-membered heterocycloalkyl optionally substituted with C0-C4 alkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl; 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.

[0149] 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.

[0150] 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, 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.

[0151] In some embodiments of formula AI and subformulas thereof, B is an optionally substituted 6-membered arylene.

[0152] In some embodiments, B is a 6-membered arylene. In some embodiments, B is [ka] In some embodiments, B is absent.

[0153] In some embodiments of formula AI and its subformulas, R 7 is methyl.

[0154] In some embodiments of formula AI and its subformulas, R 8 is methyl.

[0155] In some embodiments of formula AI and its subformulas, R 16 is hydrogen.

[0156] 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 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 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 -(B4 ) k -A 2 In 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, the linker has the following structure: [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 bis C(O) or SO2; R 15 is 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; L 3 is absent, -C(O)-, -SO2-, an optionally substituted C1-C4 alkylene, or an optionally substituted C1-C4 heteroalkylene. In some embodiments, the linker has the following structure: [ka] [ka]

[0157] 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, 3-8 membered heterocycloalkyl optionally substituted with C0-C4 alkyl, optionally substituted 3-8 membered cycloalkyl, or 3-8 membered heteroaryl.

[0158] 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 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 a 3-11 membered heterocycloalkyl optionally substituted with C0-C4 alkyl. 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).

[0159] In some embodiments, the RAS inhibitor is a RAS(MULTI) inhibitor. In some embodiments, the RAS(MULTI) inhibitor is selected from Table A1, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the RAS(MULTI) inhibitor is selected from Table A1, or a pharmaceutically acceptable salt or atropisomer thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] Table 1-12 Table 1-13 Table 1-14 Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

[0160] Note that some compounds are shown with bonds as flat or wedged. In some cases, the relative stereochemistry of stereoisomers has been determined. In some cases, the absolute stereochemistry has been determined. In some cases, a single example number corresponds to a mixture of stereoisomers. All stereoisomers of the compounds in the foregoing tables are contemplated by the present invention. In certain embodiments, atropisomers of the compounds in the foregoing tables are contemplated. Any compounds shown in parentheses indicate that the compound is a diastereomer, and that the absolute stereochemistry of such diastereomers is not necessarily known.

[0161] In some embodiments, the RAS inhibitor is a RAS(MULTI) inhibitor. In some embodiments, the RAS(MULTI) inhibitor is a compound of Table A2, or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS(MULTI) inhibitor is a compound of Table A2, or a pharmaceutically acceptable salt or atropisomer thereof. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18]

[0162] Note that some compounds depict bonds as flat or wedged. In some cases, the relative stereochemistry of stereoisomers has been determined. In some cases, the absolute stereochemistry has been determined. All stereoisomers of the compounds in the foregoing table are contemplated by the present invention. In certain embodiments, atropisomers of the compounds in the foregoing table are contemplated.

[0163] The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic, or enzymatic processes.

[0164] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of Table A1 and Table A2 can be synthesized using the methods described in the following schemes and WO 2021 / 091956, as well as synthetic methods known in the art of organic synthetic chemistry, or variations thereof that would be understood by those skilled in the art. These methods include, but are not limited to, the methods described in the following schemes or the methods described in WO 2021 / 091956 (incorporated herein by reference).

[0165] 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 may be prepared using the methods disclosed herein or may be prepared using the methods disclosed herein in combination with the knowledge of those skilled in the art.

[0166] Scheme A1. General synthesis of macrocyclic esters [ka] 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.

[0167] 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.

[0168] 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).

[0169] 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 using the methods exemplified in the Examples section of this specification.

[0170] Scheme A2. Alternative general synthesis of macrocyclic esters [ka] 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.

[0171] Scheme A3. General synthesis of macrocyclic esters [ka] 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.

[0172] Scheme A4. General synthesis of macrocyclic esters [ka] 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.

[0173] 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.

[0174] 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.

[0175] Furthermore, the compounds of the present disclosure can be synthesized using the methods described in the examples below, as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereof understood by those skilled in the art. These methods include, but are not limited to, those described in WO 2021 / 091956. For example, one skilled in the art can introduce the desired -BLW group (wherein B, L, and W are defined herein, including using the methods exemplified in WO 2021 / 091956) of a compound of formula (AI) into the macrocyclic ester.

[0176] In some embodiments of the combination therapy described herein, the first RAS inhibitor is a RAS G12C inhibitor (e.g., a compound of formula BI or a subformula thereof, or a compound of Table B1 or Table B2). RAS G12C inhibitors of formula BI are described in WO 2021 / 091982, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the RAS inhibitor is a compound having the structure of formula BI or a pharmaceutically acceptable salt thereof, i.e., [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)—; 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 C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -C(R 7 R8 )-; 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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is 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; R1 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; 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; 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 3-6 membered cycloalkyl, or an optionally substituted 3-7 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 form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; 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 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, combined with the atom to which they are attached, 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).

