Spirocyclic dihydropyranopyridine KRAS inhibitors

Abstract

This disclosure provides compounds of Formula (l-c) or pharmaceutically acceptable salts thereof, that inhibit a KRas protein. In some embodiments, the KRas protein has a dysregulation (e.g., the KRas protein is mutated or amplified). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased and / or sustained (e.g., excessive) KRas activation, for example, KRas activation associated with a mutant KRas protein, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (l-a), (I- b), (l-c), (l-d), (l-c2), (l-c3), (l-c4), (l-d), or (l-e))) or Formula (B), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

Description

[0001] Spirocyclic Dihydropyranopyridine KRas Inhibitors

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application Serial Nos. 63 / 685,160, filed August 20, 2024; 63 / 675,512, filed July 25, 2024; 63 / 653,043, filed May 29, 2024; 63 / 650,239, filed May 21, 2024; 63 / 567,238, filed March 19, 2024; 63 / 559,588, filed February 29, 2024; 63 / 614,278, filed December 22, 2023; and 63 / 539,749, filed September 21, 2023, each of which is incorporated by reference it its entirety herein.

[0004] DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0005] This application contains a Sequence Listing which has been submitted electronically in XML format. The Sequence Listing XML is incorporated herein by reference. The XML file, created on September 9, 2024, is named TRLN-008-017W01_ST26_SL.xml and is 2,075 bytes in size.

[0006] TECHNICAL FIELD

[0007] This disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (La), (Lb), (Lc), (Lcl), (Lc2), (Lc3), (Lc4), (Ld), or (Le))) or Formula (B), or pharmaceutically acceptable salts thereof, that inhibit a KRas GTPase (e.g., a KRas GTPase that has a dysregulation (referred to herein as a dysregulated KRas protein)). In some embodiments, the KRas protein is a dysregulated KRas protein that has a mutation (referred to herein as a mutant KRas protein). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased and / or sustained (e.g., excessive) KRas activation, such as KRas activation associated with a mutant KRas protein, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (La), (Lb), (Lc), (Lcl), (Lc2), (Lc3), (Lc4), (Ld), or (Le))) or Formula (B), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

[0008] BACKGROUND

[0009] The KRAS gene is frequently dysregulated (e.g., mutated or amplified) in various human cancers. Oncogenic mutations in KRas typically occur at hotspots in the protein such as at amino acids positions 12, 13, and 61. In some cases, a mutation can lead to maintenance of KRas activation (GTP -bound state), e.g., due to a deficiency of intrinsic GTPase activity and / or insensitivity for GTPase-activating proteins (GAPs) and consequent increased KRas signaling. Specifically, some of the most common protein mutations include those at position

[0010] 12 (referred to herein as G12X) such as G12A, G12C, G12D, G12R, G12S, and G12V; position

[0011] 13 (referred to herein as G13X) such as G13C, G13D, and G13V; and Q61 (referred to herein as Q61X), such as Q61E, Q61H, Q61K, Q61L, Q61P, and Q61R.

[0012] KRas is widely recognized as a target for the design and development of therapies that can specifically bind and inhibit KRas signaling in cancer cells but had long been considered to be undruggable. Currently, there are few approved KRas-targeted therapies.

[0013] In some embodiments, the KRas protein is a dysregulated KRas protein that has a mutation (referred to herein as a mutant KRas protein). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased and / or sustained (e.g., excessive) KRas activation, such as KRas activation associated with a mutant KRas protein, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.

[0014] SUMMARY

[0015] This disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-cl), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))) or Formula (B), or pharmaceutically acceptable salts thereof, that inhibit a KRas protein (e.g., a dysregulated KRas protein, such as a mutant KRas protein). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased KRas activation, such as KRas activation associated with a mutant KRas protein or KRas activation associated with KRas amplification, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I- b), (I-c), (I-cl), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))) or Formula (B), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

[0016] Provided herein are compounds of Formula (A)

[0017] Formula (A) or pharmaceutically acceptable salts thereof, wherein:

[0018] E1is selected from the group consisting of: CH and CR4, wherein R4is selected from the group consisting of: -CN, halo, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl;

[0019] R1is selected from the group consisting of:

[0020] (i) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7; wherein b2 is 0, 1, 2, or 3; and A1and A2are independently selected from the group consisting of: N, CH, and CR7;

[0021] (iii) -N(R2)2, wherein each R2is independently selected from the group consisting of: - H and Ci-6 alkyl optionally substituted with 1-3 Rc; and

[0022] (iv) -H; each R7is independently selected from the group consisting of Raand Rb;

[0023] Ring B is: , wherein the * marks the ring carbon atom common to both Ring

[0024] X1is selected from the group consisting of a bond, S(0)o-2, CH2, CHRL, C(RL)2, and X2and X3are independently selected from the group consisting of: CH2, CHRL, C(RL)2, O, and S(O)0-2, provided that no more than one of X1, X2, and X3is selected from the group consisting of: O and S(O)0-2; b1 is 0, 1, or 2; R9is selected from the group consisting of: -H, -OH, -NRdRe, and halo; each R10is independently selected from the group consisting of Raand Rb; each RLis independently selected from the group consisting of C1-3 alkoxy, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc; or one pair of RLon the same or different ring carbon atom(s) are taken together with the ring atom(s) connecting them to form a C3-6 cycloalkyl ring; Y2is a bond or a straight-chain C1-6 alkylene optionally substituted with 1-6 RY; each RYis independently selected from the group consisting of: halo, cyano, -OH, oxo, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl, and C1-6 haloalkyl, or one pair of RYon the same or different carbon atom(s) are taken together with the atom(s) connecting them to form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring, each of which is optionally substituted with 1-3 independently selected C1-3 alkyl; R3is selected from the group consisting of: (a) 4-15 membered heterocyclyl optionally substituted with 1-6 substituentsindependently selected from the group consisting of: Raand Rb; and (b) -NRdRe; each Rais independently selected from the group consisting of: (a) halo; (b) cyano; (c) -OH; (d) oxo; (e) C1-6 alkoxy; (f) C1-6haloalkoxy; (g) -NRdRe; (h) -C(=O)C1-6 alkyl; (i) -C(=O)C1-6 haloalkyl; (j) -C(=O)OH; (k) -C(=O)OC1-6 alkyl; (l) -C(=O)OC1-6 haloalkyl; (m) -C(=O)N(Rf)2; (n) -S(O)0-2(C1-6 alkyl); (o) -S(O)0-2(C1-6 haloalkyl); (p) -S(O)1-2N(Rf)2; and (q) C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1, 2, or 3; each Lbis independently selected from the group consisting of: O, N(H), N(C1-3 alkyl), S(O)0-2, C(=O), and C1-3 alkylene; and each Rb1is independently selected from the group consisting of: C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, cyano, -OH, C1-6alkoxy, C1-6 haloalkoxy, -NRdRe, -C(=O)C1-6 alkyl, -C(=O)C1-6 haloalkyl, -C(=O)OC1-6 alkyl,-C(=O)OC1-6 haloalkyl, -C(=O)OH, -C(=O)N(Rf)2, -S(O)0-2(C1-6 alkyl), -S(O)0-2(C1-6 haloalkyl), and -S(O)1-2N(Rf)2; each Rdand Reis independently selected from the group consisting of: H, -C(=O)C1-6 alkyl, -C(=O)C1-6 haloalkyl, -C(=O)OC1-6 alkyl, -C(=O)OC1-6 haloalkyl, -C(=O)N(Rf)2, - S(O)1-2(C1-6 alkyl), -S(O)1-2(C1-6 haloalkyl), -S(O)1-2N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rh; each Rfis independently selected from the group consisting of: -H and C1-6 alkyl optionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, C1-3 alkyl, C1-3 haloalkyl, C3-5cycloalkyl, and 4-5 membered heterocyclyl; and each Rhis independently selected from the group consisting of: halo, cyano, -OH, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -N(H)(C1-3 alkyl), and -N(C1-3 alkyl)2. Also provided herein are pharmaceutical compositions comprising a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I- d), or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Provided herein are methods for treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I- d), or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Also provided herein are methods for treating cancer in a subject in need thereof, the methods comprising (a) determining that the cancer has a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, or a KRas G12V mutation)); and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein are methods of treating a KRas-associated disease or disorder (e.g., a mutant KRas-associated disease or disorder (e.g., a mutant KRas-associated disease or disorder(e.g., a KRas G12A-associated cancer, a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, a KRas G12S-associated cancer, or a KRas G12V-associated cancer))in a subject, the methods comprising administering to a subject identified or diagnosed as having a KRas-associated disease or disorder a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides methods of treating a KRas-associated disease or disorder (e.g., a mutant KRas-associated disease or disorder (e.g., a KRas G12A-associated disease or disorder, a KRas G12C-associated disease or disorder, a KRas G12D-associated disease or disorder, a KRas G12R-associated disease or disorder, a KRas G12S-associated disease or disorder, or a KRas G12V-associated disease or disorder)) in a subject, the methods comprising: determining that the disease or disorder in the subject is a KRas-associated disease or disorder (e.g., a mutant KRas-associated disease or disorder (e.g., a KRas G12A-associated disease or disorder, a KRas G12C-associated disease or disorder, a KRas G12D-associated disease or disorder, a KRas G12R-associated disease or disorder, a KRas G12S-associated disease or disorder, or a KRas G12V-associated disease or disorder)); and administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein are methods of treating a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas G12A-associated cancer, a KRas G12C- associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, a KRas G12S-associated cancer, or a KRas G12V-associated cancer))in a subject, the methods comprising administering to a subject identified or diagnosed as having a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas G12A-associated cancer, a KRas G12C-associated cancer, a mutant KRas-associated cancer (e.g., a KRas G12D-associated cancer, a KRas G12R-associated cancer, a KRas G12S-associated cancer, or a KRas G12V- associated cancer)) a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides methods of treating a KRas-associated cancer (e.g., amutant KRas-associated cancer (e.g., a KRas G12A-associated cancer, a KRas G12C- associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, a KRas G12S-associated cancer, or a KRas G12V-associated cancer)) in a subject, the methods comprising: determining that the cancer in the subject has a KRas dysregulation (e.g., a KRas G12A mutation, a KRas G12C- mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, or a KRas G12V mutation)); and administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. To facilitate understanding of the disclosure set forth herein, a number of terms are provided. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. In the case of conflict between the present disclosure and any content incorporated by reference, the present disclosure controls. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION This disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))) or Formula (B), or pharmaceutically acceptable salts thereof, that inhibit a KRas protein (e.g., a dysregulated KRas protein, such as a mutant KRas protein). These compounds are useful, e.g., for treating a disease, disorder, or condition associated with a KRas dysregulation (e.g., a KRas mutation or amplification) in which increased and / or sustained (e.g., excessive) KRas activation contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). These compounds can also be useful, e.g., for treating a disease, disorder, or condition in which a mutant KRas protein (e.g., a resistancemutation) confers intrinsic resistance to one or more KRas inhibitors (e.g., a KRas inhibitorselective for a KRas G12C mutant protein), or to a non-KRas-targeted therapeutic agent. See, e.g., Misale, et al., Nature 486.7404 (2012): 532-536 and Awad, et al., New England Journal of Medicine 384.25 (2021): 2382-2393. This disclosure also provides compositions containing the compounds provided herein as well as methods of using and making the same. Ras family genes (e.g., KRAS, NRAS, and HRAS) were the first oncogenes identified and are some of the most commonly mutated of all discovered oncogenes. See, e.g., Hunter et al. Mol Cancer Res. 2015;13(9):1325-35. The Ras family are guanine nucleotide binding proteins generally found at the inner leaflet of the cell membrane. A wild type Ras protein becomes activated when bound to GTP, but it is inactive when bound to GDP. Normally, growth factors bind to extracellular receptors to induce nucleotide exchange with the help of guanine nucleotide exchange factors (GEF) (e.g., Son of sevenless homolog 1 (SOS1)). These GEFs allow GDP to dissociate from a Ras protein and GTP to bind. Ras proteins can interact with effector proteins such as cRAF when bound to GTP Hydrolysis of GTP to form GDP can deactivate Ras proteins, and the hydrolysis can be achieved through the intrinsic GTPase activity, which may be enhanced by binding to a GTPase activating protein (GAP). There are 3 major RAS proteins in humans: KRas, HRas, and NRas. Some oncogenic KRas missense mutations can prevent or slow GTP hydrolysis and result in the accumulation of KRas in the active state. Signaling pathways associated with KRas are persistently activated in many cancers, where they participate in cellular growth and proliferation, differentiation, protein synthesis, glucose metabolism, cell survival, and inflammation. Mutant KRas proteins often have altered Raf affinity and / or altered intrinsic GTPase activity. See, for example, Table 1 reproduced from Hunter et al. Mol Cancer Res. 2015;13(9):1325-35. These changes and other factors can contribute to increased KRas signaling in mutant KRas proteins. Table 1 KRas inhibitors are described in, for example, International Publication Nos. WO 2024 / 112654; WO 2023 / 154766; WO 2023 / 143623; WO 2022 / 240971; WO 2020 / 236940; WO 2022 / 115439; WO 2023 / 086383; WO 2021 / 093758; WO 2022 / 135546; WO 2021 / 139748; WO 2022 / 251576; and WO 2023 / 025116. Additional examples of KRas inhibitors are described in, for example, International Publication Nos. WO 2022 / 132200; WO 2022 / 133038; WO 2023 / 150284; WO 2022 / 261154; WO 2023 / 183585; WO 2023 / 099592; WO 2023 / 099623; WO 2023 / 099624; WO 2023 / 099608; WO 2022 / 250170; WO 2022 / 173870; WO 2022 / 236578; WO 2022 / 237649; WO 2022 / 248885; WO 2022 / 256459; WO 2022 / 258974; WO 2022 / 266015; WO 25 2023 / 018809; WO 2023 / 018810; WO 2023 / 018812; WO 2023 / 020518; WO 2023 / 020519; WO 2023 / 020521; WO 2023 / 020523; WO 2023 / 046135; WO 2023 / 061294; WO 2023 / 097227; WO 2023 / 114733; WO 2023 / 137223; WO 2023 / 141300; WO 2023 / 138583; WO 2023 / 159086; WO 2023 / 159087; WO 2023 / 173016; WO 2023 / 173017; WO 2023 / 179703; WO 2023 / 125627; WO 2022 / 216762; WO 2024 / 030633; WO 2023 / 230190; and CN 116143806. Compound Embodiments Provided herein are compounds of Formula (A): Formula (A) or pharmaceutically acceptable salts thereof, wherein: E1is selected from the group consisting of: CH and CR4, wherein R4is selected from the group consisting of: -CN, halo, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; R1is selected from the group consisting of: (i) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7; , wherein b2 is 0, 1, 2, or 3; and A1and A2are independently selected from the group consisting of: N, CH, and CR7; (iii) -N(R2)2, wherein each R2is independently selected from the group consisting of: - H and C1-6 alkyl optionally substituted with 1-3 Rc; and (iv) -H; each R7is independently selected from the group consisting of Raand Rb;