[0177] 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.

[0178] In some embodiments of Formula BI, R 21 is hydrogen.

[0179] In some embodiments, the RAS inhibitor is a compound having the structure of formula BIa, or a pharmaceutically acceptable salt thereof, i.e., [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 -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 C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is 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; 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; 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 3-6 membered cycloalkyl, or an optionally substituted 3-7 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 form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; 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.

[0180] In some embodiments, the RAS inhibitor is 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 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-[wherein the 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 C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is 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 5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; 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; 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 C-C alkyl; 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 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 is hydrogen or C1-C3 alkyl.

[0181] In some embodiments of formula BI and subformulas thereof, G is an optionally substituted C1-C4 heteroalkylene.

[0182] In some embodiments, the RAS inhibitor is a compound having the structure of formula BIc, or a pharmaceutically acceptable salt thereof, i.e., [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 6-membered heteroarylene; B is -CH(R 9 )-[wherein the 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; 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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is 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; 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; 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 C-C alkyl; 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 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 is hydrogen or C1-C3 alkyl.

[0183] 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.

[0184] In some embodiments, the RAS inhibitor has the structure of Formula BId, or a pharmaceutically acceptable salt thereof: [ka] wherein the dotted lines represent 0, 1, 2, 3 or 4 non-adjacent double bonds; A is —N(H or CH3)C(O)—(CH2)—, where the amino nitrogen is —CH(R 10 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, 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; 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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is 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 5is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; 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; 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; 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.

[0185] 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 subformulas thereof, 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.

[0186] 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.

[0187] In some embodiments, the RAS 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 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-, 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; 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; 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; 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 C-C alkyl; 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.

[0188] 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 2 is 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 C-C alkyl. In some embodiments, R 7 is C1-C3 alkyl. In some embodiments, R 8 is an optionally substituted C-C alkyl. In some embodiments, R 8 is C1-C3 alkyl.

[0189] In some embodiments, the RAS 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 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9)-, 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; 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 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 3-6 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.

[0190] 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.

[0191] In some embodiments of Formula B1 and subformulas thereof, R1 is [ka] In some embodiments of formula BI and its subformulas, R 12 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R 12 teeth, [ka] In some embodiments, R 12 teeth [ka] is.

[0192] In some embodiments, the RAS 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)—; 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 C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N; Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; 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; R 7 and R8 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 3-6 membered cycloalkyl, or an optionally substituted 3-7 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 form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; 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.

[0193] In some embodiments, the RAS 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 )-, 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; 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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); 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.

[0194] 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.

[0195] In some embodiments, the RAS 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 )-, 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; R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl; or L is absent or a linker, and W is a bridging group comprising a vinyl ketone, vinyl sulfone, ynone, or alkynyl sulfone.

[0196] In some embodiments of Formula BI or subformulas thereof, A is an optionally substituted 6-membered arylene.

[0197] In some embodiments, the RAS 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)—; 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 C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’is independently H or optionally substituted C1-C4 alkyl; Y 1 is C, CH, or N; Y 2 , Y 3 , Y 4 , and Y 7 are independently C or N, Y 5 is CH, CH2, or N, Y 6 is C(O), CH, CH2, or N, R 2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 3 does not exist, or R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 14-membered heterocycloalkyl; R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens; R 5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl; R 6 is hydrogen or methyl; 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; 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 3-6 membered cycloalkyl, or an optionally substituted 3-7 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 form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; 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 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).

[0198] In some embodiments of formula BI and subformulas thereof, A has the following structure: [ka] wherein R 13 is hydrogen, halo, hydroxy, amino, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 13a is hydrogen or halo. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 and R13a are each hydrogen. In some embodiments, R 13 is hydroxy, methyl, fluoro or difluoromethyl.

[0199] In some embodiments of formula BI and subformulas thereof, A is an optionally substituted 5- to 6-membered heteroarylene. [ka] is.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] In some embodiments of formula B1 and its subformulas, R 7 is methyl.

[0204] In some embodiments of formula B1 and its subformulas, R 8 is methyl.

[0205] In some embodiments of formula B1 and its subformulas, R 21 is hydrogen.

[0206] 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, A1 is the bond between the linker and B; A 2 is the bond between W and the linker; B 1 , B 2 , B 3 , and B 4 are each independently an optionally substituted C1-C2 alkylene, an optionally substituted C1-C3 heteroalkylene, O, S, and NR N Selected from;R N is hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted C1-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, the linker has the following structure: [ka]

[0207] 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.

[0208] In some embodiments of Formula B1 and subformulas thereof, the linker has the structure of Formula BIIb-1: [ka] wherein o is 0 or 1; R 15 is hydrogen, or optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heterocycloalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene, and L 3 is absent, -SO2-, an optionally substituted C1-C4 alkylene, or an optionally substituted C1-C4 heteroalkylene.

[0209] 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 15dcombine 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.

[0210] In some embodiments of Formula BI and subformulas thereof, the linker has the structure: [ka] [ka]

[0211] In some embodiments of Formula BI and subformulas thereof, the linker has the following structure: [ka] [ka] [ka] [ka]

[0212] In some embodiments of formula BI and subformulas thereof, the linker has the structure [ka] It has.

[0213] In some embodiments of formula BI and subformulas thereof, the linker has the structure [ka] In some embodiments of Formula B1 and its subformulas, W is a bridging group comprising a vinyl ketone. In some embodiments, W has the structure of Formula BIIIa: [ka] [In the formula, R 16a , R 16b , and R 16c are independently hydrogen, -CN, halogen, or -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 4-7 membered saturated heterocycloalkyl. In some embodiments, W is [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]

[0214] In some embodiments, W is [ka] is.

[0215] In some embodiments of Formula B1 and its subformulas, W is a bridging group comprising a vinyl sulfone. In some embodiments, W has the structure of Formula BIIIc: [ka] [In the formula, R 18a , R 18b , and R 18c are independently hydrogen, -CN, or -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 4-7 membered saturated heterocycloalkyl. In some embodiments, W is [ka] In some embodiments of Formula B1 and its subformulas, W is a bridging group comprising an alkynyl sulfone. In some embodiments, W has the structure of Formula BIIId: [ka] [In the formula, R 19 is hydrogen; -C1-C3 alkyl optionally substituted with one or more substituents independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or 4- to 7-membered saturated heterocycloalkyl; or 4- to 7-membered saturated heterocycloalkyl. In some embodiments, W is [ka] is.

[0216] In some embodiments of Formula B1 and its subformulas, W has the structure of Formula BIIIe: [ka] [where, X e is a halogen, and R 20 is hydrogen; -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or -C1-C3 alkyl optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl. In some embodiments of Formula BI and subformulas thereof, R1 is: In some embodiments of Formula BI and subformulas thereof, W is not haloacetyl.

[0217] In some embodiments, the RAS inhibitor is a RAS G12C inhibitor. In some embodiments, the RAS G12C inhibitor is selected from Table B1, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the RAS G12C inhibitor is selected from Table B1, or a pharmaceutically acceptable salt or atropisomer thereof.

[0218] [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

[0219] In some embodiments, the RAS G12C inhibitor is a compound of Table B2, or a pharmaceutically acceptable salt thereof. In some embodiments, the RAS G12C inhibitor is selected from Table B2, or a pharmaceutically acceptable salt or atropisomer thereof.

[0220] [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

[0221] Note that some compounds depict bonds as flat or wedged. In some cases, the relative stereochemistry of stereoisomers has been determined. In some cases, the absolute stereochemistry has been determined. All stereoisomers of the compounds in the foregoing table are contemplated by the present invention. In certain embodiments, atropisomers of the compounds in the foregoing table are contemplated.

[0222] In some embodiments, the RAS inhibitor is or acts as a prodrug, including for administration to a cell or to a subject in need thereof.

[0223] Also provided is a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0224] In some embodiments, the RAS G12C inhibitor is provided as a conjugate comprising the structure of formula BIV or a salt thereof.

[0225] MLP formula BIV wherein L is a linker, P is a monovalent organic moiety, and 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 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is absent or -CH(R 9 )-,>C=CR 9 R 9’ , or >CR 9 R 9’ wherein carbon is —N(R 11 )C(O)—; 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 C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is 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; 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; 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 3-6 membered cycloalkyl, or an optionally substituted 3-7 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 form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; 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 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.

[0226] 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, and 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 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 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 an optionally substituted C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is 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, Y5 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; 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; 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 3-6 membered cycloalkyl, or an optionally substituted 3-7 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 form a carbonyl; R 7’ is hydrogen, halogen, or optionally substituted C-C alkyl; 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.

[0227] 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, and 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 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R 9 )-[wherein the carbon is -N(R11 )C(O)—; optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is -C(R 7 R 8 )-. ], -C(O)NH-CH(R 6 )-[wherein the second C is -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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); Each R ’ is 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; 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; 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 C-C alkyl; 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 10 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 is hydrogen or C1-C3 alkyl.

[0228] In some embodiments, the RAS G12C inhibitor has the structure of formula BIV. MLP formula BIV wherein L is a linker, P is a monovalent organic moiety, and M has the structure of formula Vd. [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 )-, 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; 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 C-C alkyl, optionally substituted C-C alkenyl, optionally substituted C-C alkynyl, C(O)R', C(O)OR', C(O)N(R'), S(O)R', S(O)R', or S(O)N(R'); 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.

[0229] 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.

[0230] In some embodiments, the RAS G12C inhibitor has the structure of formula BIV. MLP formula BIV wherein L is a linker, P is a monovalent organic moiety, and M has a 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)-, 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, wherein the carbon is bonded to the carbonyl carbon of —NHC(O)—; 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.