[0025] X1is selected from the group consisting of a bond, S(O)0-2, CH2, CHRL, C(RL)2, and O; X2and X3are independently selected from the group consisting of: CH2, CHRL, C(RL)2, O, and S(O)0-2, provided that no more than one of X1, X2, and X3is selected from the group consisting of: O and S(O)0-2; b1 is 0, 1, or 2; R9is selected from the group consisting of: -H, -OH, -NRdRe, and halo; each R10is independently selected from the group consisting of Raand Rb; each RLis independently selected from the group consisting of C1-3 alkoxy, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc; or one pair of RLon the same or different ring carbon atom(s) are taken together with the ring atom(s) connecting them to form a C3-6 cycloalkyl ring; Y2is a bond or a straight-chain C1-6 alkylene optionally substituted with 1-6 RY; each RYis independently selected from the group consisting of: halo, cyano, -OH, oxo, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl, and C1-6 haloalkyl, or one pair of RYon the same or different carbon atom(s) are taken together with the atom(s) connecting them to form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring, each of which is optionally substituted with 1-3 independently selected C1-3 alkyl; R3is selected from the group consisting of: (a) 4-15 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb; and (b) -NRdRe; each Rais independently selected from the group consisting of: (a) halo; (b) cyano; (c) -OH; (d) oxo; (e) C1-6 alkoxy; (f) C1-6 haloalkoxy; (g) -NRdRe; (h) -C(=O)C1-6 alkyl; (i) -C(=O)C1-6 haloalkyl; (j) -C(=O)OH; (k) -C(=O)OC1-6 alkyl; (l) -C(=O)OC1-6 haloalkyl; (m) -C(=O)N(Rf)2; (n) -S(O)0-2(C1-6 alkyl); (o) -S(O)0-2(C1-6 haloalkyl); (p) -S(O)1-2N(Rf)2; and (q) C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1,wherein:b is 1, 2, or 3; each Lbis independently selected from the group consisting of: O, N(H), N(C1-3 alkyl), S(O)0-2, C(=O), and C1-3 alkylene; and each Rb1is independently selected from the group consisting of: C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, cyano, -OH, C1-6 alkoxy, C1-6 haloalkoxy, -NRdRe, -C(=O)C1-6 alkyl, -C(=O)C1-6 haloalkyl, -C(=O)OC1-6 alkyl, -C(=O)OC1-6haloalkyl, -C(=O)OH, -C(=O)N(Rf)2, -S(O)0-2(C1-6alkyl), -S(O)0-2(C1-6haloalkyl), and -S(O)1-2N(Rf)2; each Rdand Reis independently selected from the group consisting of: H, -C(=O)C1-6 alkyl, -C(=O)C1-6 haloalkyl, -C(=O)OC1-6 alkyl, -C(=O)OC1-6 haloalkyl, -C(=O)N(Rf)2, - S(O)1-2(C1-6 alkyl), -S(O)1-2(C1-6 haloalkyl), -S(O)1-2N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rh; each Rfis independently selected from the group consisting of: -H and C1-6 alkyl optionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, C1-3 alkyl, C1-3 haloalkyl, C3-5 cycloalkyl, and 4-5 membered heterocyclyl; and each Rhis independently selected from the group consisting of: halo, cyano, -OH, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -N(H)(C1-3 alkyl), and -N(C1-3 alkyl)2. In some embodiments of Formula (A), E1is selected from the group consisting of: CH and CR4, wherein R4is selected from the group consisting of: -CN, halo, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; R1is selected from the group consisting of: (i) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7; and wherein b2 is 0, 1, 2, or 3; and A1and A2are independently selected from the group consisting of: N, CH, and CR7; each R7is independently selected from the group consisting of Raand Rb; X1is selected from the group consisting of a bond, S(O)0-2, CH2, CHRL, C(RL)2, and O; X2and X3are independently selected from the group consisting of: CH2, CHRL, 25 C(RL)2, O, and S(O)0-2, provided that no more than one of X1, X2, and X3is selected from the group consisting of: O and S(O)0-2; b1 is 0, 1, or 2; R9is selected from the group consisting of: -H, -OH, -NRdRe, and halo; each R10is independently selected from the group consisting of Raand Rb; each RLis independently selected from the group consisting of C1-3 alkoxy, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc; or one pair of RLon the same or different ring carbon atom(s) are taken together with the ring atom(s) connecting them to form a C3-6 cycloalkyl ring; Y2is a bond or a straight-chain C1-6 alkylene optionally substituted with 1-6 RY; each RYis independently selected from the group consisting of: halo, cyano, -OH, oxo, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl, and C1-6 haloalkyl, or one pair of RYon the same or different carbon atom(s) are taken together with the atom(s) connecting them to form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring, each of which is optionally substituted with 1-3 independently selected C1-3 alkyl; R3is selected from the group consisting of: (a) 4-15 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb; and (b) -NRdRe; each Rais independently selected from the group consisting of: (a) halo; (b) cyano; (c) -OH; (d) oxo; (e) C1-6 alkoxy; (f) C1-6 haloalkoxy; (g) -NRdRe; (h) C(=O)C1-6 alkyl; (i) C(=O)C1-6haloalkyl; (j) C(=O)OH; (k) C(=O)OC1-6 alkyl; (l) C(=O)OC1-6 haloalkyl; (m) C(=O)N(Rf)2; (n) S(O)0-2(C1-6 alkyl); (o) S(O)0-2(C1-6 haloalkyl); (p) S(O)1-2N(Rf)2; and (q) C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1, 2, or 3; each -Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3 alkyl)-, -S(O)0-2-, C(=O), and C1-3 alkylene; and each Rb1is independently selected from the group consisting of: C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, cyano, -OH, C1-6 alkoxy, C1-6 haloalkoxy, -NRdRe, C(=O)C1-6 alkyl, C(=O)C1-6 haloalkyl, C(=O)OC1-6 alkyl, C(=O)OC1-6 haloalkyl, C(=O)OH, C(=O)N(Rf)2, S(O)0-2(C1-6 alkyl), S(O)0-2(C1-6 haloalkyl), and S(O)1-2N(Rf)2; each Rd and Re is independently selected from the group consisting of: H, C(=O)C1-6alkyl, C(=O)C1-6 haloalkyl, C(=O)OC1-6 alkyl, C(=O)OC1-6 haloalkyl, C(=O)N(Rf)2, S(O)1- 2(C1-6 alkyl), S(O)1-2(C1-6 haloalkyl), S(O)1-2N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rh; each Rfis independently selected from the group consisting of: H and C1-6 alkyl optionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, C1-3 alkyl, C1-3 haloalkyl, C3-5 cycloalkyl, and 4-5 membered heterocyclyl; and each Rhis independently selected from the group consisting of: halo, cyano, -OH, -C1- 6 alkoxy, -C1-6 haloalkoxy, -NH2, -N(H)(C1-3 alkyl), and -N(C1-3 alkyl)2. In some embodiments, the compounds of Formula (A) are compounds of Formula (I): Formula (I) or pharmaceutically acceptable salts thereof. In some embodiments of Formula (A) (e.g., Formula (I)), R9is selected from the group consisting of: -OH and -NRdRe. In some embodiments of Formula (A) (e.g., Formula (I)), R9is -NRdRe. In some embodiments of Formula (A) (e.g., Formula (I)), R9is -NH2. In some embodiments of Formula (A) (e.g., Formula (I)), b1 is 1 or 2. In some embodiments of Formula (A) (e.g., Formula (I)), each R10is independently selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc(e.g., C1-3 alkyl optionally substituted with 1-3 -F). In some embodiments, the compounds of Formula (A) (e.g., Formula (I)) are compounds of Formula (I-a): Formula (I-a) or pharmaceutically acceptable salts thereof, wherein: b1 is 1 or 2. In some embodiments of Formula (I-a), each R10is independently selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc(e.g., C1-3 alkyl optionally substituted with 1-3 -F). In some embodiments of Formula (I-a), b1 is 1.25In some embodiments, the compounds of Formula (A) (e.g., Formula (I)) are compounds of Formula (I-b): Formula (I-b) or pharmaceutically acceptable salts thereof, wherein: b4 is 0 or 1; and R10is selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc(e.g., C1-3 alkyl optionally substituted with 1-3 -F). In some embodiments of Formula (I-b), R9is -NRdRe(e.g., -NH2). In some embodiments of Formula (I-b), b4 is 0. In some embodiments of Formula (I-b), R9is -NRdRe(e.g., -NH2); and b4 is 0. In some embodiments, the compounds of Formula (A) (e.g., Formula (I)) are compounds of Formula (I-c): Formula (I-c) or a pharmaceutically acceptable salt thereof, wherein: b4 is 0 or 1; and R10is selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc(e.g., C1-3 alkyl optionally substituted with 1-3 -F). In some embodiments of Formula (I-c), b4 is 0. In some embodiments of the compounds of Formula (A) (e.g., Formula (I) (e.g.,25Formula (I-a), (I-b), or (I-c))), X1is -CH2-. In some embodiments of the compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), or (I-c))), X2and X3are independently selected from the group consisting of: -CH2-, -CHRL-, -C(RL)2-, and -O-. In some embodiments of the compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), or (I-c))), X1is -CH2-; and X2and X3are both -CH2-. In some embodiments of the compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), or (I-c))), X1is -CH2-; X2is -CH2-; and X3is -CHRL-. In some embodiments, RLis selected from the group consisting of: -CH3, -CF3, -CHF2, and -CH2F (e.g., -CH3). In some embodiments of the compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), or (I-c))), X1is -CH2-; X2is -O-; and X3is selected from the group consisting of: -CH2-, -CHRL-, and -C(RL)2- (e.g., X3is -CH2- or -CHRL-). In some embodiments of the compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), or (I-c))), each RLis independently selected from the group consisting of: -CH3, -CF3, -CHF2, and -CH2F (e.g., -CH3). In some embodiments of the compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), or (I-c))), X1is -CHRL-; X2is -O- or -CH2-; and X3is -CHRL-, wherein the pair of RLare taken together with the ring atoms connecting them to form a C3-4 (e.g., C4) cycloalkyl ring. For example, the moiety can . In some embodiments, the compounds of Formula (A) (e.g., Formula (I)) are compounds of Formula (I-d): Formula (I-d) 25 or pharmaceutically acceptable salts thereof, wherein: X1is selected from the group consisting of a bond, -S(O)0-2-, -CH2-, -CHRL-, -C(RL)2- , and -O-; and X2and X3are independently selected from the group consisting of: -CH2-, -CHRL-, - C(RL)2-, -O-, and -S(O)0-2-, provided that: at least one of X1, X2, and X3is -CHRL- or -C(RL)2-, and no more than one of X1, X2, and X3is selected from the group consisting of: -O- and -S(O)0-2-. In some embodiments of Formula (I-d), X1is -CH2-; X2is -CH2-; and X3is -CHRL-. In some embodiments of Formula (I-d), RLis selected from the group consisting of: - CH3, -CF3, -CHF2, and -CH2F (e.g., CH3). In some embodiments of Formula (I-d), X1is -CH2-; X2is -CH2-; and X3is -CHRL-, wherein RLis selected from the group consisting of: -CH3, -CF3, -CHF2, and -CH2F (e.g., - CH3). In some embodiments, the compounds of Formula (A) (e.g., Formula (I)) are compounds of Formula (I-e): Formula (I-e) or pharmaceutically acceptable salts thereof, wherein: X1is selected from the group consisting of a bond, -S(O)0-2-, -CH2-, -CHRL-, -C(RL)2- , and -O-; X2and X3are independently selected from the group consisting of: -CH2-, -CHRL-, - C(RL)2-, -O-, and -S(O)0-2-, provided that 2-3 of X1, X2, and X3are independently -CHRL- or -C(RL)2-, wherein: one pair of RLon the same or different ring carbon atom(s) are taken together with the ring atom(s) connecting them to form a C3-6 cycloalkyl ring; and each additional RLis independently selected from the group consisting of: C1-3 alkoxy, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc(e.g., C1-3 alkyl optionally substituted with 1-3 -F). In some embodiments of Formula (I-e), X2is -CH2- or -O- (e.g., -CH2-). In some embodiments of Formula (I-e), X1is -CHRL-; X3is -CHRL-; and the pair of RLare taken together with the ring atoms connecting them to form a C3-4 (e.g., C4) cycloalkyl ring. In some embodiments of Formula (I-d) or (I-e), R9is -NRdRe(e.g., -NH2). In some embodiments of Formula (I-d) or (I-e), b1 is 1 or 2; and each R10is independently selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc(e.g., C1-3 alkyl optionally substituted with 1-3 -F). In some embodiments of Formula (I-d) or (I-e), the moiety is , wherein b4 is 0 or 1; and R10is selected from the group consisting of: - Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc(e.g., C1-3 alkyl optionally substituted with 1-3 -F). In some embodiments, b4 is 0. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), E1is CH. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), E1is CR4. For example, E1can be CF. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), Y2is -CH2-; and R3is a 4-10 membered heterocyclyl having one ring nitrogen atom and 0-1 additional ring heteroatom selected from the group consisting of oxygen and nitrogen, wherein the heterocyclyl is optionally substituted with 1-6 Ra. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F, C1-3 alkoxy, and C1-3 haloalkoxy. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), R1is , wherein b2 is 0, 1, or 2, and A1and A2are independently selected from the group consisting of: N, CH, and CR7. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- wherein: R7ais selected from the group consisting of: -C(=O)N(Rf)2, -C(=O)N(C1-3 alkyl)Rb1, - C(=O)N(H)Rb1, Rb1, and -C(=O)Rb1; and R7bis selected from the group consisting of: halo, cyano, and C1-3 alkyl optionally substituted with 1-3 Rc(e.g., C1-3 alkyl optionally substituted with 1-3 -F). In some embodiments, R7ais selected from the group consisting of: (a) -C(=O)N(Rf)2, wherein each Rfis independently -H or C1-3 alkyl optionally substituted with 1-3 Rh; (b) -C(=O)N(C1-3 alkyl)Rb1or -C(=O)N(H)Rb1, wherein: Rb1is C3-6 cycloalkyl or 4-6 membered heterocyclyl, each of which is optionally substituted with 1-3 Rg; and (c) -C(=O)Rb1, wherein Rb1is a 4-10 membered heterocyclyl optionally substituted with 1-3 Rg, wherein Rb1is attached to the C(=O) via a ring nitrogen atom. In some embodiments, R7bis halo or C1-3 alkyl (e.g., -F, -Cl, or methyl). In some embodiments, R7ais -C(=O)N(Rf)2, wherein each Rfis independently -H or C1-3 alkyl optionally substituted with 1-3 Rh. In some embodiments, R7bis halo (e.g., -Cl). In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- , wherein each Rfis independently C1-3 alkyl optionally substituted with 1-3 Rh. For example, R1can . In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), R1is a 7-10 (e.g., 7) membered heterocyclyl having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, wherein the 7-10 membered heterocyclyl is optionally substituted with 1-4 R7. In some embodiments, each R7is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 Rc, wherein: each Rcpresent on R7is independently selected from the group consisting of: -F, -OH, and -CN. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), R1is a 7-10 (e.g., 7) membered monocyclic heterocyclyl having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, wherein the 7-10 membered monocyclic heterocyclyl is optionally substituted with 1-4 (e.g., 1-2) R7. In some embodiments, each R7is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 Rc, wherein: each Rcpresent on R7is independently selected from the group consisting of: -F, -OH, and -CN. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- optionally substituted with 1-4 R7at one or more ring carbon atoms. In some embodiments, each R7is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 Rc, wherein: each Rcpresent on R7is independently selected from the group consisting of: -F, -OH, and -CN. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), each R7is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 Rc, wherein: each Rcpresent on R7is independently selected from the group consisting of: -F, -OH, and -CN. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- wherein R7is a 5-membered heteroaryl optionally substituted with 1-3 Rg. In some embodiments, R7is pyrazolyl optionally substituted with 1-2 Rg(e.g., R7is optionally substituted with one Rg); or wherein R7is oxazolyl optionally substituted with one Rg(e.g., R7is optionally substituted with one Rg). In some embodiments, . In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), R1is a 7-10 (e.g., 7) membered spirocyclic bicyclic heterocyclyl having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, wherein the 7-10 membered spirocyclic bicyclic heterocyclyl is optionally substituted with 1-4 (e.g., 1-2) R7. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- , wherein: Ring A1 is a 4-7 membered heterocyclyl ring having one ring oxygen atom and no additional ring heteroatoms; n4 is 0, 1, or 2; and n5 is 0, 1, or 2, provided that n4 + n5 is 0, 1, or 2. In some embodiments, each R7is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 Rc, wherein: each Rcpresent on R7is independently selected from the group consisting of: -F, -OH, and -CN. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), R1is , which is optionally substituted with 1-2 R7. For example, R1can . In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), R1is , each of which is optionally substituted with In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), R1is a 4-7 (e.g., 4 or 7) membered heterocyclyl having one ring nitrogen atom or having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, wherein the 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-4 (e.g., 1-2) R7. In some embodiments, each R7is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 Rc, wherein: each Rcpresent on R7is independently selected from the group consisting of: -F, -OH, and -CN. In some embodiments, R1is a monocyclic heterocyclyl. In some embodiments, R1is a spirocyclic bicyclic heterocyclyl. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), R1is optionally substituted with 1-4 (e.g., 1-2) R7. In some embodiments, each R7is independently selected from the group consisting of: -F; -CN; -OH; C1-3 alkyl optionally substituted with 1-3 Rc; -C(=O)N(Rf)2; and Rb1, wherein the Rb1is a 5-6 membered heteroaryl optionally substituted with 1-2 Rg. In some embodiments, each R7is independently selected from the group consisting of: -F; -CN; -OH; Rb1, wherein the Rb1is a 5-6 membered heteroaryl optionally substituted with 1-2 Rg; C1-3 alkyl optionally substituted with 1-3 -F; C1-3 alkyl substituted with -OH or C1-3 alkoxy; and -C(=O)N(Rf)2. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), R1is . In some embodiments, each R7is independently selected from the group consisting of: -F; -CN; -OH; C1-3 alkyl optionally substituted with 1-3 Rc; -C(=O)N(Rf)2; and Rb1, wherein the Rb1is a 5-6 membered heteroaryl optionally substituted with 1-2 Rg. In some embodiments, each R7is independently selected from the group consisting of: -F; -CN; -OH; Rb1, wherein the Rb1is a 5-6 membered heteroaryl optionally substituted with 1-2 Rg; C1-3 alkyl optionally substituted with 1-3 -F; C1-3 alkyl substituted with -OH or C1-3 alkoxy; and -C(=O)N(Rf)2. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- wherein R7is C1-3 alkyl substituted with - OH or C1-3 alkoxy (e.g., C1-3 alkyl substituted with -OH). In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), R1is , wherein each R7is independently selected from the group consisting of: C1-3 alkyl optionally substituted with 1-3 -F; and C1-3 alkyl substituted with -OH or C1-3 alkoxy. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- wherein R7ais C1-3 alkyl substituted with -OH (e.g., -CH2OH); and R7bis selected from the group consisting of: (a) C1-3 alkyl optionally substituted with 1-3 -F (e.g., methyl), and (b) C1-3 alkyl substituted with -OH or C1-3 alkoxy. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), R1is a 4-10 membered heterocyclyl substituted with -CN, –(C1-3 alkylene)- CN, or –(C3-6 cycloalkylene)-CN on a ring carbon atom, wherein the heterocyclyl is further optionally substituted with 1-3 R7. In some embodiments, each R7is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 Rc(e.g., C1-3 alkyl optionally substituted with 1-3 -F). In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), R1is a 6-8 membered heterocyclyl substituted with -CN or –(C1-3 alkylene)- CN on a ring carbon atom, wherein: the heterocyclyl has one ring nitrogen atom and 0-1 ring oxygen atom; and the heterocyclyl is further optionally substituted with 1-3 R7. In some embodiments, each R7is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 Rc(e.g., C1-3 alkyl optionally substituted with 1- 3 -F). In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-d), or (I-e))), R1 is -N(R2)2. In some embodiments, each R2 is independently methyl orethyl, each optionally substituted with 1-3 Rc, wherein each Rcpresent on R2is independently selected from the group consisting of: -F, cyano, -OH, C1-6 alkoxy, and C1-6 haloalkoxy. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), the ring carbon atom labelled with * has (S)-stereochemistry. In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- c), (I-d), or (I-e))), the In some embodiments, the compounds of Formula (I-c) are compounds of Formula (I- c1) or (I-c2): Formula (I-c1) Formula (I-c2) or pharmaceutically acceptable salts thereof, wherein: E1is CH; b4 is 0 or 1; R10is selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc; X1is -CH2-; and X2and X3are independently selected from the group consisting of: -O-, -CH2-, -CHRL- , and -C(RL)2-; R7ais selected from the group consisting of: (a) -C(=O)N(Rf)2, wherein each Rfis independently -H or C1-3 alkyl optionally substituted with 1-3 Rh; (b) -C(=O)N(C1-3 alkyl)Rb1 or -C(=O)N(H)Rb1, wherein: Rb1 is C3-6 cycloalkyl or4-6 membered heterocyclyl, each of which is optionally substituted with 1-3 Rg; and (c) -C(=O)Rb1, wherein Rb1is a 4-10 membered heterocyclyl optionally substituted with 1-3 Rg, wherein Rb1is attached to the C(=O) via a ring nitrogen atom; and R7bis halo or C1-3 alkyl (e.g., -F, -Cl, or methyl). In some embodiments of Formula (I-c1) or (I-c2), b4 is 0. In some embodiments of Formula (I-c1) or (I-c2), X2is -CH2-; and X3is -CH2- or - CHRL-. In some embodiments of Formula (I-c1) or (I-c2), X2is -CH2-; and X3is -CH2-. In some embodiments of Formula (I-c1) or (I-c2), X2is -CH2-; and X3is -CHRL-. In some embodiments of Formula (I-c1) or (I-c2), X2is -CH2-; and X3is -CHMe-. In some embodiments of Formula (I-c1) or (I-c2), R7ais -C(=O)N(Rf)2, wherein each Rfis an independently selected C1-3 alkyl; and R7bis -F, -Cl, or methyl. For example, R7acan be -C(=O)N(Me)2; and R7bcan be -F, -Cl, or methyl. In some embodiments, the compounds of Formula (I-c) are compounds of Formula (I- c3) or (I-c4): Formula (I-c4) or pharmaceutically acceptable salts thereof, wherein: E1is CH; R7is C1-3 alkyl substituted with -OH; b4 is 0 or 1 (e.g., 0); R10is selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc; X1is -CH2-; and X2and X3are independently selected from the group consisting of: -O-, -CH2-, -CHRL- , and -C(RL)2-. In some embodiments of Formula (I-c3) or (I-c4), X2is -CH2-; and X3is -CH2- or - CHRL-. In some embodiments of Formula (I-c3) or (I-c4), X2is -CH2-; and X3is -CH2-. In some embodiments of Formula (I-c3) or (I-c4), X2is -CH2-; and X3is -CHRL-. In some embodiments of Formula (I-c3) or (I-c4), X2is -CH2-; and X3is -CHMe-. In some embodiments of Formula (I-c4), the moiety is . In some embodiments of Formula (I-c4), R7is -CH2OH. In some embodiments of Formula (I-c1), (I-c2), (I-c3), or (I-c4), Y2is -CH2-; and R3is optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F, C1-3 alkoxy, and C1-3 haloalkoxy. In some embodiments of Formula (I-c1), (I-c2), (I-c3), or (I-c4), Y2is -CH2-; and R3 optionally substituted with 1-2 -F. In some embodiments of Formula (I-c1), In some embodiments of Formula (I-c1), (I-c2), (I-c3), or (I-c4), the moiety i . In some embodiments, the compounds of Formula (A) or Formula (I) are selected from the group consisting of compounds depicted in Table C1, or pharmaceutically acceptable salts thereof. Table C1

[0026]

[0027] In certain compounds of Table Cl, one or more stereogenic centers are denoted with the “V3000 enhanced stereochemical notation” (see: support.collaborativedrug.com / hc / en- us / articles / 360020872171 -Advanced- Stereochemistry -Registration- Atropisomers-Mixtures-

[0028] Unknowns-and-Non-Tetrahedral-Chirality, accessed on November 29, 2023 and Accelrys Chemical Representation Guide, Accelrys Software Inc., 2014, each of which is incorporated by reference herein in its entirety). Using this stereochemical notation, certain stereogenic centers are denoted with “’abs”, “dcx”, or “orx”, wherein x is an integer (e.g., 1 or 2). For avoidance of doubt, the stereochemical notations in Table Cl have the following meaning:

[0029] When a structure does not contain any wedged or hashed bonds (i.e., each stereogenic center is undefined), then each stereogenic center can independently adopt a (A) or (5) stereochemical configuration. For avoidance of doubt, such structures also encompass mixtures of stereoisomers. For example, represents or a mixture

[0030] When a structure contains a stereogenic center or a plurality of stereogenic centers that is depicted with wedges and hashes (i.e., one or more stereogenic center is defined), the following notations are used:

[0031] (1) When a defined stereogenic center is denoted with ''ahs'' or when the defined stereogenic center is not denoted with an enhanced stereochemical notation (e.g., “abs”, “<£x”, or “orx”), the defined stereogenic center has the absolute configuration as depicted by the structural formula. For example, both of the structures and refer to (S)-(1-methylpyrrolidin-2-yl)methanol. (2) When a defined stereogenic center is denoted with “orx” in a structural formula, the defined stereogenic center has been resolved but the configuration at the defined stereogenic center has not been determined. For example, the structure refers to one stereoisomer selected from the group consisting of (S)-(1- methylpyrrolidin-2-yl)methanol and (R)-(1-methylpyrrolidin-2-yl)methanol. (3) When a defined stereogenic center is denoted with “&x” in a structural formula, a stereoisomeric mixture differing at this stereogenic center is represented. For example, the structure: represents a mixture of (S)-(1-methylpyrrolidin-2- yl)methanol and (R)-(1-methylpyrrolidin-2-yl)methanol. As another example, the structure: represents a mixture of ((2S,3S)-1,3-dimethylpyrrolidin-2- yl)methanol and ((2R,3S)-1,3-dimethylpyrrolidin-2-yl)methanol. (4) When two or more defined stereogenic centers are denoted with “orx” in a structural formula, each of these defined stereogenic centers has been resolved but the configurations at the defined stereogenic centers have not been determined. Specifically: a. For any pair of defined stereogenic centers denoted with “orx” in a structural formula, when the numerical parts in the notation are different (e.g., two defined stereogenic centers denoted with “or1” and “or2” respectively), each defined stereogenic center should be independently interpreted according to “(2)” supra. For example, the structure refers to one stereoisomer selected from the group consisting of: , b. For any pair of defined stereogenic centers denoted with “orx” in a structural formula, when the numerical part in the notation is identical (e.g., two defined stereogenic centers are each denoted with “or1”), the structural formula refers to one stereoisomer having the relative stereochemistry at these stereogenic centers as depicted in the structural formula, but the absolute configurations of these stereogenic centers have not been determined. For example, the structure to one of the “anti” stereoisomers: . (5) When two or more defined stereogenic centers are denoted with “&x” in a structural formula, the structural formula refers to a mixture of stereoisomers that differ in the configuration at the defined stereogenic centers. Specifically: a. For any pair of defined stereogenic centers denoted with “&x” in a structural formula, when the numerical parts in the notation are different (e.g., two defined stereogenic centers denoted with “&1” and “&2” respectively), the structural formula refers to a mixture of stereoisomers at these two defined stereogenic centers, wherein the configuration at each of the defined stereogenic centers can vary independently of one another. For example, the structure refers to a mixture of four stereoisomers: , , b. For any pair of defined stereogenic centers denoted with “&x” in a structural formula, when the numerical part in the notation is identical (e.g., two defined stereogenic centers are each denoted with “&1”), the structural formula refers to a mixture of stereoisomers at these two defined stereogenic centers, wherein the relative configurations are as depicted in the structural formula. For example, the structure refers to a mixture of “syn” . Certain examples of Formula (A) or Formula (I) were synthesized using methods involving resolution of stereoisomeric mixture(s) (e.g., SFC separation of stereoisomers). In Table C1, the resolved stereogenic centers in these compounds are labelled with the “or1” and / or “or2” the stereoisomeric resolutions were performed during the last step of the synthesis, thereby providing the individual stereoisomers of the compounds. Alternatively, in some other instances, the resolutions were performed on an intermediate or starting material, wherein each of the constituent stereoisomers of the intermediate or starting material could be separately subjected to the subsequent steps of the synthesis to provide the respective compounds as separate stereoisomers. A person of ordinary skill in the art would understand that, under either approach for stereoisomeric resolution, stereoisomers having both (R)- and (S)-configurations at a resolved stereogenic center are provided. See Table C2, wherein Table C1 compounds whose stereoisomers contain the or1 and / or or2 stereochemical notations are provided in non- stereogenic form, followed by the respective stereoisomers having the (R)- and (S)- configurations. Table C2