[0231] 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 .

[0232] 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.

[0233] 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.

[0234] The compound of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis.For example, the compound of the present invention can be synthesized by the method shown in the following scheme, or by the synthetic method known in the art of organic synthetic chemistry, or by those skilled in the art will understand the variations thereof.These methods include but are not limited to the method shown in the following scheme, or the method described in WO 2021 / 091982 (incorporated herein by reference).

[0235] Scheme B1. General synthesis of macrocyclic esters [ka] 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.

[0236] 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.

[0237] 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)).

[0238] 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.

[0239] Scheme B2. Alternative general synthesis of macrocyclic esters [ka] 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.

[0240] 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.

[0241] 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.

[0242] Scheme B3. General synthesis of macrocyclic esters [ka] 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.

[0243] 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.

[0244] 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.

[0245] Scheme B4. General synthesis of macrocyclic esters [ka] 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.

[0246] 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.

[0247] Scheme B5. General synthesis of macrocyclic esters [ka] 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.

[0248] 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.

[0249] 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, including, but not limited to, those described in the Examples below and in WO 2021 / 091982. For example, one skilled in the art can introduce the desired -BLW group (where B, L, and W are defined herein, including using the methods exemplified in WO 2021 / 091982) into the macrocyclic ester of a compound of formula (BI).

[0250] In some embodiments, the RAS inhibitor is selective for RAS comprising a G12C amino acid substitution compared to wild-type RAS or other RAS mutants. In some embodiments, the RAS inhibitor is a KRAS inhibitor that is selective for KRAS comprising a G12C amino acid substitution compared to wild-type KRAS or other KRAS mutants. In some embodiments, the RAS inhibitor is an NRAS inhibitor that is selective for NRAS comprising a G12C amino acid substitution compared to wild-type NRAS or other NRAS mutants. In some embodiments, the RAS inhibitor is an HRAS inhibitor that is selective for HRAS comprising a G12C amino acid substitution. In some embodiments, the HRAS inhibitor is selective for HRAS comprising a G12C amino acid substitution compared to wild-type NRAS or other NRAS mutants.

[0251] In some embodiments of the combination therapy described herein, the second RAS inhibitor is a RAS(MULTI) inhibitor (e.g., a compound of Formula DIa or a subformula thereof, or a compound of Table D1a, Table D1b, Table 2, or Table 3). RAS(MULTI) inhibitors of Formula DIa are described in WO 2022 / 060836, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the RAS inhibitor is a compound having the structure of Formula DIa, or a pharmaceutically acceptable salt thereof, i.e., [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, an optionally substituted 5- to 6-membered heteroarylene, an optionally substituted C2-C4 alkylene, or an optionally substituted C2-C4 alkenylene; Y is [ka] and W is hydrogen, C1-C4 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted 3-10 membered cycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; X 1 and X 4 are each independently CH or NH, R 1 is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; 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; R 10 is hydrogen, hydroxy, optionally substituted C1-C3 alkyl, or optionally substituted C1-C6 heteroalkyl.

[0252] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIa-2: [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; Y is [ka] and W is hydrogen, C1-C4 alkyl, 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; R 1 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, an optionally substituted 3- to 6-membered cycloalkenyl, an optionally substituted 3- to 6-membered heterocycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl; 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 or optionally substituted C1-C6 heteroalkyl. In some embodiments, R 10 is hydrogen.

[0253] In some embodiments of Formula DIa and its subformulas, R 1 is an optionally substituted 6-10 membered aryl or an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 1 is an optionally substituted phenyl or an optionally substituted pyridine.

[0254] In some embodiments of Formula DIa and its subformulas, A is optionally substituted thiazole, optionally substituted triazole, optionally substituted morpholino, optionally substituted piperidinyl, optionally substituted pyridine, or optionally substituted phenyl. In some embodiments, A is optionally substituted thiazole, optionally substituted triazole, optionally substituted morpholino, or phenyl. In some embodiments, A is not optionally substituted phenyl or benzimidazole. In some embodiments, A is not hydroxyphenyl.

[0255] In some embodiments of Formula DIa and subformulas thereof, Y is —NHC(O)— or —NHC(O)NH—.

[0256] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of Formula DIIa: [ka] wherein 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; R 1 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, an optionally substituted 3- to 6-membered cycloalkenyl, an optionally substituted 3- to 15-membered heterocycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl; and R 2is 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 a is 0 or 1.]

[0257] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIa-1: [ka] [wherein a is 0 or 1; 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 2 is N or CH, 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; Each R 3 are independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, and and n is an integer from 1 to 4.

[0258] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIa-2: [ka] [wherein a is 0 or 1; 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 2 is N or CH, 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; Each R 3 are independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, and and n is an integer from 1 to 4.

[0259] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIa-3: [ka] [wherein a is 0 or 1; 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 2 is N or CH, 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 4 and R 5 are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0260] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIa-4: [ka] [wherein a is 0 or 1; 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 2 is N or CH, 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 5 is halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0261] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIa-5: [ka] [In the formula, a is 0 or 1, 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 2 is N or CH, R 2is 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; X 3 is N or CH, m is 1 or 2, R 6 , R 7 , R 8 , and R 11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 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 8-membered heterocycloalkyl, or R 7 and R 8 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 11 and, together with the atom to which they are attached, combine to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is H. In some embodiments, X 3 is N, m is 1, and R 11 is H.

[0262] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIa-6: [ka] [In the formula, a is 0 or 1, 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 2 is N or CH, 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 6 is hydrogen, 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.

[0263] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIa-7: [ka] [In the formula, a is 0 or 1, 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 2 is N or CH, 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 6 is hydrogen, 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.

[0264] In some embodiments (e.g., of either one of Formula DIIa-6 or DIIa-7), R 6 is methyl.

[0265] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIa-8 or DIIa-9, i.e., [ka] [In the formula, a is 0 or 1, 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 2is N or CH, 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.

[0266] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of Formula DIIIa: [ka] [In the formula, a is 0 or 1, 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; R 1 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, an optionally substituted 3- to 6-membered cycloalkenyl, an optionally substituted 3- to 15-membered heterocycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl; and R 2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl.

[0267] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIIa-1: [ka] [wherein a is 0 or 1; 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 2 is N or CH, 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, or optionally substituted 5- or 6-membered heteroaryl; Each R 3 are independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, and and n is an integer from 1 to 4.

[0268] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIIa-2: [ka] [wherein a is 0 or 1; 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; 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, or optionally substituted 5- or 6-membered heteroaryl; Each R 3 are independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, and and n is an integer from 1 to 4.

[0269] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIIa-3: [ka] [wherein a is 0 or 1; 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; R 2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl; R 4 and R 5 are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0270] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIIa-4: [ka] [In the formula, a is 0 or 1, 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; 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 5is halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0271] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIIa-5: [ka] [In the formula, a is 0 or 1, 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; 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, or optionally substituted 5- or 6-membered heteroaryl; X 3 is N or CH, m is 1 or 2, R 6 , R 7 , R 8 , and R 11are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 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 8-membered heterocycloalkyl, or R 7 and R 8 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 11 and, together with the atom to which they are attached, combine to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, and R 11 is H.

[0272] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIIa-6: [ka] [In the formula, a is 0 or 1, 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; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl, and R 6 is hydrogen, 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.

[0273] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIIIa-7: [ka] [In the formula, a is 0 or 1, 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; 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 6is hydrogen, 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.

[0274] In some embodiments (e.g., of either one of Formulas DIIIa-6 or DIIIa-7), R 6 is methyl.

[0275] In some embodiments, the RAS inhibitor or a pharmaceutically acceptable salt thereof has the structure of Formula DIIIa-8 or Formula DIIIa-9, i.e., [ka] [wherein a is 0 or 1; 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; 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, or optionally substituted 5- or 6-membered heteroaryl.

[0276] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIVa: [ka] [wherein a is 0 or 1; 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; 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 a is 0 or 1.]

[0277] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIVa-1: [ka] [wherein a is 0 or 1; 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 2 is N or CH, 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; Each R 3are independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; R 9 is H or C1-C6 alkyl, and and n is an integer from 1 to 4.

[0278] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIVa-2: [ka] [wherein a is 0 or 1; 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; 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; Each R 3are independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl; R 9 is H or C1-C6 alkyl, and and n is an integer from 1 to 4.

[0279] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIVa-3: [ka] [In the formula, a is 0 or 1, 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; 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 9 is H or C1-C6 alkyl, and R 4 and R 5are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0280] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIVa-4: [ka] [wherein a is 0 or 1; 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; 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 9 is H or C1-C6 alkyl, and R 5is halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0281] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIVa-5: [ka] [wherein a is 0 or 1; 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 3 is N or CH, m is 1 or 2, 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; R 9 is H or C1-C6 alkyl, R 6 , R 7 , R 8 , and R 11are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 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 8-membered heterocycloalkyl, or R 7 and R 8 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 11 and, together with the atom to which they are attached, combine to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, and R 11 is H.

[0282] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIVa-6: [ka] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIVa-7: [ka]

[0283] In some embodiments (e.g., of any one of formula DIVa-6 or DIVa-7), R 6 is methyl.

[0284] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIVa-8 or DIVa-9, i.e., [ka]

[0285] In some embodiments (e.g., of any one of formulas DIVa, DIVa-1, DIVa-2, DIVa-3, DIVa-4, DIVa-5, DIVa-6, DIVa-7, DIVa-8, or DIVa-9), R 9 is methyl.

[0286] In some embodiments, Y is —NHS(O) 2 — or —NHS(O) 2 NH—.