[0032] In some embodiments, the compounds of Formula (A) or Formula (I) are selected from the group consisting of: or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of Formula (A) or Formula (I) are selected from the group consisting of the compounds depicted in Table C1s of U.S. Provisional Application Serial Nos. 63 / 685,160, filed August 20, 2024; 63 / 675,512, filed July 25, 2024; 63 / 653,043, filed May 29, 2024; 63 / 650,239, filed May 21, 2024; 63 / 567,238, filed March 19, 2024; 63 / 559,588, filed February 29, 2024; 63 / 614,278, filed December 22, 2023; and 63 / 539,749, filed September 21, 2023, each Table C1 is incorporated by reference it its entirety herein. Also provided herein are compounds of Formula (B): Formula (B) or pharmaceutically acceptable salts thereof, or prodrugs thereof, wherein: E1is selected from the group consisting of: CH and CR4, wherein R4is selected from the group consisting of: -CN, halo, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; R1is selected from the group consisting of: (i) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7; wherein b2 is 0, 1, 2, or 3; and A1and A2are independently selected from the group consisting of: N, CH, and CR7; (iii) -N(R2)2, wherein each R2is independently selected from the group consisting of: - H and C1-6alkyl optionally substituted with 1-3 Rc; and (iv) -H; each R7is independently selected from the group consisting of Raand Rb; R2aand R2bare independently selected from the group consisting of: -H, C1-3 alkyl, C1- 3 haloalkyl, a R2aand R2btaken together with the ring carbon atom to which each is attached form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring; R2cand R2dare independently selected from the group consisting of: -H, halo, -CN, C1- 3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; or R2cand R2dtaken together with the ring carbon atom to which each is attached form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring; Ring B is: , wherein the * marks the ring carbon atom common to both Ring X1is selected from the group consisting of a bond, -S(O)0-2-, -CH2-, -CHRL-, -C(RL)2- , and -O-; X2and X3are independently selected from the group consisting of: -CH2-, -CHRL-, - C(RL)2-, -O-, and -S(O)0-2-, provided that no more than one of X1, X2, and X3is selected from the group consisting of: -O- and -S(O)0-2-; b1 is 0, 1, or 2; R9is selected from the group consisting of: -H, -OH, -NRdRe, and halo; each R10is independently selected from the group consisting of Raand Rb; each RLis independently selected from the group consisting of C1-3 alkoxy, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc; or one pair of RLon the same or different ring carbon atom(s) are taken together with the ring atom(s) connecting them to form a C3-6 cycloalkyl ring; Y2is a bond or a straight-chain C1-6 alkylene optionally substituted with 1-6 RY; each RYis independently selected from the group consisting of: halo, cyano, -OH, oxo, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl, C1-6 haloalkyl, and , or a pair f RYth diff t b t ( ) t k t ther with the atom(s) connecting them forms a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of F and C1-3 alkyl; R3is selected from the group consisting of: (a) a 4-15 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of: Ra, Rb, (b) -NRdRe; each Rois independently selected from the group consisting of: -H, -F, C1-3 alkyl, and C1-3 haloalkyl; Roxis -H or C1-3 alkyl; each Rais independently selected from the group consisting of: (a) halo; (b) cyano; (c) -OH; (d) oxo; (e) C1-6 alkoxy; (f) C1-6 haloalkoxy; (g) -NRdRe; (h) -C(=O)C1-6 alkyl; (i) -C(=O)C1-6 haloalkyl; (j) -C(=O)OH; (k) -C(=O)OC1-6 alkyl; (l) -C(=O)OC1-6 haloalkyl; (m) -C(=O)N(Rf)2; (n) -S(O)0-2(C1-6 alkyl); (o) -S(O)0-2(C1-6 haloalkyl); (p) -S(O)1-2N(Rf)2; and (q) C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1, 2, or 3; each -Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3 alkyl)-, -S(O)0-2-, -C(=O)-, and C1-3 alkylene; and each Rb1is independently selected from the group consisting of: C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, cyano, -OH, C1-6 alkoxy, C1-6 haloalkoxy, -NRdRe, -C(=O)C1-6 alkyl, -C(=O)C1-6 haloalkyl, -C(=O)OC1-6 alkyl, -C(=O)OC1-6 haloalkyl, -C(=O)OH, -C(=O)N(Rf)2, -S(O)0-2(C1-6 alkyl), -S(O)0-2(C1-6 haloalkyl), and -S(O)1-2N(Rf)2; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6 alkyl, -C(=O)C1-6 haloalkyl, -C(=O)OC1-6 alkyl, -C(=O)OC1-6 haloalkyl, -C(=O)N(Rf)2, - S(O)1-2(C1-6 alkyl), -S(O)1-2(C1-6 haloalkyl), -S(O)1-2N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rh; each Rfis independently selected from the group consisting of: -H and C1-6 alkyl optionally substituted with 1-3 Rh; each Rg is independently selected from the group consisting of: Rh, C1-3 alkyl, C1-3haloalkyl, C3-5 cycloalkyl, and 4-5 membered heterocyclyl; and each Rhis independently selected from the group consisting of: halo, cyano, -OH, C1-6 alkoxy, C1-6 haloalkoxy, -NH2, -N(H)(C1-3 alkyl), and -N(C1-3 alkyl)2. The term “prodrug” as used herein refers to a derivative of a compound of Formula (B) which releases the Formula (B) compound under appropriate conditions (e.g., under in vivo conditions) via non-enzymatic (e.g., chemical reduction, oxidation, or hydrolysis (e.g., acid catalyzed hydrolysis)) or enzymatic (e.g., esterase, nuclease, lipase, amidase, or protease catalyzed reactions) processes. A prodrug can be used to change the biological distribution of a compound of Formula (B) or its pharmacokinetics. A variety of groups have been used to modify compounds to form prodrugs, such as esters (e.g., benzoates, acetates, etc.), ethers, carbamates, carbonates, N,O-acetals, phosphate esters / salts, etc. A compound of Formula (B) may form prodrugs at NH2 (eg at R9when R9is NH2) or OH (eg at R7when R7is -OH or C1-3 alkyl substituted with -OH) functionalities. Further information on the use of prodrugs may be found in WO 2024 / 050640; ACS Omega 2023, 8, 7, 7211–7221, doi: 10.1021 / acsomega.3c00329; Nat Rev Drug Discov 7, 255–270 (2008), doi: 10.1038 / nrd246; Chem Biol Drug Des 82: 643-668 (2013), doi: 10.1111 / cbdd.12224; Pro- drugs as Novel Delivery Systems, Vol.14, ACS Symposium Series; Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association. In some embodiments of Formula (B), Ring B is: , wherein X3is -CH2-, - CHRL-, or -C(RL)2-. In some embodiments, R9is selected from the group consisting of: -OH, NRdRe(e.g., -OH and -NH2). In some embodiments, each RLis independently C1-3 alkyl optionally substituted with 1-3 -F. In some embodiments of Formula (B), Ring B is: , wherein X3is -CH2-, - CHRL-, or -C(RL)2-. In some embodiments, each RLis independently C1-3alkyl optionally substituted with 1-3 -F. In some embodiments of Formula (B), Ring . example, RLcan be methyl, ethyl, or -CF3. For example, RLcan be methyl. In some embodiments of Formula (B), Ring . In some embodiments of Formula (B), Ring . In some embodiments of Formula (B), Ring . In some embodiments of Formula (B), R2a, R2b, R2c, and R2dare each -H. In some embodiments of Formula (B), E1is CH. In some embodiments of Formula (B), R2a, R2b, R2c, and R2dare each -H; and E1is CH. In some embodiments of Formula (B), R2a, R2b, R2c, and R2dare each -H; E1is CH; and Ring B is: In some embodiments of Formula wherein: Ring A1 is a 4-7 membered heterocyclyl ring having one ring oxygen atom and no additional ring heteroatoms; n4 is 0, 1, or 2; and n5 is 0, 1, or 2, provided that n4 + n5 is 0, 1, or 2. In some embodiments, n4 is 0. In some embodiments, n5 is 0. In some embodiments n4 is 0; and n5 is 0. In some embodiments, each R7is independently selected from the group consisting of: -F, - OH, oxo, Rb1, and C1-3 alkyl optionally substituted with 1-3 Rc, wherein the Rb1is a 5-6 membered heteroaryl optionally substituted with 1-2 Rg. In some embodiments of Formula (B), R1is selected from the group consisting of: each of which is optionally substituted with 1-2 R7. In some embodiments of Formula (B), R1is a 4-membered heterocyclyl optionally substituted w y selected from the group consisting of: -F, -OH, oxo, Rb1, and C1-3 alkyl optionally substituted with 1-3 Rc, wherein the Rb1is a 5-6 membered heteroaryl optionally substituted with 1-2 Rg. In some embodiments of Formula (B), R1is optionally substituted with 1-4 (e.g., 1-2) R7. In some embodiments, each R7is independently selected from the group consisting of: -F, oxo, -OH, Rb1, and C1-3 alkyl optionally substituted with 1-3 Rc, wherein the Rb1is a 5- 6 membered heteroaryl optionally substituted with 1-2 Rg. In some embodiments of Formula (B), R1is selected from the group consisting of: . In some embodiments, each R7is independently selected from the group consisting of: (a) -F; (b) cyano; (c) -OH; (d) Rb1, wherein the Rb1is a 5-6 membered heteroaryl optionally substituted with 1-2 Rg; (e) C1-3 alkyl optionally substituted with 1-3 -F; and (f) C1-3 alkyl substituted with -OH or C1-3 alkoxy. In some embodiments of Formula (B), R1is (e.g., ), wherein R7is C1-3 alkyl substituted with -OH or C1-3 alkoxy (e.g., C1-3 alkyl substituted with -OH). In some embodiments, In some embodiments of Formula , wherein R7ais C1-3 alkyl substituted with -OH (e.g., -CH2OH); and R7bis selected from the group consisting of: C1-3 alkyl optionally substituted with 1-3 -F (e.g., methyl), and C1-3alkyl substituted with -OH or C1-3 alkoxy. For example R1can In some embodiments of Formula wherein R7is a 5-membered heteroaryl optionally substituted with 1-3 Rg. In some embodiments, R7is selected from the group consisting of pyrazolyl and oxazolyl, each of which is optionally substituted with 1-2 Rg. In some embodiments, R7is pyrazolyl optionally substituted with 1-2 Rg(e.g., R7is optionally substituted with one Rg). For example, R7can be . In some embodiments, R7is oxazolyl optionally substituted with one Rg(e.g., R7is optionally substituted with one Rg). For example, R7can be . In some embodiments of Formula (B), Y2is -CH2- or -CD2- (e.g., -CH2-). In some embodiments of Formula (B), Y2is -CH2- or -CD2- (e.g., -CH2-); and R3is optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F, -C1-3 alkoxy, and -C1-3 haloalkoxy. In some embodiments of Formula (B), Y2is -CH2- or -CD2- (e.g., -CH2-); and R3is a 9-14 (e.g., 9-12) membered heterocyclyl optionally substituted with 1-3 substituents independently selected from the group consisting of: Ra, Rb, and . In some embodiments, R3is a 9-12 membered heterocyclyl optionally substituted with 1-3 Ra. In some embodiments, R3is a 9-12 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from the group consisting of: -F, C1-3 alkyl, and C1-3 alkoxy. For example, R3can be selected from the group consisting of: , , , , In some embodiments of Formula (B), Y2is -CH2- or -CD2- (e.g., -CH2-); and R3is an 8-12 membered heterocyclyl substituted with 1-2 further optionally substituted with 1-2 independently selected Ra. In some embodiments, R3is selected from the group In some embodiments of Formula (B), Y2is -CH2- or -CD2- (e.g., -CH2-); and R3is an 8-12 membered heterocyclyl substituted with Rband further optionally substituted with 1-2 substituents independently selected from the group consisting of: Raand . In some embodiments , , . In some embodiments of Formula (B), Y2is -CH2- or -CD2- (e.g., -CH2-); and R3is selected from the group consisting of: wherein each Ra3is an independently selected C1-3 alkyl optionally substituted with 1-3 -F. For example, R3can be selected from the group consisting of: , In some embodiments of Formula (B), Y2is -CH2- or -CD2- (e.g., -CH2-); and R3is , ptionally substituted with 1-3 -F. For example, R3can be selected from the group consisting of: , In some embodiments of Formula (B), Y2is a straight-chain C3-6 alkylene optionally substituted with 1-6 RY. In some embodiments, Y2is selected from the group consisting of: In some embodiments of Formula (B), Y2is a straight-chain C3-6 alkylene optionally substituted with 1-6 RY; and R3is -NRdRe. In some embodiments, Y2is selected from the In some embodiments of Formula (B), Y2is a straight-chain C3-6 alkylene optionally substituted with 1-6 RY; and R3is a 4-8 membered heterocyclyl optionally substituted with 1- 3 substituents independently selected from the group consisting of: Ra, , and . In some embodiments, Y2is selected from the group consisting of: , , , ; and R3is selected from the group consisting

[0033] Also provided herein is a KRas protein (e.g., a dysregulated KRas protein (e.g., a mutated KRas protein)) non-covalently bound with a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof. In some embodiments, Gly10 of the KRas protein interacts non-covalently with the R1group of the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof, (e.g., via a hydrogen bond between the carbonyl of Gly10 and an -OH group of R1and / or via a water mediated interaction between the -NH group of Gly10 and an -OH group of R1). Without wishing to be bound by theory, in some embodiments, the interaction between Gly10 of the KRas protein and the R1group of the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I- c3), (I-c4), (I-d), or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof , facilitates the inhibition of interaction between the KRas protein and Raf-RBD. In some embodiments, Arg68 of the KRas protein interacts non-covalently with the R1group of the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I- c3), (I-c4), (I-d), or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof, (e.g., via a hydrogen bond between the guanidine of Arg68 and a CN group of R1). Without wishing to be bound by theory, in some embodiments, the interaction between Arg68 of the KRas protein and the R1group of the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof facilitates the inhibition of interaction between the KRas protein and Raf-RBD. Chemical definitions The term “halo” refers to fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I). The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls. The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo (e.g., -CF3, -CHF2, or -CH2F). The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3). The term “haloalkoxy” refers to an -O-haloalkyl radical (e.g., -OCF3, -OCHF2, or -OCH2F). The term “alkylene” refers to a divalent alkyl (e.g., -CH2-). Similarly, terms such as “cycloalkylene” and “heterocyclylene” refer to divalent cycloalkyl and heterocyclylrespectively. For avoidance of doubt, in “cycloalkylene” and “heterocyclylene”, the tworadicals can be on the same ring carbon atom (e.g., a geminal diradical such as ) or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring carbon and / or nitrogen atoms) The term “alkenyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents. The term “alkynyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched c ynyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents. The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14- carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like. The term “cycloalkyl” as used herein refers to mono-, bi-, tri-, or polycyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 15 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. Examples of saturated cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Partially unsaturated cycloalkyl may have any degree of unsaturation provided that one or more double bonds is present in the cycloalkyl, none of the rings in the ring system are aromatic, and the partially unsaturated cycloalkyl group is not fully saturated overall. Examples of partially unsaturated cycloalkyl include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples offused / bridged cycloalkyl includes: bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, spiro[3.6]decyl, spiro[5.5]undecyl, and the like. The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 15 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of and P (inclusive of oxidized forms such as: ) (e.g., N, O, and S (inclusive of oxidized forms such as: )) and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4- c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non- wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring). The term “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-15 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-15 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, S (inclusive of oxidized forms such as: ), and P (inclusive of oxidized forms such as: (e.g., N, O, and S (inclusive of oxidized forms such as: )) (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, S, or P if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. Examples of saturated heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Partially unsaturated heterocyclyl groups may have any degree of unsaturation provided that one or more double bonds is present in the heterocyclyl, none of the rings in the ring system are aromatic, and the partially unsaturated heterocyclyl group is not fully saturated overall. Examples of partially unsaturated heterocyclyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2- azabicyclo[1.1.1]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3- azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7- azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 2-oxabicyclo[1.1.0]butyl, 2- oxabicyclo[2.1.0]pentyl, 2-oxabicyclo[1.1.1]pentyl, 3-oxabicyclo[3.1.0]hexyl, oxabicyclo[2 4.1.0]heptyl, 7- oxabicyclo[2.2.1]heptyl, 6-oxabicyclo[3.1.1]heptyl, 7-oxabicyclo[4.2.0]octyl, 2- oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2.1]octyl, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentyl, 4- azaspiro[2.5]octyl, 1-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2- azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, 1,7-diazaspiro[4.5]decyl, 7-azaspiro[4.5]decyl 2,5- diazaspiro[3.6]decyl, 3-azaspiro[5.5]undecyl, 2-oxaspiro[2.2]pentyl, 4-oxaspiro[2.5]octyl, 1- oxaspiro[3.5]nonyl, 2-oxaspiro[3.5]nonyl, 7-oxaspiro[3.5]nonyl, 2-oxaspiro[4.4]nonyl, 6- oxaspiro[2.6]nonyl, 1,7-dioxaspiro[4.5]decyl, 2,5-dioxaspiro[3.6]decyl, 1- oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl and the like. As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher orderring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclicgroups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C. In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses the tautomeric form containing the moiety: . Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms. The compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Certain combinations of heteroatoms (e.g., N, O, S, or halo) define compounds which are less stable under physiological conditions. Examples include (1) compounds containing acetal or aminal linkages; (2) compounds containing acyclic N-O, N-N, or N-S(O)0 bonds; and (3) compounds containing O-O, O-S(O)0-2, N-halo, O-halo, and S(O)0-2-halo bonds. Accordingly, such compounds are less preferred. As used herein, “acyclic bonds” mean chemical bonds that are not part of a ring. Examples include the N-O bond in and . For avoidance of doubt, acyclic N-O, N-N, or N-S(O)0 bonds (i.e., those bonds that are not part of a ring (e.g., in or )) are less preferred, but compounds provided herein can include N-O, N-N, or N-S(O)0 bonds that form part of a ring (e.g., the N-N bond in Methods of Treatment Indications Provided herein are methods for inhibiting a KRas protein. For example, provided herein are inhibitors of a KRas protein (e.g., a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein))) useful for treating or preventing diseases or disorders associated with the KRas dysregulation (i.e., a KRas-associated disease or disorder), such as a cardiovascular disease, an inflammatory and / or autoimmune disease, or a cancer (e.g., a KRas-associated cancer). The term "KRas-associated disease or disorder" as used herein refers to diseases or disorders associated with or having a dysregulation of a KRAS gene, a KRas protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulations of a KRAS gene, a KRas protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of a KRas-associated disease or disorder include, for example, cancer, a cardiovascular disease (e.g., arteriovenous malformations), endometriosis, and an inflammatory and / or autoimmune disease (e.g., a nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis). See, e.g., Adashek et al. Genome Med. 2020; 12: 16, doi: 10.1186 / s13073-020-0714-y; Niemela et al. Blood. 2011; 117(10):2883-6, doi: 10.1182 / blood-2010-07-295501; Nosan et al. Croat Med J.2013; 54(6):574–578, doi: 10.3325 / cmj.2013.54.574; and Messina et al. Small GTPases 11.5 (2020): 312-319, 10.1080 / 21541248.2018.1502591. The term “mutant KRas-associated disease or disorder” as used herein refers to diseases or disorders associated with or having a KRas mutation (e.g., a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation). Non- limiting examples of a mutant KRas-associated disease or disorder include, for example, cancer, a cardiovascular disease (e.g., arteriovenous malformations), endometriosis, and an inflammatory and / or autoimmune disease (e.g., a nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis). See, e.g., Adashek et al. Genome Med. 2020; 12: 16, doi: 10.1186 / s13073-020-0714-y; Niemela et al. Blood.2011; 117(10):2883-6, doi: 10.1182 / blood- 2010-07-295501; Nosan et al. Croat Med J. 2013; 54(6): 574–578, doi: 10.3325 / cmj.2013.54.574; and Messina et al. Small GTPases 11.5 (2020): 312-319, 10.1080 / 21541248.2018.1502591. The phrase “dysregulation of a KRAS gene, a KRas protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a KRAS gene that results in the expression of a KRas protein that includes a deletion of at least one amino acid as compared to a wild type KRas protein, a mutation in a KRAS gene that results in the expression of a KRas protein with one or more point mutations as compared to a wild type KRas protein, a mutation in a KRAS gene that results in the expression of a KRas protein with at least one inserted amino acid as compared to a wild type KRas protein, a gene duplication that results in an increased level of KRas protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of KRas protein in a cell); an alternative spliced version of a KRas mRNA that results in a KRas protein having a deletion of at least one amino acid in the KRas protein as compared to the wild type KRas protein; or increased expression (e.g., increased levels) of a wild type KRas protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non-cancerous cell). As an example, a dysregulation of a KRAS gene, a KRas protein, or expression or activity, or level of any of the same, can be a mutation in a KRAS gene that encodes a KRas protein that has low GTPase activity and / or has increased signaling activity as compared to a protein encoded by a KRAS gene that does not include the mutation. As another example, a dysregulation of a KRAS gene, a KRas protein, or expression or activity, or level of any of the same, can be a KRas amplification. In some embodiments, aKRas amplification is an amplification of the wild type KRas. In some embodiments, a KRasamplification is an amplification of a mutant KRas. A “dysregulated KRas protein” as used herein refers to (i) a KRas protein having a mutation (e.g., a deletion of at least one amino acid as compared to a wild type KRas protein, one or more point mutations as compared to a wild type KRas protein, or an insertion of at least one amino acid as compared to a wild type KRas protein); (ii) a KRas protein resulting from a gene duplication event, e.g., of the gene encoding the KRas protein (e.g., the wild type KRas protein), thus resulting in an increased level and / or activity of the KRas protein (e.g., the wild type KRas protein) in a cell; (iii) a KRas protein resulting from a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that can also result in an increased level and / or activity of the KRas protein (e.g., the wild type KRas protein) in a cell); (iv) a KRas protein resulting from an alternative spliced version of a KRas mRNA that results in a KRas protein having a deletion of at least one amino acid in the KRas protein as compared to the wild type KRas protein); or (v) a KRas protein resulting from increased expression (e.g., increased levels) of a wild type KRas protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non-cancerous cell). In some embodiments, a dysregulated KRas protein is a dysregulated human KRas protein. A “mutant KRas protein” as used herein refers to a KRas protein including a substitution, an insertion, a deletion, a truncation and / or a fusion relative to the wild type human KRas sequence shown in SEQ ID NO:1. For example, a mutant human KRas protein includes a substitution at any amino acid position (relative to SEQ ID NO: 1). A “KRas G12X mutant protein” as used herein refers to a KRas protein including substitution of a glycine to any other amino acid at the twelfth amino acid position (relative to SEQ ID NO: 1). A “KRas G12A mutant protein” as used herein refers to a KRas protein including a glycine to alanine substitution at the twelfth amino acid position (relative to SEQ ID NO: 1). A “KRas G12C mutant protein” as used herein refers to a KRas protein including a glycine to cysteine substitution at the twelfth amino acid position (relative to SEQ ID NO: 1). A “KRas G12D mutant protein” as used herein refers to a KRas protein including a glycine to aspartic acid substitution at the twelfth amino acid position (relative to SEQ ID NO: 1). A “KRas G12R mutant protein” as used herein refers to a KRas protein including a glycine to arginine substitution at the twelfth amino acid position (relative to SEQ ID NO: 1). A“KRas G12S mutant protein” as used herein refers to a KRas protein including aglycine to serine substitution at the twelfth amino acid position (relative to SEQ ID NO: 1). A “KRas G12V mutant protein” as used herein refers to a KRas protein including a glycine to valine substitution at the twelfth amino acid position (relative to SEQ ID NO: 1). A “KRas G13X mutant protein” as used herein refers to a KRas protein including substitution of a glycine to any other amino acid at the thirteenth amino acid position (relative to SEQ ID NO: 1). A “KRas G13C mutant protein” as used herein refers to a KRas protein including a glycine to cysteine substitution at the thirteenth amino acid position (relative to SEQ ID NO: 1). A “KRas G13D mutant protein” as used herein refers to a KRas protein including a glycine to aspartic acid substitution at the thirteenth amino acid position (relative to SEQ ID NO: 1). A “KRas G13V mutant protein” as used herein refers to a KRas protein including a glycine to valine substitution at the thirteenth amino acid position (relative to SEQ ID NO: 1). A “KRas Q61X mutant protein” as used herein refers to a KRas protein including substitution of a glutamine to any other amino acid at the sixty-first amino acid position (relative to SEQ ID NO: 1). A “KRas Q61E mutant protein” as used herein refers to a KRas protein including a glutamine to glutamic acid substitution at the sixty-first amino acid position (relative to SEQ ID NO: 1). A “KRas Q61H mutant protein” as used herein refers to a KRas protein including a glutamine to histidine substitution at the sixty-first amino acid position (relative to SEQ ID NO: 1). A “KRas Q61K mutant protein” as used herein refers to a KRas protein including a glutamine to lysine substitution at the sixty-first amino acid position (relative to SEQ ID NO: 1). A “KRas Q61L mutant protein” as used herein refers to a KRas protein including a glutamine to leucine substitution at the sixty-first amino acid position (relative to SEQ ID NO: 1). A “KRas Q61P mutant protein” as used herein refers to a KRas protein including a glutamine to proline substitution at the sixty-first amino acid position (relative to SEQ ID NO:1).A “KRas Q61R mutant protein” as used herein refers to a KRas protein including a glutamine to arginine substitution at the sixty-first amino acid position (relative to SEQ ID NO: 1). A “KRas inhibitor” as used herein includes any compound exhibiting KRas protein inactivation activity (e.g., inhibiting or decreasing KRas signaling activity). In some embodiments, a KRas inhibitor as described herein has an IC50 value of 1 µM or less in a nucleotide exchange assay as described herein, an IC50 value of 1 µM or less in a Raf kinase interaction assay as described herein, or both. In some embodiments, a KRas inhibitor inhibits the signaling activity of a wild type KRas protein. In some embodiments, a KRas inhibitor inhibits the signaling activity of a dysregulated KRas protein, for example, resulting in a decrease in activated Raf or other downstream effectors, such as ERK. In some embodiments, a KRas inhibitor inhibits the signaling activity of a mutant KRas protein. In some embodiments, a KRas inhibitor inhibits both the signaling activity of a wild type KRas protein and the signaling activity of one or more mutant KRas proteins and can be termed a “pan KRas inhibitor”. In some embodiments, a KRas inhibitor inhibits one or more mutant KRas proteins, and such a KRas inhibitor can be termed a “mutant KRas inhibitor”, and also termed by the mutant(s) it inhibits. For example, a KRas inhibitor that inhibits KRas G12R mutant protein could be termed a “KRas G12R inhibitor”. As another example, a KRas inhibitor that inhibits both KRas G12C mutant protein and KRas G12D mutant protein could be termed a “KRas G12C inhibitor” and / or a “KRas G12D inhibitor”. In some embodiments, a “mutant KRas inhibitor” inhibits two or more mutant KRas proteins and can be termed a “pan mutant KRas inhibitor”. In some embodiments, a pan mutant KRas inhibitor inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. For example, a “KRas G12X inhibitor” can inhibit two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. As yet another example, a KRas inhibitor that inhibits a KRas G13D mutant protein could be termeda “KRas G13D inhibitor”. In some embodiments, a KRas inhibitor can inhibit a KRas proteinhaving one or more mutations, and such a KRas inhibitor can be termed a “mutant KRas inhibitor” whether or not the mutant KRas inhibitor also inhibits wild type KRas protein. In some embodiments, a KRas inhibitor is a mutant KRas inhibitor. In some embodiments, a KRas inhibitor is an allosteric inhibitor. The term “compound(s) provided herein” refers to compound(s) of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))) or Formula (B) as disclosed herein. The compounds provided herein, or pharmaceutically acceptable salts thereof, are KRas inhibitors. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is a mutant KRas inhibitor. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein a KRas G12D mutant protein a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, or a combination thereof. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12V mutant protein, or a combination thereof. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein, a KRas G12V mutant protein, or both. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12R mutant protein, a KRas G12V mutant protein, or both. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12A mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12C mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof,inhibits a KRas G12R mutant protein. In some embodiments, a compound provided herein, ora pharmaceutically acceptable salt thereof, inhibits a KRas G12S mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is a KRas G12X inhibitor. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein In some embodiments a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits four or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits five or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptablesalt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of:a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits four or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments a compound provided herein or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein, a KRas G12V mutant protein, or both. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12A mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12C mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, does not inhibit a KRas G12C mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, does not inhibit a KRas G12D mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12S mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is a KRas G13X inhibitor. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G13C mutant protein, a KRas G13D mutant protein, and a KRas G13V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selectedfrom the group consisting of: a KRas G13C mutant protein, a KRas G13D mutant protein, anda KRas G13V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G13C mutant protein, a KRas G13D mutant protein, and a KRas G13V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G13C mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G13D mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G13V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is a KRas Q61X inhibitor. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein In some embodiments a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits four or more mutant KRas proteins selected from the group consisting of: a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits five or more mutant KRas proteins selected from the group consisting of: a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound providedherein, or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61E mutant protein. Insome embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61H mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61K mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61L mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61P mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12X mutant protein, a KRas G13X mutant protein, and a KRas Q61X mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12X mutant protein, a KRas G13X mutant protein, and a KRas Q61X mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant human KRas proteins selected from the group consisting of: a KRas G12X mutant protein, a KRas G13X mutant protein, and a KRas Q61X mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12X mutant protein, a KRas G13X mutant protein, and a KRas Q61X mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, aKRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and aKRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits four or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein a KRas Q61E mutant protein a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, five or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61Kmutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61Rmutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12V mutant protein, a KRas G13D mutant protein, and a KRas Q61H mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12V mutant protein, a KRas G13D mutant protein, and a KRas Q61H mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12V mutant protein a KRas G13D mutant protein and a KRas Q61H mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some such embodiments, the compounds provided herein, orpharmaceutically acceptable salts thereof, are useful for treating a bladder cancer.In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12V mutant protein, and a KRas G13D mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12V mutant protein, and a KRas G13D mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12V mutant protein, and a KRas G13D mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein a KRas G12D mutant protein and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12C mutant protein, a KRas G12D mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein, a KRas G12V mutant protein, or both. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating a cervical cancer. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, aKRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein.In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating a colorectal cancer. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61H mutant protein, and a KRas Q61L mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61H mutant protein, and a KRas Q61L mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or moremutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, aKRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61H mutant protein, and a KRas Q61L mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12A mutant protein, a KRas G12D mutant protein, and a KRas G12V mutant protein. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating an endometrial cancer. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, and a KRas Q61H mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, aKRas G13D mutant protein, and a KRas Q61H mutant protein. In some embodiments, acompound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, and a KRas Q61H mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein, a KRas G12V mutant protein, or both. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating an esophageal or stomach cancer. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein.In some embodiments, a compound provided herein, or a pharmaceutically acceptable saltthereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein a KRas G12C mutant protein a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating a leukemia. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of:a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, aKRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, and a KRas G12R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, and a KRas G12R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12C mutant protein, a KRas G12D mutant protein, and a KRas G12R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein, a KRas G12R mutant protein, or both. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating a melanoma. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G13D mutant protein, and a KRas Q61L mutation. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G13D mutant protein, and a KRas Q61L mutation. In some embodiments, a compoundprovided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutantKRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G13D mutant protein, and a KRas Q61L mutation. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12S mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12S mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12S mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12C mutant protein, a KRas G12D mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein, a KRas G12V mutant protein, or both. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating an ovarian cancer.