[0287] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVa: [ka] [wherein a is 0 or 1].

[0288] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVa-1: [ka] [where, X 2 is N or CH, Each R 3are independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, and and n is an integer from 1 to 4.

[0289] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVa-2: [ka]

[0290] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVa-3: [ka] [In the formula, R 4 and R 5 are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0291] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVa-4: [ka]

[0292] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVa-5: [ka] [where, X 3 is N or CH, m is 1 or 2, R 6 , R 7 , R 8 , and R 11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 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 8-membered heterocycloalkyl, or R 7 and R 8 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 11 and, together with the atom to which they are attached, combine to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, and R 11is H.

[0293] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIa: [ka] [wherein a is 0 or 1].

[0294] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIa-1: [ka] [where, X 2 is N or CH, Each R 3 are independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, and and n is an integer from 1 to 4.

[0295] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIa-2: [ka]

[0296] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIa-3: [ka] [In the formula, R 4 and R 5 are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0297] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIa-4: [ka]

[0298] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIa-5: [ka] [where, X 3 is N or CH, m is 1 or 2, R 6 , R 7 , R 8 , and R 11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R6 and R 7 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 8-membered heterocycloalkyl, or R 7 and R 8 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 11 and, together with the atom to which they are attached, combine to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, and R 11 is H.

[0299] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of Formula DVIIa: [ka] [In the formula, R 9 is H or C1-C6 alkyl, and a is 0 or 1.]

[0300] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIIa-1: [ka] [where, X 2 is N or CH, Each R 3are independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, and and n is an integer from 1 to 4.

[0301] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIIa-2: [ka]

[0302] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIIa-3: [ka] [In the formula, R 4 and R 5 are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0303] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIIa-4: [ka]

[0304] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIIa-5: [ka] [where, X 3 is N or CH, m is 1 or 2, R 6 , R 7 , R 8 , and R 11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 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 8-membered heterocycloalkyl, or R 7 and R 8 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 11 and, together with the atom to which they are attached, combine to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, and R 11is H.

[0305] In some embodiments (e.g., of any one of Formulas DVIIa, DVIIa-1, DVIIa-2, DVIIa-3, DVIIa-4, or DVIIa-5), R 9 is methyl.

[0306] In some embodiments, Y is —NHS(O)— or —NHS(O)NH—.

[0307] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIIIa: [ka] [wherein a is 0 or 1].

[0308] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of Formula VIIIa-1: [ka] [where, X 2 is N or CH, Each R 3 are independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, and and n is an integer from 1 to 4.

[0309] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIIIa-2: [ka]

[0310] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIIIa-3: [ka] [In the formula, R 4 and R 5 are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0311] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIIIa-4: [ka]

[0312] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DVIIIa-5: [ka] [where, X 3 is N or CH, m is 1 or 2, R 6 , R 7 , R 8 , and R 11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 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 8-membered heterocycloalkyl, or R 7 and R 8 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 11 and, together with the atom to which they are attached, combine to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, and R 11 is H.

[0313] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIXa: [ka] [wherein a is 0 or 1].

[0314] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIXa-1: [ka] [where, X 2 is N or CH, Each R 3 are independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, and and n is an integer from 1 to 4.

[0315] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIXa-2: [ka]

[0316] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIXa-3: [ka] [In the formula, R 4 and R 5are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0317] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIXa-4: [ka]

[0318] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIXa-5: [ka] [where, X 3 is N or CH, m is 1 or 2, R 6 , R 7 , R 8 , and R 11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or an optionally substituted 3- to 8-membered heterocycloalkyl, or R 7 and R 8 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 11 and, together with the atom to which they are attached, combine to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, and R 11 is H.

[0319] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DXa: [ka] [In the formula, R 9 is H or C1-C6 alkyl, and a is 0 or 1.]

[0320] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DXa-1, i.e., [ka] [where, X 2 is N or CH, Each R 3are independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amide, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl, and and n is an integer from 1 to 4.

[0321] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DXa-2: [ka]

[0322] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DXa-3: [ka] [In the formula, R 4 and R 5 are each independently selected from halogen, cyano, hydroxy, optionally substituted amine, optionally substituted amido, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted 3-11 membered heterocycloalkyl (e.g., optionally substituted 3-6 membered heterocycloalkyl), optionally substituted 6-10 membered aryl, or optionally substituted 5-10 membered heteroaryl.

[0323] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DXa-4: [ka]

[0324] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DXa-5: [ka] [where, X 3 is N or CH, m is 1 or 2, R 6 , R 7 , R 8 , and R 11 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 6 and R 7 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 8-membered heterocycloalkyl, or R 7 and R 8 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered heterocycloalkyl; or R 7 and R 11 and, together with the atom to which they are attached, combine to form an optionally substituted 4- to 8-membered heterocycloalkyl. In some embodiments, X 3 is N. In some embodiments, m is 1. In some embodiments, R 11 is hydrogen. In some embodiments, X 3 is N, m is 1, and R 11is H.