[0034] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas Q61H mutant protein, and a KRas Q61L mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas Q61H mutant protein, and a KRas Q61L mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas Q61H mutant protein, and a KRas Q61L mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12A mutant protein, a KRas G12D mutant protein, and a KRas G12V mutant protein. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating a lung cancer (e.g., non-small cell lung cancer).

[0035] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas Q61H mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas Q61H mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas Q61H mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating a pancreatic cancer.

[0036] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12A mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating a testicular cancer (e.g., seminoma).

[0037] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can bind to a KRas protein in the GTP -bound state. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can bind selectively to a KRas protein in the GTP -bound state.

[0038] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can bind to a KRas protein in the GDP -bound state. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can bind selectively to a KRas protein in the GDP -bound state.

[0039] An exemplary sequence of mature human KRas protein is shown below (UniProtKB entry P01116) (SEQ ID NO: 1)

[0040] MTEYKLVWG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQWIDGET

[0041] CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI

[0042] KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ

[0043] RVEDAFYTLV REIRQYRLKK ISKEEKTPGC VKIKKCI IM As used herein, “selective” or “selectively”, when referring to an assayed compound, indicates at least a 5-fold (e.g., at least a 10-fold, at least a 25-fold, at least a 50-fold, or at least a 100-fold) superior performance in an assay (e.g., binding affinity and / or potency) for a specified condition with reference to a comparator protein variant in the assay. For example, if a compound provided herein, or a pharmaceutically acceptable salt thereof, binds “selectively” to a KRas G12X mutant protein over the wild type KRas protein as determined by a surface plasmon resonance (SPR) assay, then the compound provided herein, or a pharmaceutically acceptable salt thereof, has at least a 5-fold (e.g., at least a 10-fold, at least a 25-fold, at least a 50-fold, or at least a 100-fold) smaller KD value for any one or more KRas mutant proteins selected from the group consisting of the KRas G12X mutant proteins than for the wild type KRas protein when measured by the SPR assay. As a further example, if a compound provided herein, or a pharmaceutically acceptable salt thereof, “selectively” reduces the viability of the KRas G12V mutant protein-expressing cells over the cells expressing KRas G12C protein as determined by a cell proliferation assay, then the compound has at least a 5-fold (e.g., at least a 10-fold, at least a 25-fold, at least a 50-fold, or at least a 100-fold) smaller ECso value for the KRas G12V mutant protein-expressing cells than for the KRas G12C protein-expressing cells when measured by the cell proliferation assay. In another example, if a compound provided herein, or a pharmaceutically acceptable salt thereof, “selectively” inhibits a KRas G13X mutant protein over the wild type KRas protein as determined by a Raf kinase interaction assay, then the compound provided herein, or a pharmaceutically acceptable salt thereof, has at least a 5-fold (e.g., at least a 10-fold, at least a 25-fold, at least a 50-fold, or at least a 100-fold) smaller IC50 value for the KRas G13X protein than for the wild type KRas protein when measured by the Raf kinase interaction assay. As a further example, if a compound provided herein, or a pharmaceutically acceptable salt thereof, “selectively” inhibits the KRas G12R mutant protein over the wild type KRas protein as determined by a nucleotide exchange assay, then the compound provided herein, or a pharmaceutically acceptable salt thereof, has at least a 5-fold (e.g., at least a 10-fold, at least a 25-fold, at least a 50-fold, or at least a 100-fold) smaller IC50 value for the KRas G12R mutant protein than for the wild type KRas protein when measured by the nucleotide exchange assay.

[0044] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is a pan mutant KRas inhibitor (i.e., can inhibit two or more mutant KRas proteins (e.g., two or more of a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein)). For example, such a compound can inhibit each mutant KRas protein (e.g., two or more mutant KRas proteins) with an IC50 of less than 1 pM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). As another example, such a compound can inhibit ERK phosphorylation in cell lines each expressing a mutant KRas protein with an independent IC50 of less than 1 pM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM) in at least two of the cell lines. For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can inhibit ERK phosphorylation in a cell line expressing a KRas G12R mutant protein with an IC50 of less than 1 pM, and the compound provided herein, or a pharmaceutically acceptable salt thereof, can inhibit ERK phosphorylation in a cell line expressing a KRas G12V mutant protein with an IC50 of less than 1 pM. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is a pan KRas inhibitor (i.e., the compound can inhibit wild type KRas and one or more mutant KRas proteins). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, does not inhibit certain KRas proteins (e.g., wild type KRas or one or more dysregulated KRas proteins). For example, such a compound can inhibit the interaction between a KRas protein (e.g., a dysregulated KRas protein) and one or more Raf proteins with an IC50 of 1 pM or greater than 1 pM (e.g., greater than 2 pM, greater than 5 pM, greater than 10 pM, or greater than 30 pM). As another example, such a compound can inhibit ERK phosphorylation in cell lines expressing the KRas protein (e.g., a dysregulated KRas protein) with an IC50 of 1 pM or greater than 1 pM (e.g., greater than 2 pM, greater than 5 pM, greater than 10 pM, or greater than 30 pM).

[0045] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein and a KRas G12V mutant protein. In some such embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC) with an IC50 that is within about 10-fold, i.e., within about 10-fold less or within about 10-fold more (e.g., within about 9-fold less or within about 9-fold more, within about 8-fold less or within about 8-fold more, within about 7-fold less or within about 7-fold more, within about 6-fold less or within about 6-fold more, within about 5-fold less or within about 5-fold more, or within about 2-fold less or within about 2-fold more) of the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480). For example, if the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein with an IC50 of about 150 nM, then the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein would be within about 10-fold more than about 150 nM, thus ranging from about 150 nM to about 1500 nM, or within about 10-fold less than 150 nM, thus ranging from about 15 nM to about 150 nM. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can inhibit ERK phosphorylation in a GP2d cell line with an IC50 that is within about 10-fold, i.e., within about 10-fold less or within about 10-fold more (e.g., within about 9-fold less or within about 9-fold more, within about 8- fold less or within about 8-fold more, within about 7-fold less or within about 7-fold more, within about 6-fold less or within about 6-fold more, within about 5-fold less or within about 5-fold more, or within about 2-fold less or within about 2-fold more) of the IC50 measured for inhibition of ERK phosphorylation by the compound in a SW620 cell line. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC) with an IC50 that is within about 10-fold less (e.g., within about 9-fold less, within about 8-fold less, within about 7-fold less, within about 6-fold less, within about 5-fold less, or within about 2-fold less) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480). For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can inhibit ERK phosphorylation in a GP2d cell line with an IC50 that within about 10-fold less (e.g., within about 9-fold less, within about 8-fold less, within about 7-fold less, within about 6-fold less, within about 5-fold less, or within about 2-fold less) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a SW620 cell line. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC ) with an IC50 that is within about 10-fold more (e.g., within about 9-fold more, within about 8-fold more, within about 7-fold more, within about 6-fold more, within about 5-fold more, or within about 2-fold more) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480). For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can inhibit ERK phosphorylation in a GP2d cell line with an IC50 that is within about 10-fold more (e.g., within about 9-fold more, within about 8-fold more, within about 7-fold more, within about 6-fold more, within about 5- fold more, or within about 2-fold more) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a SW620 cell line.

[0046] In some such embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a cell line expressing a KRas G12V mutant protein (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480) with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can inhibit ERK phosphorylation in a SW620 cell line with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). In some such further embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC) with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). For example, the compound provided herein, or a pharmaceutically acceptable salt thereof, can inhibit ERK phosphorylation in a GP2d cell line with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM).

[0047] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC) with an IC50 that is within about 10-fold, i.e., within about 10-fold less or within about 10-fold more (e.g., within about 9-fold less or within about 9-fold more, within about 8-fold less or within about 8-fold more, within about 7-fold less or within about 7-fold more, within about 6- fold less or within about 6-fold more, within about 5-fold less or within about 5-fold more, or within about 2-fold less or within about 2-fold more) of the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480), wherein the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in the cell line expressing a KRas G12V mutant protein (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480) with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). In some such embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in the cell line expressing a KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC) with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM).

[0048] For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can inhibit ERK phosphorylation in a GP2d cell line with an IC50 that is within about 10-fold, i.e., within about 10-fold less or within about 10-fold more (e.g., within about 9-fold less or within about 9-fold more, within about 8-fold less or within about 8-fold more, within about 7-fold less or within about 7-fold more, within about 6-fold less or within about 6-fold more, within about 5-fold less or within about 5-fold more, or within about 2-fold less or within about 2-fold more) of the IC50 measured for inhibition of ERK phosphorylation by the compound in a SW620 cell line, wherein the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a SW620 cell line with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). In some such embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a GP2d cell line with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC) with an IC50 that is within about 10-fold less (e.g., within about 9-fold less, within about 8-fold less, within about 7-fold less, within about 6-fold less, within about 5-fold less, or within about 2- fold less) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480), wherein the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in the cell line expressing a KRas G12V mutant protein (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480) with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). In some such embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in the cell line expressing a KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC) with an ICso of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM).

[0049] For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can inhibit ERK phosphorylation in a GP2d cell line with an ICso that is within about 10-fold less (e.g., within about 9-fold less, within about 8-fold less, within about 7-fold less, within about 6-fold less, within about 5-fold less, or within about 2-fold less) than the ICso measured for inhibition of ERK phosphorylation by the compound in a SW620 cell line, wherein the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a SW620 cell line with an ICso of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). In some such embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a GP2d cell line with an ICso of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM).

[0050] In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC) with an IC50 that is within about 10-fold more (e.g., within about 9-fold more, within about 8- fold more, within about 7-fold more, within about 6-fold more, within about 5-fold more, or within about 2-fold more) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480), wherein the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in the cell line expressing a KRas G12V mutant protein (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480) with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). In some such embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in the cell line expressing a KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC) with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM).

[0051] For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can inhibit ERK phosphorylation in a GP2d cell line with an IC50 that is within about 10-fold more (e.g., within about 9-fold more, within about 8-fold more, within about 7-fold more, within about 6-fold more, within about 5 -fold more, or within about 2-fold more) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a SW620 cell line, wherein the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a SW620 cell line with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). In some such embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a GP2d cell line with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM).

[0052] The ability of a compound provided herein, or a pharmaceutically acceptable salt thereof, to bind to a KRas protein can be measured, for example, by a direct determination method (e.g., surface plasmon resonance or isothermal titration calorimetry); by radio labelling the compound prior to binding, isolating the compound / protein complex, and determining the amount of radio label bound; or by running a competition experiment where new compounds are incubated with the protein bound to known radioligands. As another example, the occupancy of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be determined using a proximity-based technique, such as time-resolved Fluorescence Resonance Energy Transfer (FRET); for instance, using a labeled probe that binds mutually exclusively with the inhibitor, and using an antibody that binds to a position on the protein separate from where the compound provided herein, or a pharmaceutically acceptable salt thereof, binds (for example, an antibody that binds to an N-terminal tag). It will be understood that the antibody and probe can be tagged with any appropriate FRET pair. See, e.g., International Publication Nos. WO 2021 / 041671, WO 2021 / 120890, and U.S. Publication No. US 2021 / 0179633.

[0053] In some cases, binding affinities (e.g., as measured by dissociation constant KD) of the compounds provided herein, or pharmaceutically acceptable salts thereof with a KRas protein (e.g., a wild type KRas protein or a mutant KRas protein) in the GDP -bound and / or GTP -bound state can be measured using methods known in the art (e.g., using SPR (e.g., using one or more methods described herein (e.g., using the methods described in Example Bl or in Example B5 herein))). Binding affinity with the KRas protein in the GDP -bound state can be measured by loading the KRas protein with GDP (e.g., at the concentrations described in Example Bl or in Example B5). Binding affinity with the KRas protein in the GTP -bound state can be measured by loading the KRas protein with GMPPNP (e.g., at the concentrations described in Example Bl).

[0054] Another exemplary assay for determining the potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, includes measuring the effect of the compound provided herein, or a pharmaceutically acceptable salt thereof, on cell proliferation. Cell proliferation assays can be performed in a number of formats, including 2D and 3D. Similarly, a cell proliferation assay can be performed with any appropriate cell line, including, for example, A375, A427, A549, AGS, ASPC1, CAL62, CALU1, CAPAN1, CAPAN2, CFPAC1, GP2D, H358, H441, H460, H727, HCT116, HKA1, HP AC, HPAFII, HTK, HUPT3, KMS20, KP2, LS123, LS180, MIAPaCa-2, MKN1, NCI-H1993, NCI-H211, NCI-H424, NCI-H526, Panc02.03, Panc04.03, PATC50, PC9, PK8, PSN1, RKN, SW480, SW620, and / or TCCPAN2. In some embodiments, the cell line can be AGS, A375, A427, ASPC1, H727, H441, RKN, and / or SW620. As an illustrative example, a 3D cell proliferation assay can include growing cells in a 3D medium, contacting the cells with a compound provided herein, or a pharmaceutically acceptable salt thereof, measuring the cellular proliferation using an appropriate reagent (e.g., CELLTITERGLO® 3D), and then comparing the signal from the experiment with the compound provided herein, or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound provided herein). As another illustrative example, a 2D cell proliferation assay can include plating cells onto a growth surface, optionally letting the cells grow for a period of time, contacting the cells with a compound provided herein, or a pharmaceutically acceptable salt thereof, measuring the cellular proliferation using an appropriate reagent (e.g., CELLTITERGLO®), and then comparing the signal from the experiment with a compound provided herein, or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound provided herein, or a pharmaceutically acceptable salt thereof). See, e.g., Example B7 herein. In some embodiments, cellular proliferation can be assessed using a platform for live cell imaging (e.g., an INCUCYTE® SX5 Live-Cell Analysis Instrument). See also, e.g., U.S. Publication No. US 2021 / 0179633, US 2021 / 0230142, and US 2019 / 0284144.

[0055] As another example, the potency and / or efficacy of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, for example, a xenograft model (e.g., using an established cancer cell line such as AGS, A375, A427, ASPC1, H727, H441, RKN, and / or SW620, or a patient-derived xenograft (PDX) model). See, e.g., U.S. Publication No. US 2021 / 0179633.

[0056] In some embodiments, the potency and / or efficacy of a compound provided herein, or a pharmaceutically acceptable salt thereof can be evaluated in a cell-derived xenograft (CDX) model. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is assessed in a CDX (e.g., H727, RKN, or SW620) mouse model. For example, mice can be implanted with a cell line of interest (e.g., H727, RKN, or SW620) and the tumor allowed to grow for a period of time, then the mice can be administered a compound provided herein, or a pharmaceutically acceptable salt thereof. The effect of the compound provided herein, or a pharmaceutically acceptable salt thereof, can be determined by measuring tumor growth (or regression). An exemplary protocol follows.

[0057] All the procedures related to animal handling, care, and treatment in the efficacy study are performed according to guidelines approved by the Institutional Animal Care and Use Committee (IACUC) following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). 6-8 week old BALB / c nude female mice are inoculated subcutaneously on the right flank with 5 x 106H727, RKN, or SW620 tumor cells in 0.1 mL of 1 : 1 medium / Matrigel for tumor development. Treatments start and groupings are assigned when the mean tumor volume reaches about 175-225 mm3. Based on the tumor volume, mice are randomly assigned to respective groups such that the average starting tumor size is the same for each treatment group. Tumor-bearing mice are treated orally twice daily with a compound provided herein, or a pharmaceutically acceptable salt thereof (e.g., a dose of about 1 mg / kg to about 200 mg / kg, such as 1 mg / kg, 3 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 50 mg / kg, 75 mg / kg, 100 mg / kg, 150 mg / kg, or 200 mg / kg). The body weight of each animal is measured and recorded twice weekly throughout the study. The measurement of tumor size is conducted twice weekly with a caliper and recorded. The tumor volume (mm3) is estimated using the formula: TV=a x b2 / 2, where “a” and “b” are long and short diameters of a tumor, respectively. In some embodiments, the tumor volume is plotted as a function of time.

[0058] Additional assays can include, for example, assays based on hydrogen exchange (HX) mass spectrometry. Such assays can be useful, for example, to evaluate whether a compound (e.g., a compound provided herein, or a pharmaceutically acceptable salt thereof) stabilizes the GTP -bound state or GDP -bound state of a KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)). In such assays, the rate of hydrogen exchange of the backbone amide hydrogens can be measured for a KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) bound to a non -hydrolyzable GTP mimic (GMPPNP), GDP, or a compound provided herein, or a pharmaceutically acceptable salt thereof. See, e.g., Lim et al. Angew Chem Int Ed Engl. 2014; 53(1): 199-204, doi: 10.1002 / anie.201307387.