[0325] In some (e.g., of any one of formulas DXa, DXa-1, DXa-2, DXa-3, DXa-4, or DXa-5) embodiments, R 9 is methyl.

[0326] In some embodiments of Formula DIa or subformulas thereof, a is 0. In some embodiments of Formula DIa or subformulas thereof, a is 0.

[0327] In some embodiments of Formula DIa or subformulas thereof, R 2 is an optionally substituted C1-C6 alkyl. In some embodiments, R 2 is selected from -CH2CH3 or -CH2CF3.

[0328] In some embodiments of Formula DIa or subformulas thereof, W is C1-C4 alkyl. [ka] is.

[0329] In some embodiments of Formula DIa or a subformula thereof, W is optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyridine, or optionally substituted phenyl.

[0330] In some embodiments of Formula DIa or a subformula thereof, W is an optionally substituted 3-10 membered heterocycloalkyl, an optionally substituted 3-10 membered cycloalkyl, an optionally substituted 6-10 membered aryl, or an optionally substituted 5-10 membered heteroaryl.

[0331] In some embodiments of Formula DIa or subformulas thereof, W is an optionally substituted 3-10 membered heterocycloalkyl. In some embodiments, W is selected from the following, or a stereoisomer thereof: [ka] [ka] [ka] [ka] In some embodiments, W is selected from the following, or a stereoisomer thereof: [ka]

[0332] In some embodiments of Formula DIa or a subformula thereof, W is an optionally substituted 3-10 membered cycloalkyl. In some embodiments, W is selected from the following, or a stereoisomer thereof: [ka] In some embodiments, W is selected from the following, or a stereoisomer thereof: [ka]

[0333] In some embodiments of Formula DIa or subformulas thereof, W is an optionally substituted 5-10 membered heteroaryl. In some embodiments, W is selected from the following, or stereoisomers thereof: [ka]

[0334] In some embodiments of Formula DIa or subformulas thereof, W is optionally substituted 6-10 membered aryl. In some embodiments, W is optionally substituted phenyl.

[0335] In some embodiments of Formula DIa or a subformula thereof, W is an optionally substituted C1-C3 heteroalkyl. In some embodiments, W is selected from the following, or a stereoisomer thereof: [ka]

[0336] In some embodiments, the RAS inhibitor, or a pharmaceutically acceptable salt thereof, has the structure of formula DIb: [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, 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; or W is -R 14 C(=O)R 15 [In the formula, R 14is a 3- to 10-membered cycloalkyl, and R 15 is an optionally substituted 3- to 10-membered cycloalkyl, an optionally substituted 6- to 10-membered aryl, or an optionally substituted 5- to 10-membered heteroaryl; X 1 and X 4 are each independently CH2, CH(CH3), or NH; 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 15-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 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 10 is hydrogen, hydroxy, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; and R 12 and R 13 are each independently selected from F or CH3, or R 12 and R 13 combine with the atom to which they are attached to form a three-membered cycloalkyl.

[0337] In some embodiments, the RAS inhibitor is a RAS(MULTI) inhibitor. In some embodiments, the RAS(MULTI) inhibitor is selected from Table D1a, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the RAS(MULTI) inhibitor is selected from Table D1a, or a pharmaceutically acceptable salt or atropisomer thereof. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12] Table 5-13 Table 5-14 Table 5-15 Table 5-16 Table 5-17 Table 5-18 Table 5-19 Table 5-20 Table 5-21 Table 5-22 Table 5-23 Table 5-24 Table 5-25 Table 5-26 [Table 5-27] [Table 5-28] [Table 5-29] [Table 5-30] [Table 5-31] [Table 5-32] ...

Claims

1. 1. A method of treating cancer in a subject, comprising administering to the subject: a) a first RAS inhibitor, or a pharmaceutically acceptable salt thereof; and b) a second RAS inhibitor, or a pharmaceutically acceptable salt thereof; and c) administering an SHP2 inhibitor, or a pharmaceutically acceptable salt thereof.

2. 10. The method of claim 1, wherein the cancer is an immunorefractory cancer.

3. 3. The method of claim 1 or 2, wherein the subject has previously been administered an immune checkpoint inhibitor.

4. The method of any one of claims 1 to 3, wherein the subject is resistant to treatment with an immune checkpoint inhibitor.

5. 5. The method of claim 4, wherein the subject has acquired resistance to treatment with an immune checkpoint inhibitor.

6. The method of any one of claims 1 to 5, wherein said administering sensitizes the cancer to treatment with an immune checkpoint inhibitor.

7. The method of any one of claims 1 to 6, further comprising administering to the subject an immune checkpoint inhibitor.

8. The method of claim 7, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

9. The method of any one of claims 1 to 8, wherein the inhibitors are administered simultaneously or sequentially.

10. The method of any one of claims 1 to 9, wherein the inhibitors are administered as a single formulation or in separate formulations.

11. The method of any one of claims 1 to 10, wherein the subject has one or more tumors with a low tumor mutation burden.

12. The method of any one of claims 1 to 11, wherein the subject has one or more microsatellite-stable tumors.

13. The method of any one of claims 1 to 12, wherein the subject has one or more tumors with low microsatellite instability.

14. The method of any one of claims 1 to 13, wherein the subject has one or more tumors with a low tumor immune infiltrate.

15. The method of any one of claims 1 to 14, wherein said administering alters the tumor immune infiltrate.

16. 16. The method of claim 14 or 15, wherein the tumor immune infiltrate comprises antigen-presenting cells, myeloid cells, or lymphoid cells.

17. The method of any one of claims 1 to 16, wherein said administering modulates an anti-tumor immune response.

18. The method of any one of claims 1 to 17, wherein said administering alters the tumor microenvironment.

19. 19. The method of any one of claims 1 to 18, wherein said administering converts an immunologically cold tumor into an immunologically hot tumor.

20. 20. The method of any one of claims 1 to 19, wherein the method reduces tumor size or inhibits tumor growth.

21. 21. The method of any one of claims 1 to 20, wherein the first RAS inhibitor is a RAS G12C inhibitor.

22. 22. The method of any one of claims 1 to 21, wherein the second RAS inhibitor is a RAS(MULTI) inhibitor.

23. 23. The method of any one of claims 1 to 22, wherein the first RAS inhibitor is a RAS G12C inhibitor and the second RAS inhibitor is a RAS (MULTI) inhibitor.

24. The method of any one of claims 1 to 23, wherein the SHP2 inhibitor is RMC-4550, or a pharmaceutically acceptable salt thereof.

25. The method of any one of claims 1 to 23, wherein the SHP2 inhibitor is RMC-4630, or a pharmaceutically acceptable salt thereof.

26. The second RAS inhibitor has the formula AI 【Chemistry 1】 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, —C(O)O—CH(R ６ )-[wherein the second C is -C(R ７ R ８ )-], —C(O)NH—CH(R ６ )-[wherein the second C is -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 optionally substituted with alkyl, 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 is 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, 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; 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, 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 C optionally substituted with hydrogen or 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 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, 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 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, 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 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 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 The method of any one of claims 1 to 25, wherein the aryl group is alkyl.

27. 27. The method of any one of claims 1 to 26, wherein the second RAS inhibitor is a compound selected from Table A1 or Table A2.

28. The first RAS inhibitor has the formula BI 【Chemistry 2】 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, —C(O)O—CH(R ６ )-[wherein the second C is -C(R ７ R ８ )-], —C(O)NH—CH(R ６ )-[wherein the second C is -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' is independently H or an 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 is 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, 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; 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, 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 C optionally substituted with hydrogen or 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 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, 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 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, 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 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, combined with the atom to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R ９’ is hydrogen or an optionally substituted C １ -C ６ 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 alkyl, and R ２１ is hydrogen or C １ -C ３ The method of any one of claims 1 to 27, wherein the group has the structure:

29. 29. The compound of any one of claims 1 to 28, wherein the first RAS inhibitor is a compound selected from Table B1 or Table B2.

30. The second RAS inhibitor has the formula DIa 【Transformation 3】 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 C ２ -C ４ alkylene, or optionally substituted C ２ -C ４ is alkenylene, Y is, 【Chemistry 4】 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; 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; R １０ is hydrogen, hydroxy, optionally substituted C １ -C ３ alkyl, or optionally substituted C １ -C ６ The compound according to any one of claims 1 to 25, 28 and 29, which is a compound having the structure:

31. 31. The compound of any one of claims 1 to 30, wherein the second RAS inhibitor is a compound selected from Table DIa, Table DIb, Table D2 or Table D3.

32. The method of any one of claims 1 to 31, wherein the cancer is lung cancer.

33. 33. The method of claim 32, wherein the lung cancer is immunorefractory lung cancer.

34. 34. The method of claim 33, wherein the immunorefractory lung cancer is non-small cell lung cancer or small cell lung cancer.

35. 35. The method of claim 33 or 34, wherein the immunorefractory lung cancer comprises a Ras mutation.

36. 36. The method of claim 35, wherein the Ras mutation is K-Ras G12C, H-Ras G12C, or N-Ras G12C.

37. 37. The method of claim 36, wherein the Ras mutation is K-Ras G12C.

38. 1. Use of a first RAS inhibitor, or a pharmaceutically acceptable salt thereof, a second RAS inhibitor, or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

39. 1. A composition comprising a first RAS inhibitor, or a pharmaceutically acceptable salt thereof, a second RAS inhibitor, or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, for use in a method for treating cancer in a subject in need thereof.

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