[0059] In some embodiments, potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, as provided herein can be determined by ECso value. A compound with a lower ECso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ECso value. In some embodiments, an ECso value can be determined (e.g., using a KRas-dependent phosphorylation level (e.g., a phosphoERK level (sometimes called a “pERK” level)) or using a cell viability assay) in cells (e.g., in tumor cells, (e.g., cell lines such as A375, A427, A549, AGS, ASPC1, CAL62, CALU1, CAPAN1, CAPAN2, CFPAC1, GP2D, H358, H441, H460, H727, HCT116, HKA1, HP AC, HPAFII, HTK, HUPT3, KMS20, KP2, LS123, LS180, MIAPaCa-2, MKN1, NCI-H1993, NCI-H211, NCI-H424, NCI-H526, Panc02.03, Panc04.03, PATC50, PC9, PK8, PSN1, RKN, SW480, SW620, and / or TCCPAN2) expressing a KRas protein, such as a dysregulated KRas protein (e.g., a mutant KRas protein or an amplified KRas protein), or a fragment thereof).

[0060] In some embodiments, potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, as provided herein can also be determined by ICso value. A compound with a lower ICso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ICso value. In some embodiments, an ICso value can be determined (e.g., using a KRas-dependent phosphorylation level (e.g., a phosphoERK level) or using a cell viability assay), in cells (e.g., in tumor cells, (e.g., cell lines such as A375, A427, A549, AGS, ASPC1, CAL62, CALU1, CAPAN1, CAPAN2, CFPAC1, GP2D, H358, H441, H460, H727, HCT116, HKA1, HP AC, HPAFII, HTK, HUPT3, KMS20, KP2, LS123, LS180, MIAPaCa-2, MKN1, NCI-H1993, NCI-H211, NCI-H424, NCI-H526, Panc02.03, Panc04.03, PATC50, PC9, PK8, PSN1, RKN, SW480, SW620, and / or TCCPAN2) expressing a KRas protein, such as a dysregulated KRas protein (e.g., a mutant KRas protein or an amplified KRas protein), or a fragment thereof). In some embodiments, measuring the potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, includes measuring the phosphorylation of a downstream kinase, such as ERK (e.g., ERK1 and / or ERK2) or MEK. Such assays can be used to measure the inhibition of KRas signaling activity, for instance, in a cell line (e.g., A375, A427, A549, AGS, ASPC1, CAL62, CALU1, CAPAN1, CAPAN2, CFPAC1, GP2D, H358, H441, H460, H727, HCT116, HKA1, HP AC, HPAFII, HTK, HUPT3, KMS20, KP2, LS123, LS180, MIAPaCa-2, MKN1, NCI-H1993, NCI-H211, NCI-H424, NCI-H526, Panc02.03, Panc04.03, PATC50, PC9, PK8, PSN1, RKN, SW480, SW620, and / or TCCPAN2 (e.g., AGS, A375, A427, ASPC1, H727, H441, RKN, and / or SW620)). For example, cells can be contacted with a compound provided herein, or a pharmaceutically acceptable salt thereof for a period of time, then lysed or permeabilized, and total ERK or MEK and phosphoERK or phosphoMEK content can be determined (e.g., using antibodies, or a kit, such as Invitrogen InstantOne ERK1 / ERK2 (Phospho) [pT202 / pY204] / [pT185 / pY187] ELISA, MesoScale Discovery p / t ERK1 / 2, AlphaScreen SUREFIRE® p-ERKl / 2 (Thr202 / Tyr204), or an HTRF® PhosphoERK (Thr202 / Tyr204) cellular kit (CisBio)). In some embodiments, multiple concentrations of a compound provided herein, or a pharmaceutically acceptable salt thereof can be used to construct a dose response curve. See, e.g., Example B6 herein. See, e.g., International Publication No. WO 2021 / 041671, U.S. Publication Nos. US 2021 / 0122764, US 2018 / 0334454, US 2021 / 0179633, US 2018 / 0334454, and US 2019 / 0144444.

[0061] An exemplary ERK phosphorylation protocol follows. In some embodiments, an ERK phosphorylation assay can be carried out using the AlphaLisa SUREFIRE® Ultra Multiplex Phospho / Total ERK1 / 2 (Thr202 / Tyr204) Assay Kit. In a plate (e.g., a white, opaquebottom Perkin Elmer CulturPlate-384 (product number 6007680)), cells are seeded at the desired concentration one day prior to treatment with compounds provided herein, or pharmaceutically acceptable salts thereof, and incubated overnight in a standard 37 °C, 5% CO2 humidified incubator. The cells can be any cells of interest, such as MIAPaCa-2 (KRas G12C), H358 (KRas G12C), AGS (KRas G12D), ASPC1 (KRas G12D), GP2D (KRas G12D), LS180 (KRas G12D), Panc04.03 (KRas G12D), HPAFII (KRas G12D), Panc02.03 (KRas G12D), A427 (KRas G12D), HP AC (KRas G12D), TCCPAN2 (KRas G12R), PSN1 (KRas G12R), KP2 (KRas G12R), LS123 (KRas G12S), SW620 (KRas G12V), H727 (KRas G12V), CFPAC1 (KRas G12V), CAPAN1 (KRas G12V), CAPAN2 (KRas G12V), RKN (KRas G12V), H441 (KRas G12V), SW480 (KRas G12V), PACADD159 (KRas G12V / G12S), HS766T (KRas Q61H), H460 (KRas Q61H), PANC0213 (KRas Q61R), or A3735 (KRas WT). The day after seeding, compounds provided herein, or pharmaceutically acceptable salts thereof, are dispensed into the treatment plates (e.g., using a Tecan D300e compound printer in 9-point DRC format (1 :3 dilution), 10-pM top concentration, in triplicate). Treatment plates are then returned to a standard 37 °C, 5% CO2 humidified incubator for the pre-determined treatment time. Following compound treatment, all media is removed from the treatment plate(s), and the cells are subsequently lysed (e.g., using IX Lysis Buffer in accordance with manufacturer protocol). Next, the Acceptor Mix (prepared in accordance with manufacturer’s protocol) is added to each well of the assay plate and incubated on an orbital shaker at room temperature for 2 hours. Following incubation with the Acceptor Mix, the Donor Mix (prepared in accordance with manufacturer protocol) is added to each well of the assay plate, covered to protect from light, and incubated on an orbital shaker at room temperature overnight. Assay plates are read the following day (e.g., on a BMG Labtech PHERAstar FSX microplate reader). Data are then analyzed by calculating the ratio of ERKl / 2-phosphorylation relative to Total ERK1 / 2 for each individual well.

[0062] The replicate ratios for each concentration are averaged and normalized to a DMSO control or other corresponding co-treatment before performing a variable slope (4-parameter), non-linear regression curve fit for each compound of interest. Data can be reported as IC50 values.

[0063] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit ERK phosphorylation in a cell line expressing a KRas protein (e.g., a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein))) with an IC50 of less than 1 pM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compounds inhibit ERK phosphorylation in a cell line expressing the KRas protein (e.g., a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein))) with an IC50 of less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM). For example, the compounds can inhibit ERK phosphorylation in a cell line expressing the KRas protein (e.g., a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein))) with an IC50 of 0.1 nM to 100 nM, 0.1 nM to 50 nM, 1 nM to 50 nM, or 1 nM to 20 nM.

[0064] In some cases, a KRas A59G mutant protein (e.g., as a single mutant or as a double mutant with another mutation of interest, e.g., KRas G12X) can be used to “lock” the KRas protein in the GTP -bound state (e.g., by abrogating the GTPase activity of the protein); such an assay can be useful, for example, to determine the affinity of a compound provided herein, or a pharmaceutically acceptable salt thereof for the GTP -bound state and / or to determine the effect of the compound on downstream signaling (e.g., interaction with an RBD and / or the phosphorylation of a downstream kinase, such as ERK), potentially independent of the GTP cycling of the KRas protein. See, e.g., Hall, et al. Proceedings of the National Academy of Sciences 99.19 (2002): 12138-12142, doi: 10.1073 / pnas.192453199; Lu, et al. Biochemistry 57.3 (2018): 324-333, doi: 10.1021 / acs.biochem.7b00974; and Lim, Shuhui, et al. Chemical Science 12.48 (2021): 15975-15987, doi: 10.1039 / D1SC05187C.

[0065] In some embodiments, the potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, as a KRas inhibitor can be evaluated by its effect on the nucleotide exchange of GDP for GTP. For example, nucleotide exchange can be measured via the increase in fluorescence of protein-bound N-methylanthraniloyl (MANT)-GDP upon the addition of an excess amount of a non-hydrolyzable GTP analog such as guanosine-5'- [(P,y)-imido]triphosphate (GppNHp, sometimes also referred to as GMPPNP), when exchange is inhibited. See, e.g., Kanie and Jackson, Bio Protoc. 2018; 8(7): e2795, doi: 10.21769 / BioProtoc.2795. As another example, nucleotide exchange can be measured via the decrease in fluorescence of an incubated mixture of KRas protein-bound fluorophore-tagged GDP (e.g., Bodipy-GDP (e.g., EDA-GTP-DY-647P1)) and a compound provided herein, or a pharmaceutically acceptable salt thereof, followed by treatment with unlabeled GTP. In such an assay, an exchange of fluorophore-tagged GDP (e.g., Bodipy-GDP) for unlabeled GTP results in a reduced TR-FRET signal. As another example, nucleotide exchange can be measured via the increase in fluorescence of an incubated mixture of KRas protein-bound GDP and a compound provided herein, or a pharmaceutically acceptable salt thereof, followed by treatment with labeled GTP. In such an assay, an exchange of GDP for labeled GTP results in an increased FRET signal. See, e.g., International Publication No. WO 2020 / 085493 and U.S. Publication Nos. US 2021 / 0122764, US 2021 / 0269434, and US 2018 / 0334454. In some embodiments of nucleotide exchange assays, a guanine nucleotide exchange factor (e.g., S0S1) can be added to accelerate nucleotide exchange.

[0066] Inhibition of SOS 1 -catalyzed exchange of GDP for GTP on the KRas protein by compounds provided herein, or pharmaceutically acceptable salts thereof can be measured using methods known in the art (e.g., using one or more methods described herein (e.g., using methods described in Example B2 herein)). Additional examples of in vitro assays include assays that determine inhibition of the GTPase activity of KRas protein. In some embodiments, the potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be evaluated by its effect on GTPase activity (or lack thereof, as a decrease in GTPase activity is generally believed to be associated with aberrant signaling). For example, GTPase activity of a KRas protein can be measured using a phosphate assay system that continuously measures phosphate release. In some embodiments, a purine nucleoside phosphorylase-based (PNP) assay can be used to measure GTPase activity of a KRas protein. See, e.g., Hunter et al. Mol Cancer Res. 2015; 13(9):1325-35, doi: 10.1158 / 1541-7786.MCR-15-0203. In some embodiments, an enzyme-linked immunosorbent assay (ELISA) can be used to measure the effect of a compound provided herein, or a pharmaceutically acceptable salt thereof, on the GTPase activity of a KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)), for example, by detecting a change in the amount of GST-Ras-RBD that binds to the KRas protein following pull-down and antibody detection of the complex. See, e.g., US 2021 / 0179633. An exemplary SOS1-catalyzed nucleotide exchange assay protocol follows. GST-KRas G12R (1-169) loaded with GDP nucleotide is mixed with Anti-GST (Cisbio) antibody in assay buffer (20 mM HEPES pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.005% NP40, 1%DMSO) to produce a 1.5x solution. 10 µL of the 1.5x KRas-Ab solution is added to wells of ablack, low-volume 384-well assay plate. Compounds provided herein, or pharmaceutically acceptable salts thereof, are added to wells using acoustic transfer technology. A 10-point dose response of each compound is performed with a 30 µM top dose. The KRas / Ab-compound mixture is incubated 1 hour at room temperature. A 3x solution of SOS1 (564-1049) and EDA- GTP-DY-647P1 (Jena Bioscience) is prepared in assay buffer.5 µL of the SOS1-labeled GTP solution is added to the wells to initiate the nucleotide exchange reaction. The final concentration of KRas G12R and SOS1 are 10 nM and 200 nM, respectively. Time resolved fluorescence is read on a PHERAstar plate reader equipped with a filter module with excitation = 337 nm and emission 1 = 620 nm, emission 2 = 665 nm. The HTRF signal is calculated as the ratio of fluorescence intensity [emission 665 nm] / [emission 620 nm]. IC50values are calculated using a four-parameter, variable response sigmoidal dose response curve fit in Graphpad Prism software. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits SOS1-catalyzed exchange of GDP for GTP on the KRas protein with an IC50 of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compound inhibits SOS1-catalyzed exchange of GDP for GTP on the KRas protein with an IC50 of less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM, less than 0.1 nM, or less than 0.01 nM). For example, the compound can inhibit SOS1-catalyzed exchange of GDP for GTP on the KRas protein with an IC50 of 0.001 nM to 500 nM, 0.005 nM to 100 nM, 0.025 nM to 100 nM, 0.1 nM to 50 nM, or 0.1 nM to 10 nM. Additional assays for evaluating the potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, can also include, for example, a RAF kinase interaction assay. Such assays can be used to measure the affinity of KRas:nucleotide complexes for the Ras Binding Domain (RBD) of a RAF protein kinase (e.g., as impacted by a compound provided herein, or a pharmaceutically acceptable salt thereof). For example, FLAG tagged KRas protein can be preloaded with the GTP analog GppNHp and then incubated with biotinylated Raf-RBD to form complexes. A competition assay can then be performed by adding untagged KRas protein preloaded with GppNHp, which had been preloaded with various test molecules, over a range of concentrations. The proximity-dependent signal after addition of streptavidin donor and anti-flag acceptor beads (e.g., ALPHASCREEN® beads)can be measured to determine the affinity of the KRas protein for the Raf kinase. See, e.g.,Hunter et al. Mol Cancer Res. 2015; 13(9):1325-35, doi: 10.1158 / 1541-7786.MCR-15-0203; Lim et al. Angew Chem Int Ed Engl.2014; 53(1): 199–204, doi: 10.1002 / anie.201307387; and Durrant, et al. Molecular Cancer Therapeutics 20.9 (2021): 1743-1754, doi: 10.1158 / 1535- 7163.MCT-21-0175. As another example, for compounds provided herein, or pharmaceutically acceptable salts thereof, that may bind selectively to the GTP-bound state, His-tagged KRas protein can be preloaded with the GTP analog GppNHp and then incubated with a compound provided herein, or a pharmaceutically acceptable salt thereof, to form complexes. A competition assay can then be performed by adding Raf-RBD. The proximity-dependent signal after addition of Alpha detection reagents, compared to the signal from the same experiment using GDP instead of GppNHP, can be used to determine an IC50value. See, e.g., International Publication No. WO 2021 / 085653. It will be understood that in many cases, tagging technologies (e.g., FLAG tag, His tag, biotinylation) may be altered in an assay by one of skill in the art. In some embodiments, a RAF kinase interaction assay can be coupled with a nucleotide exchange assay; for example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be incubated with a KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) and GDP, then GTP (and optionally, a GEF such as SOS1) can be introduced. Then, RAF (e.g., cRAF) acceptor beads (e.g., GST-tagged acceptor beads) can be incubated with the KRas mixture, followed by introduction of donor beads (e.g., glutathione donor beads) and measurement using ALPHASCREEN® technology. As an alternative to ALPHASCREEN® technology, any appropriate FRET pair can be used to perform homogenous time resolved fluorescence. See, e.g., U.S. Publication Nos. US 2018 / 0334454 and US 2021 / 0230142. Another exemplary assay to measure the affinity of KRas:nucleotide complex for a RBD is to incubate cells with a compound provided herein, or a pharmaceutically acceptable salt thereof, lyse the cells, then pull down non-RBD-bound KRas using an immobilized RBD. See, e.g., U.S. Publication No. US 2019 / 0233440. As another example, the effect of a compound provided herein, or a pharmaceutically acceptable salt thereof, on the interaction between KRas and Raf-RBD can be evaluated using HiBiT and / or NANOBIT™ technology, wherein two parts of an enzyme are fused to or inserted into two proteins of interest (e.g., KRas and Raf-RBD); when the two proteins of interest are in proximity, the two parts of the enzyme complement each other to complete an enzyme that has signaling activity (e.g., that produces luminescence). In some such assays, the affinity of thetwo parts of the enzyme can be tuned, for example, to reduce or eliminate signal based onproximity driven by the two parts of the enzyme. See, e.g., Schwinn, et al. ACS Chemical Biology 13.2 (2018): 467-474, doi: 10.1021 / acschembio.7b00549. Similarly, the effect of a compound provided herein, or a pharmaceutically acceptable salt thereof, on the interaction between KRas and Raf-RBD can be evaluated using NANOBRET™ technology, wherein two parts of signaling system (e.g., a protein and a ligand) are fused to or inserted into two proteins of interest (e.g., KRas and Raf-RBD); when the two proteins of interest are in proximity, the two parts of the signaling system have signaling activity (e.g., producing fluorescence). See, e.g., Durrant, et al. Molecular Cancer Therapeutics 20.9 (2021): 1743-1754, doi: 10.1158 / 1535-7163.MCT-21-0175. In some embodiments, a RAF kinase interaction assay can be used to determine if a compound provided herein, or a pharmaceutically acceptable salt thereof, is selective for a KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) in the GDP-bound state or the GTP-bound state. Inhibition of the interaction between the KRas protein and Raf-RBD by compounds provided herein, or pharmaceutically acceptable salts thereof, can be measured using methods known in the art (e.g., using one or more methods described herein (e.g., using methods described in Example B3 or Example B4 herein)). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, modulates the interaction between the KRas protein and one or more Raf proteins. In some embodiments, the compound inhibits the interaction between the KRas protein and Raf-RBD with an IC50 of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compound inhibits the interaction between the KRas protein and Raf-RBD with an IC50 of less than 200 nM (e.g., e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM, less than 0.1 nM, or less than 0.01 nM). For example, the compound inhibits the interaction between the KRas protein and Raf- RBD with an IC50 from 0.001 nM to 500 nM, from 0.005 nM to 100 nM, from 0.025 nM to 100 nM, from 0.1 nM to 50 nM, or from 0.1 nM to 10 nM. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits the interaction between the KRas protein and Raf-RBD with an IC50 of less than 1 µM in the absence of cyclophilin A (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compounds inhibit the interaction between the KRas protein and Raf-RBD with an IC50 of less than 200 nM in the absence of cyclophilin A(e.g., e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1nM, less than 0.1 nM, or less than 0.01 nM). For example, the compounds inhibit the interaction between the KRas protein and Raf-RBD with an IC50 from 0.001 nM to 500 nM, from 0.005 nM to 100 nM, from 0.025 nM to 100 nM, from 0.1 nM to 50 nM, or from 0.1 nM to 10 nM in the absence of cyclophilin A. Another exemplary assay for evaluating the potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, includes measuring the phosphorylation of a downstream kinase, such as ERK (e.g., ERK1 and / or ERK2) or MEK. Such assays can be used to measure the inhibition of KRas signaling activity, for instance, in a cell line (e.g., A375, A427, A549, AGS, ASPC1, CAL62, CALU1, CAPAN1, CAPAN2, CFPAC1, GP2D, H358, H441, H460, H727, HCT116, HKA1, HPAC, HPAFII, HTK, HUPT3, KMS20, KP2, LS123, LS180, MIAPaCa-2, MKN1, NCI-H1993, NCI-H211, NCI-H424, NCI-H526, Panc02.03, Panc04.03, PATC50, PC9, PK8, PSN1, RKN, SW480, SW620, and / or TCCPAN2). For example, cells can be contacted with a compound provided herein, or a pharmaceutically acceptable salt thereof, for a period of time, then lysed or permeabilized, and total ERK or MEK and phosphoERK or phosphoMEK content can be determined (e.g., using antibodies, or a kit, such as Invitrogen InstantOne ERK1 / ERK2 (Phospho) [pT202 / pY204] / [pT185 / pY187] ELISA or MesoScale Discovery p / t ERK1 / 2). In some embodiments, multiple concentrations of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be used to construct a dose response curve. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit ERK phosphorylation in a cell line expressing a KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) with an IC50 of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compounds inhibit ERK phosphorylation in a cell line expressing a KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) with an IC50 of less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM). For example, the compounds can inhibit ERK phosphorylation in a cell line expressing a KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) with an IC50 from 0.1 nM to 100 nM, from 0.1 nM to 50 nM, from 1 nM to 50 nM, or from 1 nM to 20 nM. In some embodiments, a compound provided herein, or a pharmaceutically acceptablesalt thereof, can selectively inhibit one or more mutant KRas proteins over wild type KRas protein. The selectivity between wild type KRas protein and a mutant KRas protein as described herein can be measured using cellular proliferation assays where cell proliferation is dependent on signaling activity. For example, HEK293 cells transfected with a suitable version of wild type KRas, or HEK293 cells transfected with KRas containing one or more mutations as described herein (e.g., a G12D mutation, a G12R mutation, or a G12V mutation) can be used. Proliferation assays are performed at a range of inhibitor concentrations (e.g., 10 µM, 3 µM, 1.1 µM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and an EC50 is calculated. See also the assays described in International Publication Nos. WO 2021 / 120890; WO 2021 / 041671; and U.S. Publication Nos. US 2021 / 0130369; US 2021 / 0179633; US 2018 / 0334454; and US 2021 / 0122764. The pharmacokinetic parameters of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, for instance, a mouse model, a rat model, a dog model, or a nonhuman primate (e.g., cynomolgus monkey) model. Pharmacokinetics parameters, including clearance (CL), volume of distribution (Vd), maximum plasma concentration (Cmax), time of maximum plasma concentration (tmax), half- life (t1 / 2), area under the curve (AUC), and oral bioavailability (%F) can be calculated using, e.g., a non-compartmental model. In some embodiments, a reference compound (e.g., a first KRas inhibitor (e.g., MRTX1133)) may be used as a comparator. See, e.g., Example 3 (“Pharmacokinetic experiments in mice”) of International Publication No. WO 2023 / 098425. Certain pharmacokinetic parameters of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be evaluated in hepatocytes, such as in mouse, rat, dog, nonhuman primate (e.g., cynomolgus monkey), or human hepatocytes. Pharmacokinetics parameters, including clearance (CL) and half-life (t1 / 2), can be calculated. In some embodiments, a reference compound (e.g., a first KRas inhibitor (e.g., MRTX1133)) may be used as a comparator. See, e.g., Example VI (“Liver microsomal metabolically stability”) of International Publication No. WO 2023 / 284881. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof can be assessed for its pharmacokinetic parameters and / or its ability to cause toxicity (e.g., skin toxicity) in an animal model. For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be administered to an animal (e.g., rat), and body fluid (e.g., blood) samples can be taken at various time points and analyzed for the amountof the compound provided herein, or a pharmaceutically acceptable salt thereof, remaining. Asanother example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be administered to an animal (e.g., rat), and the skin of the animal can be assessed for redness, scaling, and / or thickness. An exemplary protocol follows. Rats (e.g., male RNU Nude Rat or Sprague-Dawley IGS rats, 6-8 weeks of age) are dosed with a compound provided herein, or a pharmaceutically acceptable salt thereof, once per day orally (e.g., via gavage) for several days (e.g., 14 days). The compound provided herein, or a pharmaceutically acceptable salt thereof, is administered to the rat at a given dose level (e.g., 1, 3, 5, 10, 25, 30, 50, or 100 mg / kg) in a solution or suspension formulation (e.g., 10% DMSO / 90% hydroxypropyl methylcellulose). The rats have access to food and water ad libitum. Blood samples (e.g., 200 µL per sample) from the rats are taken at predetermined intervals, such as 4, 8, or 24 hours after the first dose is administered. The blood is sampled via jugular vein puncture, then the blood samples (e.g., with K2EDTA as anticoagulant) are temporarily put on ice and then centrifuged (e.g., at 4 °C and 4600 RPM for 5 minutes) within 30 minutes. Plasma samples can be diluted 1:1 v / v with acidified phosphate buffer and are put on dry ice. After the completion of the last sampling, all samples are stored at -80 °C or analyzed in a short time following collection. The concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, measured in an acidified plasma sample (e.g., diluted 1:1 v / v with pH 3 phosphate buffer) can be determined (e.g., via LC / MS / MS). For example, an acidified plasma sample is prepared for analysis using protein precipitation (e.g., by the addition of acetonitrile), and an internal standard is spiked in at a known concentration. The spiked sample is mixed, centrifuged, and the supernatant is used in an LC / MS / MS method. The LC / MS / MS method uses an ACQUITY UPLC BEH C181.7 μm (2.1*50 mm) column with a first mobile phase of 5 mM NH4OAc (0.05% formic acid (FA) or 0.1% FA) and a second mobile phase of acetonitrile (0.1% FA). Multiple reaction monitoring is used to measure the analyte(s) of interest. Using the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, in the plasma sample, pharmacokinetic parameters of t1 / 2 (hr), tmax (hr), Cmax (ng / mL), AUClast (hr*ng / mL), AUCInf (hr*ng / mL), AUCExtr (%), MRTInf (hr), AUCInf / D (hr*kg*ng / mL / mg), F (%), are determined. The clinical signs, body weight and food consumption of the rats are tracked during dosing. The potential for skin rash is tracked intermittently before and during dosing using one or more methodologies. A skin scoring system is used to evaluate skin redness (erythema) orskin scaling on a gradation of 0-4. Thickness of the back skin is measured using a micrometer(MITUTOYO ABSOLUTE Digimatic Micrometer Series 227-211). For the back skin, thickness measurement is performed by doing a skin folding of the applied area between the thumb and index fingers followed by measuring with the micrometer. The mice are then sacrificed and assessed for any abnormalities. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be tested for its potency in inhibiting hERG potassium channels. The cardiac potassium channel hERG is responsible for a rapid delayed rectifier current (IKr) in human ventricle, and inhibition of IKr is the most common cause of cardiac action potential prolongation by non-cardiac drugs. Increased action potential duration causes prolongation of the QT interval that has been associated with a dangerous ventricular arrhythmia, torsade de pointes. There are several methods of testing hERG inhibition potency, including SyncroPatch hERG and manual patch clamp experiments. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is tested for its potency in inhibiting hERG potassium channels using a SyncroPatch hERG assay. For example, in some embodiments, solutions or suspension of a compound provided herein, or a pharmaceutically acceptable salt thereof, at several concentrations (0.30 μM, 1.00 μM, 3.00 μM, 10.00 μM and 30.00 μM) can be exposed to single CHO or HEK293 cells. The effect of the compound provided herein, or a pharmaceutically acceptable salt thereof, on the inhibition of hERG potassium channels can be measured in this system using an electrical pulse pattern, the data plotted, and an IC50 value calculated for the inhibition of hERG by the compound provided herein, or a pharmaceutically acceptable salt thereof. An exemplary protocol follows. hERG potassium channels are expressed in a Chinese Hamster Ovarian (CHO (Sophian Biosciences)) cell line that lacks endogenous IKr. See, e.g., Brown, Arthur M., and David Rampe. Pharmaceutical News 7.4 (2000): 15-20; Weirich, Jörg, and H. Antoni, Basic Research in Cardiology 93 (1998): s125-s132, doi: 10.1007 / s003950050236; Yap, Yee Guan, and A. J. Camm. Clinical & Experimental Allergy 29 (1999): 174-181, doi: 10.1046 / j.1365- 2222.1999.0290s3174.x; Haraguchi, Yuji, et al. BMC Pharmacology and Toxicology 16 (2015): 1-6, doi: 10.1186 / s40360-015-0042-9; and Walker, B. D., et al. British Journal of Pharmacology 127.1 (1999): 243-251, 10.1038 / sj.bjp.0702502. All chemicals used in solution preparations are purchased from a commercial supplier(e.g., Sigma-Aldrich) and are of ACS reagent grade purity or higher. Stock solutions of thecompound provided herein, or a pharmaceutically acceptable salt thereof, positive control compound(s), and reference substance(s) are prepared in dimethyl sulfoxide (DMSO) and stored frozen. Solutions of each tested compound provided herein, or a pharmaceutically acceptable salt thereof, positive control compound(s), and reference substance(s) are prepared fresh daily by diluting stock solutions into HEPES-buffered physiological saline solution (HB- PS; 140 mM NaCl, 4 mM KCl, 2.0 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 5 mM glucose, pH 7.4). Since previous results have shown that ≤ 0.3% DMSO does not affect channel current, all test and control solutions can contain up to 0.3% DMSO. In some embodiments, a positive control compound can be included in the experiment. In some such embodiments, the positive control compound can be amitriptyline (Sigma- Aldrich), for example, in a HB-PS and 0.3% DMSO solution. In some embodiments, a positive control compound can be included in the experiment. In some such embodiments, the positive control compound can be E-4031 (4ʹ-[[1-[2-(6- Methyl-2-pyridinyl)ethyl-4-piperidinyl]carbonyl]methanesulfonanilide, 2HCl) (Sigma- Aldrich), for example, in a HB-PS and 0.3% DMSO solution. If necessary, solutions are sonicated to facilitate dissolution. Visible precipitate observed during preparation or exposure of formulations to the test system is noted for reference. The effect of compounds provided herein, or a pharmaceutically acceptable salt thereof, is initially evaluated at 1 µM. Subsequent concentrations are evaluated based on the inhibition observed at this initial concentration. The CHO cells, which are at least two days after plating and more than 75% confluent, are used for experiments. Before testing, cells are harvested using TrypLE and resuspended in HB-PBS at room temperature. The HB-PBS and external solution (80 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 60 mM N-Methyl-D-glucamine (NMDG), 10 mM HEPES, and 5 mM glucose, pH 7.4) are prepared and stored up to 1 month. Voltage command protocol: From a holding potential of -80 mV, the voltage is first stepped to -50 mV for 80 ms for leak subtraction, and then stepped to +20 mV for 4800 ms to open hERG channels. After that, the voltage is stepped back down to -50 mV for 5000 ms, causing a "rebound" or tail current, which is measured and collected for data analysis. Finally, the voltage is stepped back to the holding potential (-80 mV, 1000 ms). This voltage command protocol is repeated every 20,000 msec. This command protocol is performed continuouslyduring the experiment.The hERG SyncroPatch assay is conducted at room temperature. The Setup, Prime Chip, Catch and Seal Cells, Amplifier Settings, Voltage and Application Protocols are established with Biomek Software (Nanion). A single cell per well is clamped with the formation of a gigaseal. On one side of the seal, the cell is bathed in external solution. On the opposite side, addition of 40 μL of the vehicle (e.g., HB-PBS) is applied, followed by a 300 s pause to create a baseline period. Then a dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, is added (40 μL), and the process is repeated for different concentrations. The exposure of a compound provided herein, or a pharmaceutically acceptable salt thereof, at each concentration is no less than 300 s. The recording for the whole process must pass quality control criteria (e.g., seal quality, rundown attributes) or the well is abandoned, and the compound is retested, all automatically set by exclusion criteria determined prior to experiment start. Five concentrations (0.30 μM, 1.00 μM, 3.00 μM, 10.00 μM, and 30.00 μM) are tested for each tested compound provided herein, or a pharmaceutically acceptable salt thereof. A minimum of 2 replicates per concentration are obtained. Data analysis is carried out using DataControl, Excel 2013 (Microsoft) and GraphPad Prism 5.0. Within each well recording, a percent of control values is calculated for each concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, with current response based on peak current in presence of a reference compound (e.g., E- 4031) (current response / peak current) ×100%. The Dose-Response curves are fit to the standard Hill equation as shown below: where X is the logarithm of concentration, Ipost compound / Ipre compound is the normalized peak current amplitude, Top is 1, and Bottom is equal to 0. Curve-fitting and IC50 calculations are performed by GraphPad Prism 5.0. If the inhibition obtained at the lowest concentration tested is over 50%, or at the highest concentration tested is less than 50%, the IC50 is reported as less than the lowest concentration, or higher than the highest concentration, respectively. In some embodiments, a positive control can be included in the experiment. In some such embodiments, the positive control compound can be cisapride (Tocris Bioscience), for example, in a 0.3% DMSO solution. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is not a hERG inhibitor. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC50 of greater than 60 nM (e.g., greater than 100 nM, 300 nM, 500 nM, 1 µM, 3 µM, 5 µM, 10 µM, 20 µM, or 30 µM). For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC50 of greater than 500 nM (e.g., 1 µM, 3 µM, 5 µM, 10 µM, 20 µM, or 30 µM). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC50 of greater than 1 µM (e.g., greater than 3 µM, 5 µM, 10 µM, 20 µM, or 30 µM). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC50 of greater than 10 µM (e.g., greater than 20 µM or 30 µM). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC50 of greater than 30 µM. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be assessed for its stability in hepatocytes (e.g., human hepatocytes). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is assessed for stability in human hepatocytes, yielding a value for intrinsic hepatocyte clearance (CLint(hep)), from which intrinsic liver clearance (CLint (liver)) can be estimated. For example, human hepatocytes can be incubated with a compound provided herein, or a pharmaceutically acceptable salt thereof, and aliquots at various time points can be removed and analyzed for the amount of the compound provided herein, or a pharmaceutically acceptable salt thereof, remaining. First-order kinetics equations can then be used to determine half-life (t1 / 2) and CLint(hep). An exemplary protocol follows. A 1000X stock solution of a compound provided herein is prepared to a final concentration (e.g., 1 mM in DMSO). Similarly, 1000X stock solution(s) of positive control compound(s) (e.g., 7-ethoxycoumarin and / or 7-hydroxycoumarin) is prepared to a final concentration (e.g., 3 mM in DMSO). 100X stock solutions are then made by dilution with acetonitrile. To prepare a cell suspension (e.g., at 0.5 × 106cells / mL), cryopreserved hepatocytes (e.g., human hepatocytes) are thawed (e.g., in Williams’ Medium E containing 5% fetal bovine serum and 30% Percoll solution and other supplements), isolated, and suspended in incubation medium (e.g., Williams’ Medium E (no phenol red) containing 2 mM L-Glutamine and 25 mM HEPES), then diluted with pre-warmed incubation medium to 0.5 × 106cells / mL. Pre-warmed cell suspension (e.g., 198 μL) is added to a well in a testing plate (e.g., a 96-well plate). A quenching plate is prepared by transferring stop solution (e.g., acetonitrile containingtolbutamide and labetalol as internal standards) (e.g., 125 μL) to a set of pre-labeled 96-wellplates, with one quenching plate for T0 and one plate per time point to be tested. To begin the experiment, 2 μL of the 100X dosing solution of the compound provided herein, or a pharmaceutically acceptable salt thereof, or 2 μL of the 100X dosing solution of a control compound is added to a well of the testing plate. This is performed in duplicate. For T0 samples, the plate is mixed to achieve a homogenous suspension (e.g., mixed for about 1 min), then an aliquot (e.g., 25 μL) of each sample on the testing plates is immediately transferred into a well of a quenching plate containing ice-cold stop solution (e.g., 125 μL), followed by mixing. The testing plate is incubated (e.g., at 37 °C in a 95% humidified incubator at 5% CO2 with constant shaking) to start the reactions. At each time point of 15, 30, 60 and 90 minutes, the plate is mixed and then an aliquot of each sample (e.g., 25 μL) is transferred to a well in a quenching plate containing ice-cold stop solution (e.g., 125 μL) followed by mixing. Medium Control (MC) sample plates (at least one for the first and last time point; additional time points are optional) are prepared in the same way as the testing plate except that incubation medium is used instead of cell suspension. At each corresponding time point as the testing plate, the reactions are stopped by removing the corresponding MC plate from the incubator and mixing with ice-cold stop solution (e.g., 125 μL). Immediately after addition of stop solution to each plate, the plate is immediately vortexed (e.g., on a plate shaker at 600 RPM for 10 minutes). Then the plate is centrifuged (e.g., at 3220 x g for 20 min at 4 °C). After centrifugation, supernatant from the plate (e.g., 80 μL / well) is transferred to another plate (e.g., a corresponding 96-well plate) which contains ultra pure water (240 μL per well) according to the plate map. This analytical plate is sealed and stored at 4 °C until LC- MS / MS analysis. The percent remaining of the compound provided herein, or a pharmaceutically acceptable salt thereof, after incubation is calculated by the following equations. The equation of first order kinetics is used to calculate t1 / 2 and CLint: Equation of first order kinetics: CLint (liver) = CLint (hep)* liver weight (g / kg body weight) x hepatocellularity Table 2 shows reference values for liver weight, liver blood flow, and hepatocellularity for various species. See, e.g., Sohlenius-Sternbeck, Anna-Karin Toxicology in vitro 20.8 (2006): 1582-1586, doi: 10.1016 / j.tiv.2006.06.003; Davies, Brian, and Tim Morris Pharmaceutical Research 10.7 (1993): 1093-1095; and Obach, R. Scott, et al. Journal of Pharmacology and Experimental Therapeutics 283.1 (1997): 46-58. Table 2. Table 3 shows floor and ceiling values for the described assay. For example, if CLint (hep) falls below 6.4 µL / min / 106cells, an experimental value may not be able to be accurately determined. Table 3. Cut off Value in Hepatocyte Stability Assay In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof can be assessed for its stability in simulated human fluids (e.g., simulated gastric fluid or simulated intestinal fluid). For example, a compound provided herein, or a pharmaceutically acceptable salt thereof can be incubated in a simulated human fluid (e.g., simulated gastric fluid (e.g., fed or fasted state) or simulated intestinal fluid (e.g., fed or fasted state)), and aliquots at various time points can be removed and analyzed for the amount of the compound provided herein, or a pharmaceutically acceptable salt thereof, remaining. An exemplary protocol follows. Fasted state simulated gastric fluid (FaSSGF) is prepared (0.02 mM lecithin, 0.08 mM sodium taurocholate, 0.1 mg / mL pepsin, 34.2 mM sodium chloride, 25.1 mM hydrochloric acid, and deionized water, pH 1.6 ± 0.05). A working solution of a compound provided herein, or a pharmaceutically acceptable salt thereof is prepared (e.g., 2 µM in DMSO). Similarly, a working solution of a control compound (e.g., omeprazole) is prepared (e.g. 2 µM in DMSO). An aliquot (e.g., 2 µL) of either working solution is transferred to a deep-well plate, one plate per time condition to be tested (e.g., 0 minutes, 60 minutes, 120 minutes, 360 minutes, and 1440 minutes). To the plates corresponding to the later time points (e.g., T60, T120, T360, and T1440), an aliquot (e.g., 198 µL) of the FaSSGF is added, and the samples adjusted to have a final DMSO concentration of 1%. The plates are incubated at 37 °C with shaking at 600 RPM for the appointed amount of time. At the end of the appointed amount of time, the reaction is stopped by the addition of stop solution (e.g., 400 µL), and the resulting solution is mixed. A portion of this mixture (e.g., 200 µL) is removed and mixed with a further addition of stop solution (e.g., 400 µL). Similarly, the T0 samples are prepared by adding stop solution (e.g., 400 µL), mixing, then adding the FaSSGF (e.g., 200 µL) and mixing again. The T0 samples are further prepared by removing a portion of this mixture (e.g., 200 µL) and mixing with a further addition of stop solution (e.g., 400 µL). Following the second addition of stop solution at each time point, the samples are centrifuged (e.g., at 4000 RPM at 4 °C for 20 min). A portion of the supernatant (e.g., 60 µL)is removed and mixed with purified water (e.g., 180 µL) for LC-MS / MS analysis. The LC-MS / MS analysis is performed using an ACQUITY UPLC BEH C181.7 µm 2.1 * 50 mm (Part No.186002350) column, with a mobile phase A (0.1% formic acid in water) and a mobile phase B (0.1% formic acid in acetonitrile). The percent remaining of the compound provided herein, or a pharmaceutically acceptable salt thereof, at each incubation time is calculated based on peak area ratio of analyte to internal standard from the LC-MS / MS analysis using the equation below. Where PAR is the peak area ratio, the ratio of peak area of the analyte of interest and an internal standard; PART is the peak area ratio at the appointed time; and PAR0 is the peak area ratio at T0. Fed state simulated intestinal fluid (FeSSIF) is prepared (0.282% (w / v) lecithin, 0.806% (w / v) sodium taurocholate, 0.865% (w / v) acetic acid, 1.52% (w / v) potassium chloride, and deionized water, pH 5.0 ± 0.05). A working solution of a compound provided herein, or a pharmaceutically acceptable salt thereof is prepared (e.g. 2 µM in DMSO). Similarly, a working solution of a control compound (e.g., chlorambucil) is prepared (e.g. 2 µM in DMSO). An aliquot (e.g., 2 µL) of either working solution is transferred to a deep-well plate, one plate per time condition to be tested (e.g., 0 minutes, 60 minutes, 120 minutes, 360 minutes, and 1440 minutes). To the plates corresponding to the later time points (e.g., T60, T120, T360, and T1440), an aliquot (e.g., 198 µL) of the FeSSIF is added, and the samples are adjusted to have a final DMSO concentration of 1%. The plates are incubated at 37 °C with shaking at 600 RPM for the appointed amount of time. At the end of the appointed amount of time, the reaction is stopped by the addition of stop solution (e.g., 400 µL), and the resulting solution is mixed. A portion of this mixture (e.g., 200 µL) is removed and mixed with a further addition of stop solution (e.g., 400 µL). Similarly, the T0 samples are prepared by adding stop solution (e.g., 400 µL), mixing, then adding the FeSSIF (e.g., 200 µL) and mixing again. The T0 samples are further prepared by removing a portion of this mixture (e.g., 200 µL) and mixing with a further addition of stop solution (e.g., 400 µL). Following the second addition of stop solution at each time point, the samples are centrifuged (e.g., at 4000 RPM at 4 °C for 20 min). A portion of the supernatant (e.g., 60 µL) is removedand mixed with purified water (e.g., 180 µL) for LC-MS / MS analysis. The LC-MS / MS analysisis performed using an ACQUITY UPLC HSS T31.8 µm 2.1 * 50 mm, (Part No.186003538) column, with a mobile phase A (0.1% formic acid in water) and a mobile phase B (0.1% formic acid in acetonitrile). The percent remaining of the compound provided herein, or a pharmaceutically acceptable salt thereof, at each incubation time is calculated based on peak area ratio of analyte to internal standard from the LC-MS / MS analysis using the equation below. Where PAR is the peak area ratio, the ratio of peak area of the analyte of interest and an internal standard; PART is the peak area ratio at the appointed time; and PAR0 is the peak area ratio at T0. Fasted state simulated intestinal fluid (FaSSIF) is prepared (0.056% (w / v) lecithin, 0.161% (w / v) sodium taurocholate, 0.39% (w / v) monobasic potassium phosphate, 0.77% (w / v) potassium chloride, and deionized water, pH 6.5 ± 0.05). A working solution of a compound provided herein, or a pharmaceutically acceptable salt thereof is prepared (e.g. 2 µM in DMSO). Similarly, a working solution of a control compound (e.g., chlorambucil) is prepared (e.g. 2 µM in DMSO). An aliquot (e.g., 2 µL) of either working solution is transferred to a deep-well plate, one plate per time condition to be tested (e.g., 0 minutes, 60 minutes, 120 minutes, 360 minutes, and 1440 minutes). To the plates corresponding to the later time points (e.g., T60, T120, T360, and T1440), an aliquot (e.g., 198 µL) of the FaSSIF is added, and the samples adjusted to have a final DMSO concentration of 1%. The plates are incubated at 37 °C with shaking at 600 RPM for the appointed amount of time. At the end of the appointed amount of time, the reaction is stopped by the addition of stop solution (e.g., 400 µL), and the resulting solution is mixed. A portion of this mixture (e.g., 200 µL) is removed and mixed with a further addition of stop solution (e.g., 400 µL). Similarly, the T0 samples are prepared by adding stop solution (e.g., 400 µL), mixing, then adding the FaSSIF (e.g., 200 µL) and mixing again. The T0 samples are further prepared by removing a portion of this mixture (e.g., 200 µL) and mixing with a further addition of stop solution (e.g., 400 µL). Following the second addition of stop solution at each time point, the samples are centrifuged (e.g., at 4000 RPM at 4 °C for 20 min). A portion of the supernatant (e.g., 60 µL) is removedand mixed with purified water (e.g., 180 µL) for LC-MS / MS analysis. The LC-MS / MS analysisis performed using an ACQUITY UPLC HSS T31.8 µm 2.1 * 50mm, (Part No.186003538) column, with a mobile phase A (0.1% formic acid in water) and a mobile phase B (0.1% formic acid in acetonitrile). The percent remaining of the compound provided herein, or a pharmaceutically acceptable salt thereof, at each incubation time is calculated based on peak area ratio of analyte to internal standard from the LC-MS / MS analysis using the equation below. Where PAR is the peak area ratio, the ratio of peak area of the analyte of interest and an internal standard; PART is the peak area ratio at the appointed time; and PAR0 is the peak area ratio at T0. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof can be assessed for its solubility in simulated human fluids (e.g., simulated gastric fluid or simulated intestinal fluid) or aqueous solutions (eg water or pH 3.0 citrate buffer). For example, a compound provided herein, or a pharmaceutically acceptable salt thereof can be incubated in a simulated human fluid (e.g., simulated gastric fluid or simulated intestinal fluid) or an aqueous solution (e.g., water or pH 3.0 citrate buffer). For example, a compound provided herein, or a pharmaceutically acceptable salt thereof can be incubated in a simulated human fluid (e.g., simulated gastric fluid (e.g., fed or fasted state) or simulated intestinal fluid (e.g., fed or fasted state)) or an aqueous solution (e.g., water or pH 3.0 citrate buffer) , and aliquots at various time points can be removed and analyzed for the amount of the compound provided herein, or a pharmaceutically acceptable salt thereof, remaining. An exemplary protocol follows. Fasted state simulated gastric fluid (FaSSGF) is prepared (0.02 mM lecithin, 0.08 mM sodium taurocholate, 0.1 mg / mL pepsin, 34.2 mM sodium chloride, 25.1 mM hydrochloric acid, and deionized water, pH 1.6 ± 0.05). The FaSSGF is equilibrated at 37 °C. Fed state simulated intestinal fluid (FeSSIF) is prepared (0.282% (w / v) lecithin, 0.806% (w / v) sodium taurocholate, 0.865% (w / v) acetic acid, 1.52% (w / v) potassium chloride, and deionized water, pH 5.0 ± 0.05). The FeSSIF is equilibrated at 37 °C. Fasted state simulated intestinal fluid (FaSSIF) is prepared (0.056% (w / v) lecithin, 0.161% (w / v) sodium taurocholate, 0.39% (w / v) monobasic potassium phosphate, 0.77% (w / v) potassium chloride, and deionized water, pH 6.5 ± 0.05). The FaSSIF is equilibrated at 37 °C. Citrate buffer is prepared (100 mM sodium citrate, pH 3.07). Solubility in citrate bufferand water is determined at room temperature.A compound provided herein, or a pharmaceutically acceptable salt thereof, (e.g., 6 mg) is combined with FaSSGF, FeSSIF, FaSSIF, citrate buffer, or water (e.g., 3 mL). The vials are stirred (at 37 °C for simulated human fluid or room temperature for citrate buffer and water), and at 30 minutes, 3 hours, and 24 hours, an aliquot is removed and filtered (e.g., using a 0.2 µm syringe filter), then analyzed with HPLC (e.g., HPLC is conducted using an Agilent 1290 Infinity LC System equipped with a VWD (Variable Wavelength Detector) and an Agilent 1260 ELSD (Evaporative Light Scattering Detector). Flow rate range of the instrument is 0.2– 5.0 mL / min, operating pressure range is 0–1300 bar, temperature range is 5 °C above ambient to 60 °C, and wavelength range is 190–600 nm; mobile phase A of 0.1% trifluoroacetic acid (TFA) in distilled water; mobile phase B of 0.1% TFA in acetonitrile; column Waters Acuity UPLC CSH C-18, 2.1 x 150 mm, 1.7 µm) to determine the dissolved concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the kinetic solubility of a compound provided herein, or a pharmaceutically acceptable salt thereof can be determined. In some embodiments, the kinetic solubility of a compound provided herein, or a pharmaceutically acceptable salt thereof, is determined at a physiologically relevant pH (e.g., 7.4). For example, a stock solution of a compound provided herein, or a pharmaceutically acceptable salt thereof, can be prepared, and any solids separated (e.g., by centrifugation). The resulting mixture (e.g., supernatant) can be subsequently filtered, and the dissolved concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, can be determined via liquid chromatography. An exemplary protocol follows. A stock solution (e.g., a 200 µM stock solution) of a compound provided herein, or a pharmaceutically acceptable salt thereof, is diluted with buffer (e.g., phosphate buffer, pH 7.4) (e.g., 10 µL of the stock solution with 490 uL of the buffer). The diluted sample is vortexed for at least two minutes and then shaken (e.g., at 800 RPM) on a shaker for 24 hours at room temperature. The sample is then centrifuged (e.g., at 4000 RPM for 10 minutes at 25 °C). The supernatant is filtered (e.g., in a plate format by centrifugation for 5 minutes), and the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, is determined by an LC-UV system (e.g., with a mobile phase A of 0.1% TFA and 5 mM NH4OAc in water / MeCN (v:v, 95:5) and a mobile phase B of 0.1% TFA and 5 mM NH4OAc in water / MeCN (v:v, 5:95)). In some embodiments, the chemical stability of a compound provided herein, or apharmaceutically acceptable salt thereof, can be determined. For example, an aliquot of a solution of a compound provided herein, or a pharmaceutically acceptable salt thereof, is added to an acidic solution (e.g., pH 1.5 or pH 5) and incubated for a period of time. A sample of the incubation mixture can be taken, and the remaining amount of the compound provided herein, or a pharmaceutically acceptable salt thereof, can be determined via liquid chromatography- mass spectrometry (LCMS) and / or nuclear magnetic resonance (NMR). Exemplary protocols follow. To prepare a pH 1.5 HCl solution, 1 N hydrogen chloride solution (1 mL) is added to deionized water (99 mL) and stirred for 5 minutes. The pH is adjusted, while stirring and monitoring by pH meter, to the desired pH using concentrated hydrochloric acid. To prepare a pH 5 HCl solution, 1 N hydrogen chloride solution (1 mL) is added to deionized water. (99 mL) and stirred for 5 minutes. The pH is adjusted, while stirring and monitoring by pH meter, to the desired pH using 1N sodium hydroxide. A portion (e.g., 10 µL) of a stock solution (e.g., 10 mM) of a compound provided herein, or a pharmaceutically acceptable salt thereof, is added the HCl solution at pH of 1.5 or pH 5 (e.g., 90 µL) in separate vials denoted for each timepoint (e.g., T0, T30m, T60m, T90m, T240m, and T3d). The samples are incubated at 37 °C for the desired timeframe and then immediately neutralized with 10 µL of HEPES buffer to pH of 7. The T0 timepoint is neutralized immediately upon preparation of the sample. The samples are then analyzed by LCMS to determine the amount of the compound provided herein, or a pharmaceutically acceptable salt thereof, remaining. To prepare pH 1.5 and pH 5 DCl solutions, deuterium oxide (5 mL) is adjusted to the desired pH of 1.5 or 5, monitoring by pH meter, using 20% DCl in D2O and stirred at room temperature for 5 minutes. A compound provided herein, or a pharmaceutically acceptable salt thereof, is dissolved in the pH 1.5 or pH 5 DCl solution to achieve a 3 mg / mL solution. The resulting solution is incubated at 37 °C to the desired timepoint (T0, T90m, T240m, T5d) then an aliquot (e.g., 0.3 mL) is taken and analyzed by1H NMR to determine the amount of the compound provided herein, or a pharmaceutically acceptable salt thereof, remaining and / or to determine the presence of a compound that is not the compound provided herein. At the same timepoints, 30 µL of the solution was neutralized with HEPES buffer to pH of 7 and analyzed by LCMS to determine the amount of the compound provided herein, or a pharmaceutically acceptable salt thereof,remaining and / or to determine the presence of a compound that is not the compound providedherein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be assessed as a potential substrate for efflux (e.g., as a potential substrate for p-glycoprotein (P-gp)). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, is assessed as a substrate for efflux using efflux pump-expressing cells, such as MDCKII cells. For example, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be applied to one side of a cell monolayer, incubated, and then the recovery of the compound on the opposite side of the cell monolayer can be measured to determine the permeability of the compound to the cell monolayer in that direction. An exemplary protocol follows. MDCKⅡ cells (e.g., obtained from the Netherlands Cancer Institute) are seeded onto polycarbonate membranes (PC) in 96-well insert systems at 2.33 x 105cells / cm2for 4-7 days for confluent cell monolayer formation. A solution of a compound provided herein, or a pharmaceutically acceptable salt thereof, is diluted with transport buffer (e.g., Hank’s Balanced Salt Solution (HBSS) with 10 mM HEPES, pH 7.4) from a DMSO stock solution to a final concentration (e.g., of 2.00 µM (DMSO < 1%)) and applied to the apical or basolateral side of the cell monolayer. Permeation of the compound provided herein, or a pharmaceutically acceptable salt thereof, from the A to B direction and the B to A direction is determined in duplicate. For control data, digoxin is tested at 10.0 μM from A to B direction or B to A direction, while nadolol and metoprolol are tested (e.g., at 2.00 μM) in A to B direction in duplicate. The plate is incubated (e.g., for 2.5 hours in an incubator at 37.0 °C, with 5% CO2 at saturated humidity without shaking). The efflux ratio of each compound is then determined. The compound provided herein, or pharmaceutically acceptable salt thereof, and control compounds are quantified by LC-MS / MS analysis based on the peak area ratio of analyte / internal standard (IS). The apparent permeability coefficient Papp (cm / s) is calculated using the equation: Papp = (dCr / dt) x Vr / (A x C0) Where dCr / dt is the cumulative concentration of compound in the receiver chamber as a function of time; Vr is the solution volume in the receiver chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side); A is the surface area for the transport (e.g., 0.143 cm2for the area of the monolayer); and C0 is the initial concentration in the donor chamber. The efflux ratio was calculated using the equation: Efflux Ratio = Papp (BA) / Papp (AB)Without being bound by any particular theory, it is believed that the Efflux Ratio indicates how efficiently a tested compound is removed from the tested cell. Percent recovery was calculated using the equation: %Solution Recovery = 100 x [(Vr x Cr) + (Vd x Cd)] / (Vd x C0) Where Vd is the volume in the donor chamber (0.075 mL on the apical side, 0.25 mL on the basolateral side); Cd and Cr are the final concentrations of transport compound in donor and receiver chambers, respectively. Without being bound by any particular theory, it is believed that the percent recovery is informative of whether the tested compound could have a solubility issue, is stuck in the cellular membrane, metabolized, or a combination thereof. After the transport assay, a Lucifer yellow rejection assay is used to determine the cell monolayer integrity (e.g., to determine whether the cell monolayer from the efflux study is intact). Buffers are removed from both apical and basolateral chambers, followed by the addition of lucifer yellow dye (e.g., 75 µL of a 100 µM solution in transport buffer) and transport buffer (e.g., 250 µL) in the apical and basolateral chambers, respectively. The plate is incubated (e.g., for 30 minutes at 37 °C with 5% CO2 and 95% relative humidity without shaking). After incubation, a lucifer yellow (e.g., 20 µL) sample is taken from the apical side, and transport buffer (e.g., 60 µL) is added. A lucifer yellow sample (e.g., 80 µL) is taken from the basolateral side. The relative fluorescence unit (RFU) of lucifer yellow is measured at 425 / 528 nm (excitation / emission) with an Envision plate reader. Percent of lucifer yellow in the basolateral well is calculated using the equation: where RFUApical and RFUBasolateral are the relative fluorescence unit values of lucifer yellow in the apical and basolateral wells, respectively; VApical and VBasolateral are the volume of apical and basolateral wells (0.075 mL and 0.25 mL), respectively. The %Lucifer Yellow should be less than 2.0 to indicate an intact cell monolayer. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can be assessed for formation of metabolites. For example, a compound provided herein, or a pharmaceutically acceptable salt thereof can be incubated with hepatocytes (e.g., rat hepatocytes, dog hepatocytes, or human hepatocytes), and at the end of incubation, the sample can be analyzed for the amount of the compound provided herein, or a pharmaceutically acceptable salt thereof, remaining, as well as for the amount of any metabolite from Phase 1 metabolism, Phase 2 metabolism, or a combination thereof. An exemplary protocol follows. A working solution of a compound provided herein, or a pharmaceutically acceptable salt thereof, is prepared (e.g. 10 µM in DMSO). Similarly, a working solution of a control compound (e.g., 7-ethoxycoumarin) is prepared (e.g. 30 µM in DMSO). An aliquot of each working solution of a compound provided herein, or a pharmaceutically acceptable salt thereof, or the working solution of the control compound is incubated with hepatocytes (e.g., 1.0 × 106cells / mL) (e.g., rat hepatocytes, dog hepatocytes, or human hepatocytes) in incubation medium (e.g., Williams’ Medium E with HEPES (e.g., 5.958 g / L) glutamine (e.g., 0.292 g / L)), to a total volume of 200 µL, for 0 minutes or 120 minutes at 37 °C in 5% CO2 / saturated humidity. After incubation, MeCN (800 µL) is added to each sample, and the samples are centrifuged. The supernatants are dried under N2 gas, and the residue is reconstituted (e.g., with 200 µL of 10% MeCN with 0.1% FA). The reconstituted residue of the compound provided herein, or a pharmaceutically acceptable salt thereof, is subjected to LC-UV-MS (e.g., LC with a Mobile Phase A of 0.1% FA and 2 mM NH4FA in H2O / MeCN (v : v = 95 : 5), a Mobile Phase B of 0.1% FA and 2 mM NH4FA in H2O / MeCN (v : v = 5 : 95) using an ACQUITY UPLC® HSS T32.1 × 100 mm, 1.8 µm column; a UV detector with λ: 190~500 nm; and MS with a Xevo G2 Q-TOF instrument in ESI+mode with a scanning mode of MSE / MS2). The reconstituted residue of the control compound is subjected to LC-UV-MS (e.g., LC with a Mobile Phase A of 0.1% FA in H2O, a Mobile Phase B of 0.1% FA in MeCN using an ACQUITY UPLC® HSS T32.1 × 100 mm, 1.8 µm column; a UV detector with λ: 190~500 nm; and MS with a Xevo G2 Q-TOF instrument in ESI+mode with a scanning mode of MSE). The data is then analyzed to identify and, if desired, quantify the metabolites. In some embodiments, a compounds provide herein, or a pharmaceutically acceptable salt thereof, can exhibit potent and selective inhibition of a dysregulated KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can selectively inhibit a dysregulated KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) over another GTPase ornon-GTPase target. In some embodiments, a compound provided herein can exhibit nanomolarpotency against a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) with minimal activity against related GTPases (e.g., wild-type NRas protein, and / or wild-type HRas protein). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of a related GTPase (e.g., wild-type NRas protein, and / or wild-type HRas protein). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25- fold, 50-fold, or 100-fold greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of a related GTPase (e.g., wild-type NRas protein, and / or wild-type HRas protein). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit up to 10000-fold greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of a related GTPase (e.g., wild-type NRas protein, and / or wild-type HRas protein). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of a related GTPase (e.g., wild-type NRas protein, and / or wild-type HRas protein). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of a related GTPase (e.g., wild-type NRas protein,and / or wild-type HRas protein). In some embodiments, a compound provided herein, or apharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1000-fold greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative inhibition of a related GTPase (e.g., wild-type NRas protein, and / or wild-type HRas protein). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10000-fold greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of a related GTPase (e.g., wild-type NRas protein, and / or wild-type HRas protein). In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can exhibit potent and selective inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can selectively inhibit a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) over another GTPase or non-GTPase target. In some embodiments, the compounds provided herein can exhibit nanomolar potency against a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) with minimal activity against related GTPases (e.g., wild-type KRas protein, wild-type NRas protein, and / or wild-type HRas protein). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild-type KRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12Rmutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / ora KRas G12V mutant protein)) relative to inhibition of wild-type KRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit up to 10000-fold greater inhibition of a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild-type KRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild-type KRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild-type KRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1000-fold greater inhibition of a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild-type KRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10000-fold greater inhibition of a mutant KRas protein (e.ga KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild-type KRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit nanomolar potency against a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) with minimal activity against wild-type NRas protein and / or wild-type HRas protein In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12Vmutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)))relative to inhibition of wild-type NRas protein and / or wild-type HRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild-type NRas protein and / or wild-type HRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit up to 1000-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild-type NRas protein and / or wild-type HRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit up to 10000-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild-type NRas protein and / or wild-type HRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild-type NRas protein and / or wild- type HRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild-type HRas protein and / or wild-type NRas protein. In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1000-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition ofwild-type NRas protein and / or wild-type HRas protein. In some embodiments, a compoundprovided herein, or a pharmaceutically acceptable salt thereof, can exhibit from about 1000- fold to about 10000-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild-type NRas protein and / or wild-type HRas protein. Compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating diseases and disorders including cardiovascular disease (e.g., arteriovenous malformations or Noonan syndrome), endometriosis, an inflammatory and / or autoimmune disease (e.g., a nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis), proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced solid tumors), and disorders of the MAPK pathway (e.g., neurofibromatosis type 1). In some embodiments, the diseases and disorders are KRas- associated diseases and disorders (e.g., mutant KRas-associated diseases or disorders (e.g., KRas G12D-, KRas G12R-, or G12V-associated diseases or disorders)). In certain embodiments, compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for preventing diseases and disorders as defined herein (for example, a cardiovascular disease, endometriosis, and an inflammatory and / or autoimmune disease, or cancer). In some embodiments of any of the methods or uses described herein, the inflammatory and / or autoimmune disease is RAS-associated autoimmune leukoproliferative disease. See, e.g., Niemela et al. Blood.2011; 117(10):2883-6, doi: 10.1182 / blood-2010-07-295501. In some embodiments, the subject has been identified or diagnosed as having a cancer with a KRas dysregulation (e.g., a KRas mutation or amplification) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a cancer (e.g., a tumor sample) that has a KRas dysregulation (e.g., a KRas mutation or amplification) (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a cancer (e.g., one or more tumor samples) that is positive for a KRas dysregulation (e.g., a KRas mutation or amplification) (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose cancer (e.g., a tumor sample) has a KRas dysregulation (e.g., a KRas mutation or amplification) (e.g., where the cancer (e.g., tumor sample) is identified as such using aregulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, thesubject is suspected of having a mutant KRas-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a cancer (e.g., a tumor sample) that has a KRas dysregulation (e.g., a KRas mutation or amplification) (and optionally the clinical record indicates that the subject should be treated with any of the compounds and / or compositions provided herein). In some such embodiments, the cancer (e.g., a tumor sample) has a KRas mutation selected from the group consisting of: a KRas G12X mutation, a KRas G13X mutation, and a KRas Q61X mutation. In some embodiments, a KRas mutation is selected from the group consisting of: a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, a KRas G12V mutation, a KRas G13C mutation, a KRas G13D mutation, a KRas G13V mutation, a KRas Q61E mutation, a KRas Q61H mutation, a KRas Q61K mutation, a KRas Q61L mutation, a KRas Q61P mutation, and a KRas Q61R mutation. In some embodiments, a KRas mutation is selected from the group consisting of: a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, and a KRas G12V mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas mutation selected from the group consisting of: a KRas G12A mutation, a KRas G12D mutation, a KRas G12R mutation, and a KRas G12V mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12A mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12C mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12D mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12R mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12S mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12Vmutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12D mutation, a KRas G12R mutation, or KRas G12V mutation (e.g., a KRas G12D mutation or a KRas G12V mutation). In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12D mutation or a KRas G12V mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12D mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12R mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12V mutation. The term “KRas-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a KRAS gene, a KRas protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulations of a KRAS gene,a KRas protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of a KRas-associated cancer are described herein. The term “mutant KRas-associated cancer” as used herein refers to cancers associated with or having a KRas mutation (e.g., a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation). Non-limiting examples of a mutant KRas-associated cancer are described herein. The term “KRas G12X-associated cancer” as used herein refers to cancers associated with or having a KRas G12X mutation (e.g., a KRAS gene having a mutation corresponding to a G12X mutation in a KRas protein and / or a KRas protein having a G12X mutation). Non- limiting examples of a KRas G12X-associated cancer are described herein. The term “KRas G12A-associated cancer” as used herein refers to cancers associated with or having a KRas G12A mutation (e.g., a KRAS gene having a mutation corresponding to a G12A mutation in a KRas protein and / or a KRas protein having a G12A mutation). Non- limiting examples of a KRas G12A-associated cancer are described herein. The term “KRas G12C-associated cancer” as used herein refers to cancers associated with or having a KRas G12C mutation (e.g., a KRAS gene having a mutation corresponding to a G12C mutation in a KRas protein and / or a KRas protein having a G12C mutation). Non- limiting examples of a KRas G12C-associated cancer are described herein. The term “KRas G12D-associated cancer” as used herein refers to cancers associated with or having a KRas G12D mutation (e.g., a KRAS gene having a mutation corresponding to a G12D mutation in a KRas protein and / or a KRas protein having a G12D mutation). Non- limiting examples of a KRas G12D-associated cancer are described herein. The term “KRas G12R-associated cancer” as used herein refers to cancers associated with or having a KRas G12R mutation (e.g., a KRAS gene having a mutation corresponding to a G12R mutation in a KRas protein and / or a KRas protein having a G12R mutation). Non- limiting examples of a KRas G12R-associated cancer are described herein. The term “KRas G12S-associated cancer” as used herein refers to cancers associated with or having a KRas G12S mutation (e.g., a KRAS gene having a mutation corresponding to a G12S mutation in a KRas protein and / or a KRas protein having a G12S mutation). Non- limiting examples of a KRas G12S-associated cancer are described herein. The term “KRas G12V-associated cancer” as used herein refers to cancers associated with or having a KRas G12V mutation (e.g., a KRAS gene having a mutation corresponding to a G12V mutation in a KRas protein and / or a KRas protein having a G12V mutation). Non-limiting examples of a KRas G12V-associated cancer are described herein.The term “KRas G13X-associated cancer” as used herein refers to cancers associated with or having a KRas G13X mutation (e.g., a KRAS gene having a mutation corresponding to a G13X mutation in a KRas protein and / or a KRas protein having a G13X mutation). Non- limiting examples of a KRas G13X-associated cancer are described herein. The term “KRas G13C-associated cancer” as used herein refers to cancers associated with or having a KRas G13C mutation (e.g., a KRAS gene having a mutation corresponding to a G13C mutation in a KRas protein and / or a KRas protein having a G13C mutation). Non- limiting examples of a KRas G13C-associated cancer are described herein. The term “KRas G13D-associated cancer” as used herein refers to cancers associated with or having a KRas G13D mutation (e.g., a KRAS gene having a mutation corresponding to a G13D mutation in a KRas protein and / or a KRas protein having a G13D mutation). Non- limiting examples of a KRas G13D-associated cancer are described herein. The term “KRas G13V-associated cancer” as used herein refers to cancers associated with or having a KRas G13V mutation (e.g., a KRAS gene having a mutation corresponding to a G13V mutation in a KRas protein and / or a KRas protein having a G13V mutation). Non- limiting examples of a KRas G13V-associated cancer are described herein. The term “KRas Q61X-associated cancer” as used herein refers to cancers associated with or having a KRas Q61X mutation (e.g., a KRAS gene having a mutation corresponding to a Q61X mutation in a KRas protein and / or a KRas protein having a Q61X mutation). Non- limiting examples of a KRas Q61X-associated cancer are described herein. The term “KRas Q61E-associated cancer” as used herein refers to cancers associated with or having a KRas Q61E mutation (e.g., a KRAS gene having a mutation corresponding to a Q61E mutation in a KRas protein and / or a KRas protein having a Q61E mutation). Non- limiting examples of a KRas Q61E-associated cancer are described herein. The term “KRas Q61H-associated cancer” as used herein refers to cancers associated with or having a KRas Q61H mutation (e.g., a KRAS gene having a mutation corresponding to a Q61H mutation in a KRas protein and / or a KRas protein having a Q61H mutation). Non- limiting examples of a KRas Q61H-associated cancer are described herein. The term “KRas Q61K-associated cancer” as used herein refers to cancers associated with or having a KRas Q61K mutation (e.g., a KRAS gene having a mutation corresponding to a Q61K mutation in a KRas protein and / or a KRas protein having a Q61K mutation). Non- limiting examples of a KRas Q61K-associated cancer are described herein. The term “KRas Q61L-associated cancer” as used herein refers to cancers associatedwith or having a KRas Q61L mutation (e.g., a KRAS gene having a mutation corresponding to a Q61L mutation in a KRas protein and / or a KRas protein having a Q61L mutation). Non- limiting examples of a KRas Q61L-associated cancer are described herein. The term “KRas Q61P-associated cancer” as used herein refers to cancers associated with or having a KRas Q61P mutation (e.g., a KRAS gene having a mutation corresponding to a Q61P mutation in a KRas protein and / or a KRas protein having a Q61P mutation). Non- limiting examples of a KRas Q61P-associated cancer are described herein. The term “KRas Q61R-associated cancer” as used herein refers to cancers associated with or having a KRas Q61R mutation (e.g., a KRAS gene having a mutation corresponding to a Q61R mutation in a KRas protein and / or a KRas protein having a Q61R mutation). Non- limiting examples of a KRas Q61R-associated cancer are described herein. Such mutations can be associated with the development of a variety of cancers. See, e.g., Hunter et al. Mol Cancer Res. 2015;13(9):1325-35, doi: 10.1158 / 1541-7786.MCR-15- 0203. Provided herein are methods of treating a cancer in a subject in need of such treatment, the methods comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is treatment naïve with respect to the cancer. In some embodiments, the subject has received one or more lines of previous therapy for the cancer. Also provided herein are methods of treating a cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy. In some embodiments, the subject is treatment naïve with respect to the cancer. In some embodiments, the subject has received one or more lines of previous therapy for the cancer. In some embodiments, the subject has received one or more lines of previous therapy for the cancer prior to administration of a compound provided herein. In some such embodiments, the subject has received previous chemotherapy for the cancer prior to administration of a compound provided herein. In some embodiments, the subject has received first- or second-line chemotherapy prior to administration of a compound provided herein. In some embodiments, the subject has received standard of care chemotherapy prior toadministration of a compound provided herein.In some embodiments, a subject with colorectal cancer has previously received one or more of capecitabine, fluorouracil (5-FU), leucovorin, and oxaliplatin. In some embodiments, a subject with colorectal cancer has previously received FOLFOX (fluorouracil, leucovorin, and oxaliplatin). In some embodiments, a subject with colorectal cancer has previously received FOLFIRI (fluorouracil, leucovorin, and irinotecan). In some embodiments, a subject with a colorectal cancer has previously received FOLFIRINOX (fluorouracil, leucovorin (e.g., leucovorin calcium), irinotecan (e.g., irinotecan hydrochloride), and oxaliplatin). In some embodiments, a subject with colorectal cancer has previously received CAPEOX (capecitabine and oxaliplatin). In some embodiments, a subject with colorectal cancer has previously received FOLFIRI and one or more of bevacizumab, ziv-aflibercept, and ramucirumab. In some embodiments, a subject with colorectal cancer has previously received FOLFIRI and one or more of cetuximab or panitumumab. In some embodiments, a subject with colorectal cancer has previously received FOLFOX and one or more of bevacizumab, ziv-aflibercept, and ramucirumab. In some embodiments, a subject with colorectal cancer has previously received FOLFOX and one or more of cetuximab or panitumumab. In some embodiments, a subject with colorectal cancer has previously received FOLFIRINOX and one or more of bevacizumab, ziv-aflibercept, and ramucirumab. In some embodiments, a subject with colorectal cancer has previously received FOLFIRINOX and one or more of cetuximab or panitumumab. In some embodiments, a subject with colorectal cancer has previously received CAPEOX and one or more of bevacizumab, ziv-aflibercept, and ramucirumab. In some embodiments, a subject with colorectal cancer has previously received CAPEOX and one or more of cetuximab or panitumumab. In some embodiments, a subject with endometrial cancer has previously received one or more of cisplatin, carboplatin, paclitaxel, capecitabine, mitomycin, and gemcitabine. In some embodiments, a subject with endometrial cancer has previously received cisplatin and radiation therapy. In some embodiments, a subject with endometrial cancer has previously received cisplatin and radiation therapy followed by carboplatin and paclitaxel. In some embodiments, a subject with endometrial cancer has previously received capecitabine and mitomycin. In some embodiments, a subject with endometrial cancer has previously received gemcitabine. In some embodiments, a subject with endometrial cancer has previously received paclitaxel. In some embodiments, a subject with endometrial cancer has previously received carboplatin and paclitaxel. In some embodiments, a subject with endometrial cancer haspreviously received carboplatin, paclitaxel, and pembrolizumab. In some embodiments, asubject with endometrial cancer has previously received carboplatin, paclitaxel, and dostarlimab (e.g., dostarlimab-gxly). In some embodiments, a subject with endometrial cancer has previously received carboplatin, paclitaxel, and trastuzumab. In some embodiments, a subject with endometrial cancer has previously received carboplatin, paclitaxel, and bevacizumab. In some embodiments, a subject with endometrial carcinoma has previously received megestrol acetate and tamoxifen. In some embodiments, a subject with endometrial carcinoma has previously received everolimus and letrozole. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received one or more of pembrolizumab, atezolizumab, cemiplimab (e.g., cemiplimiab-rwlc), durvalumab, nivolumab, ipilimumab, tremelimumab (e.g., tremelimumab-actl), carboplatin, cisplatin, pemetrexed, paclitaxel (e.g., albumin-bound paclitaxel), and bevacizumab. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received pembrolizumab. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received carboplatin, pemetrexed, and pembrolizumab. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received cisplatin, pemetrexed, and pembrolizumab. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received cemiplimab. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received cemiplimab, pemetrexed, and carboplatin. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received cemiplimab, pemetrexed, and cisplatin. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received carboplatin, paclitaxel, bevacizumab, and atezolizumab. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received carboplatin, paclitaxel (e.g., albumin-bound paclitaxel), and atezolizumab. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received cemiplimab, paclitaxel, and carboplatin. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received cemiplimab, paclitaxel, and cisplatin. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received tremelimumab, durvalumab, carboplatin, and paclitaxel (e.g., albumin-bound paclitaxel). In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received tremelimumab, durvalumab, carboplatin, and pemetrexed. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received tremelimumab, durvalumab, cisplatin, and pemetrexed. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received tremelimumab, durvalumab,carboplatin, and paclitaxel (e.g., albumin-bound paclitaxel). In some embodiments, a subjectwith lung cancer (e.g., NSCLC) has previously received tremelimumab, durvalumab, carboplatin, and gemcitabine. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received tremelimumab, durvalumab, cisplatin, and gemcitabine. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received nivolumab and ipilimumab. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received carboplatin, paclitaxel (e.g., albumin-bound paclitaxel), and pembrolizumab. In some embodiments, a subject with lung cancer (e.g., NSCLC) has previously received nivolumab, ipilimumab, paclitaxel, and carboplatin. In some embodiments, a subject with ovarian cancer has previously received one or more of paclitaxel, carboplatin, fluorouracil, leucovorin, oxaliplatin, capecitabine, docetaxel, and doxorubicin (e.g., liposomal doxorubicin). In some embodiments, a subject with ovarian cancer has previously received paclitaxel and carboplatin. In some embodiments, a subject with ovarian cancer has previously received fluorouracil, leucovorin, and oxaliplatin. In some embodiments, a subject with ovarian cancer has previously received hormone therapy (e.g., an aromatase inhibitor such as anastrozole, letrozole, or exemestane). In some embodiments, a subject with ovarian cancer has previously received docetaxel and carboplatin. In some embodiments, a subject with ovarian cancer has previously received carboplatin and doxorubicin (e.g., liposomal doxorubicin). In some embodiments, a subject with ovarian cancer has previously received paclitaxel, carboplatin, and bevacizumab. In some embodiments, a subject with ovarian cancer has previously received fluorouracil, leucovorin, oxaliplatin, and bevacizumab. In some embodiments, a subject with ovarian cancer has previously received capecitabine, oxaliplatin, and bevacizumab.

[0067] In some embodiments, a subject with pancreatic cancer has previously received one or more of capecitabine, fluorouracil, gemcitabine, irinotecan, leucovorin, paclitaxel (e.g., albumin-bound paclitaxel), and oxaliplatin. In some embodiments, a subject with pancreatic cancer has previously received FOLFIRINOX. In some embodiments, a subject with pancreatic cancer has previously received GEMOX (gemcitabine and oxaliplatin). In some embodiments, a subject with pancreatic cancer has previously received gemcitabine. In some embodiments, a subject with pancreatic cancer has previously received gemcitabine and paclitaxel (e.g., albumin-bound paclitaxel). In some embodiments, a subject with pancreatic cancer has previously received NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, and oxaliplatin).

[0068] Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of cancer, for example, any of the cancers provided herein.

[0069] Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for the treatment of cancer, for example, any of the cancers provided herein.

[0070] Provided herein is use of a compound provided herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, for example, any of the cancers provided herein.

[0071] Provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament. Also provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the treatment of cancer, for example, any of the cancers provided herein. Provided herein is a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a cancer, for example, any of the cancers provided herein.

[0072] As used herein, “monotherapy”, when referring to a compound provided herein, or a pharmaceutically acceptable salt thereof, means that the compound provided herein, or a pharmaceutically acceptable salt thereof, is the only therapeutic agent or therapy (e.g., anticancer agent or therapy) administered to the subject during the treatment cycle (e.g., no additional targeted therapeutics, anticancer agents, chemotherapeutics, or checkpoint inhibitors are administered to the subject during the treatment cycle). As a person of ordinary skill in the art would understand, monotherapy does not exclude the co-administration of medicaments for the treatment of side effects or general symptoms associated with the cancer or treatment, such as pain, rash, edema, photosensitivity, pruritis, skin discoloration, hair brittleness, hair loss, brittle nails, cracked nails, discolored nails, swollen cuticles, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms, including nausea, diarrhea, and lack of appetite.

[0073] As used herein, “the subject has received one or more lines of previous therapy” means that the subject has been previously administered one or more therapeutic agents or therapies (e.g., anticancer agent or therapy, such as chemotherapy, radiation, or surgery) for the cancer other than a compound provided herein, or a pharmaceutically acceptable salt thereof, during a treatment cycle prior to administration of a compound provided herein. In some embodiments, the subject cannot tolerate the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject did not respond to the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject did not adequately respond to one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject has stopped responding to the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, a lack of response, an inadequate response, or a discontinued response can be determined by objective criteria (e.g., tumor volume, or by criteria such as RECIST 1.1). In some embodiments, a lack of response, an inadequate response, or a discontinued response can be determined by the subject’s physician.

[0074] As used herein, “the subject is treatment naive with respect to the cancer” means that the subject has not been previously administered one or more therapeutic agents or therapies for the cancer. For any of the solid tumors described herein, the solid tumors can be primary tumors or metastatic (or secondary) tumors. As used herein, “primary” tumors are those located at the site where the tumor began to grow (i.e., where it originated). As used herein, “metastatic” (or “secondary”) tumors are those that have spread to other parts of body from the original tumor site. In some embodiments, the metastatic or secondary tumors are the same type of cancer as the primary tumor. In some embodiments, the metastatic or secondary tumors are not genetically identical to the primary tumor.

[0075] Provided herein is a method of treating a cancer in a subject in need of such treatment, the method comprising a) detecting a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, or a KRas G12V mutation (e.g., a KRas G12D mutation or a KRas G12V mutation)) or amplification) in a sample from the subject (e.g., detecting a KRAS gene having a mutation corresponding to a mutation in KRas protein and / or detecting a KRas protein having a mutation, a KRAS gene copy number increase, and / or an increase in KRas mRNA or protein expression); and b) administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. Provided herein is a method of treating a cancer in a subject in need of such treatment, the method comprising a) detecting a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12X mutation)) or amplification) in a sample from the subject (e.g., detecting a KRAS gene having a mutation corresponding to a mutation in KRas protein and / or detecting a KRas protein having a mutation, a KRAS gene copy number increase, and / or an increase in KRas mRNA or protein expression); and b) administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. Also provided herein is a method of treating a KRas- associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas G12A-associated cancer, a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R- associated cancer, a KRas G12S-associated cancer, or a KRas G12V-associated cancer (e.g., a KRas G12D-associated cancer or a KRas G12V-associated cancer))) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas G12X- associated cancer)) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. For example, provided herein are methods for treating a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas G12A-associated cancer, a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V- associated cancer (e.g., a KRas G12D-associated cancer or a KRas G12V-associated cancer))) in a subject in need of such treatment, the methods comprising a) detecting a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation or a KRas G12V mutation (e.g., a KRas G12D mutation or a KRas G12V mutation)) or amplification) in a sample from the subject (e.g., detecting a KRAS gene having a mutation corresponding to a mutation in KRas protein and / or detecting a KRas protein having a mutation, a KRAS gene copy number increase, and / or an increase in KRas mRNA or protein expression); and b) administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. For example, provided herein are methods for treating a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas G12X- associated cancer)) in a subject in need of such treatment, the methods comprising a) detecting a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12X mutation) or amplification) in a sample from the subject (e.g., detecting a KRAS gene having a mutation corresponding to a mutation in KRas protein and / or detecting a KRas protein having a mutation, a KRAS gene copy number increase, and / or an increase in KRas mRNA or protein expression); and b) administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments of any of the methods or uses described herein, the cancer (e.g., KRas-associated cancer (e.g., mutant KRas-associated cancer (e.g., a KRas G12A-associated cancer, a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R- associated cancer, a KRas G12S-associated cancer, or a KRas G12V-associated cancer (e.g., a KRas G12D-associated cancer or a KRas G12V-associated cancer)))) is breast cancer (e.g., breast invasive carcinoma, breast invasive ductal carcinoma), central or peripheral nervous system tissue cancer (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligoastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), multiple neuroendocrine type I and type II tumors, parathyroid cancer, pituitary tumors, thyroid cancer (e.g., papillary thyroid cancer)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer, bile duct cancer (e.g., cholangiocarcinoma), colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, liver cancer (e.g., hepatocellular carcinoma, intrahepatic bile duct cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic islet cell cancer), small intestine cancer, or stomach cancer (e.g., stomach adenocarcinoma, signet ring cell carcinoma of the stomach)), genitourinary cancer (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., renal clear cell carcinoma, renal papillary cell carcinoma, kidney chromophobe), prostate cancer (e.g., prostate adenocarcinoma), testicular cancer (e.g., testicular germ cell tumors, seminoma), or ureter cancer), gynecologic cancer (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, endocervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinosarcoma, uterine endometrioid carcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, uterine corpus endometrial carcinoma), or vulvar cancer), head and neck cancer (e.g., ear cancer (e.g., middle ear cancer), head and neck squamous cell carcinoma, nasal cavity cancer, oral cancer, pharynx cancer (e.g., hypopharynx cancer, nasopharynx cancer, oropharyngeal cancer), hematological cancer (e.g., leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) (e.g., Philadelphia chromosome positive ALL), acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia (APL)), chronic myeloid leukemia (CML)), lymphoma (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)), non-Hodgkin lymphoma (e.g., Burkitt lymphoma (BL), diffuse large B- cell lymphoma (DLBCL), diffuse histiocytic lymphoma (DHL), follicular lymphoma (FL), intravascular large B-cell lymphoma (IVLBCL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL))), or myeloma (e.g., multiple myeloma)), Li-Fraumeni tumors, mesentery cancer (e.g., omentum cancer, peritoneal cancer), pleural cancer, respiratory cancer (e.g., larynx cancer, lung cancer (e.g., lung squamous cell carcinoma, lung adenocarcinoma, mesothelioma, non-small cell lung cancer (NSCLC)), tracheal cancer), sarcoma (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcoma (Ewing sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), skin cancer (e.g., melanoma), thymus cancer (e.g., thymoma), or a combination thereof.

[0077] In some embodiments, the cancer (e.g., KRas-associated cancer (e.g., mutant KRas- associated cancer)) is a hematological cancer, a soft tissue cancer, bile duct cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous carcinoma, rectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, urothelial cancer, or uterine cancer.

[0078] In some embodiments, the cancer (e.g., KRas-associated cancer (e.g., mutant KRas- associated cancer)) is colorectal cancer (e.g., a colon cancer or a rectal cancer), endometrial cancer, lung cancer (e.g., NSCLC), ovarian cancer, or pancreatic cancer.

[0079] In some embodiments, the cancer (e.g., KRas-associated cancer (e.g., mutant KRas- associated cancer)) is colon cancer, endometrial cancer, lung cancer, pancreatic cancer, and uterine cancer.

[0080] In some embodiments, the cancer is a colorectal cancer (e.g., a colon cancer or a rectal cancer). In some such embodiments, the colorectal cancer has a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12X mutation)) or amplification).

[0081] In some embodiments, the cancer is an endometrial cancer. In some such embodiments, the endometrial cancer has a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12X mutation)) or amplification).

[0082] In some embodiments, the cancer is a lung cancer (e.g., NSCLC). In some such embodiments, the lung cancer (e.g., NSCLC) has a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12X mutation)) or amplification).

[0083] In some embodiments, the cancer is an ovarian cancer. In some such embodiments, the ovarian cancer has a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12X mutation)) or amplification).

[0084] In some embodiments, the cancer is a pancreatic cancer. In some such embodiments, the pancreatic cancer has a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12X mutation)) or amplification).

[0085] In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., a mutant KRas- associated cancer (e.g., a KRas G12X-associated cancer))) is a hematological cancer, bile duct cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, testicular cancer (e.g., seminoma), skin cancer, stomach cancer, thymus cancer, thyroid cancer, urothelial cancer, or uterine cancer. In some embodiments, the cancer is brain cancer, colon cancer, lung cancer, pancreatic cancer, rectal cancer, testicular cancer (e.g., seminoma), or uterine cancer. In some embodiments, the cancer is a KRas G12A-associated cancer.

[0086] In some embodiments, the cancer is bladder cancer, breast cancer, cervical cancer, colon cancer, lung cancer, kidney cancer, liver cancer, or rectal cancer. In some embodiments, the cancer is a KRas G12C-associated cancer.

[0087] In some embodiments, the cancer is a hematological cancer, brain cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous carcinoma, ovarian cancer pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, thymus cancer, urothelial cancer, or uterine cancer. In some embodiments, the cancer is a KRas G12D-associated cancer.

[0088] In some embodiments, the cancer is a hematological cancer, bladder cancer, bile duct cancer, colon cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, or testicular cancer. In some embodiments, the cancer is a KRas G12R-associated cancer.

[0089] In some embodiments, the cancer is colon cancer, lung cancer, pancreatic cancer, rectal cancer, stomach cancer, testicular cancer (e.g., seminoma), or uterine cancer. In some embodiments, the cancer is a KRas G12S-associated cancer

[0090] In some embodiments, the cancer is a hematological cancer, bladder cancer, bile duct cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous carcinoma, ovarian cancer, pancreatic cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer (e.g., seminoma), thymus cancer, or uterine cancer. In some embodiments, the cancer is a G12V- associated cancer.

[0091] In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., a mutant KRas- associated cancer (e.g., a KRas G13X-associated cancer))) is a hematological cancer, a soft tissue cancer, cervical cancer, colon cancer, endometrial cancer, liver cancer, lung cancer, pancreatic cancer, rectal cancer, skin cancer, stomach cancer, or urothelial cancer. In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas Q61X-associated cancer)) is bladder cancer, colon cancer, lung cancer, ovarian cancer, rectal cancer, thyroid cancer, or uterine cancer. In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., a cancer associated with KRas amplification (e.g., a cancer associated with wild-type KRas amplification)) is colorectal cancer, gastric cancer, gastroesophageal cancer, head and neck squamous carcinoma, or lung cancer (e.g., NSCLC). See, e.g., the public database cBioPortal.

[0092] In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., mutant KRas- associated cancer)) is pancreatic cancer or metastatic pancreatic cancer. In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., mutant KRas-associated cancer)) is pancreatic ductal adenocarcinoma (PDAC). In some such embodiments, the pancreatic cancer is a KRas G12R-associated cancer.

[0093] In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., mutant KRas- associated cancer)) is advanced-stage lung adenocarcinoma.

[0094] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor has a KRas dysregulation (e.g., a KRas mutation or amplification). For example, the solid tumor has a KRas mutation selected from the group consisting of a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, and a KRas G12V mutation. In some embodiments, the solid tumor has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation. In some embodiments, the solid tumor has a KRas G12D mutation or a KRas G12V mutation. In some embodiments, the solid tumor has a KRas G12A mutation. In some embodiments, the solid tumor has a KRas G12C mutation. In some embodiments, the solid tumor has a KRas G12D mutation. In some embodiments, the solid tumor has a KRas G12R mutation. In some embodiments, the solid tumor has a KRas G12S mutation. In some embodiments, the solid tumor has a KRas G12V mutation.

[0095] Also provided herein is a method of treating a solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas dysregulation (e.g., a KRas mutation or amplification) in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating a solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, or a KRas G12V mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12D or a KRas G12V mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12A mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12C mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12D mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12R mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12S mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12V mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0096] Also provided herein is a method of treating an advanced solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas dysregulation (e.g., a KRas mutation or amplification) in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating an advanced solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, or a KRas G12V mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12D or a KRas G12V mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12A mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12C mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12D mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12R mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12S mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12V mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0097] As used herein, an “advanced solid tumor” is a solid tumor that has spread extensively to other anatomic sites and / or that is no longer responding to treatment. In some embodiments, classification of an advanced solid tumor can be made by the subject’s physician.

[0098] In some embodiments, the cancer is a bladder cancer. In some embodiments, the bladder cancer has a KRas dysregulation (e.g., a KRas mutation or amplification). For example, the bladder cancer has a KRas mutation selected from the group consisting of: a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12V mutation, a KRas G13D mutation, and a KRas Q61H mutation. As another example, the bladder cancer has a KRas mutation selected from the group consisting of: a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, and a KRas G12V mutation. In some embodiments, the bladder cancer has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation. In some embodiments, the bladder cancer has a KRas G12D mutation or a KRas G12V mutation. In some embodiments, the bladder cancer has a KRas G12C mutation. In some embodiments, the bladder cancer has a KRas G12D mutation. In some embodiments, the bladder cancer has a KRas G12R mutation. In some embodiments, the bladder cancer has a KRas G12V mutation.

[0099] Also provided herein is a method of treating a bladder cancer in a subject in need thereof, the method comprising: (a) detecting a KRas dysregulation (e.g., a KRas mutation or amplification) in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating a bladder cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12V mutation, a KRas G13D mutation, or a KRas Q61H mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating a bladder cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a bladder cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12D or a KRas G12V mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a bladder cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12C mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Addition...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I-c):Formula (I-c) or a pharmaceutically acceptable salt thereof, wherein: E1is selected from the group consisting of: CH and CR4, wherein R4is selected from the group consisting of: -CN, halo, C1-3alkyl, C1-3haloalkyl, and C3-6cycloalkyl; R1is a 4-10 membered heterocyclyl optionally substituted with 1-4 R7; each R7is independently selected from the group consisting of Raand Rb; X1is -CH2-; X2is -CH2-; X3is -CH2- or -CHRL-; b4 is 0; R10is selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc; RLis selected from the group consisting of: -CH3, -CF3, -CHF2, and -CH2F; Y2is -CH2-;optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F, C1-3alkoxy, and C1-3haloalkoxy; each Rais independently selected from the group consisting of: (a) halo; (b) cyano;(c) -OH; (d) oxo; (e) C1-6 alkoxy; (f) C1-6 haloalkoxy; (g) -NRdRe; (h) -C(=O)C1-6 alkyl; (i) -C(=O)C1-6 haloalkyl; (j) -C(=O)OH; (k) -C(=O)OC1-6 alkyl; (l) -C(=O)OC1-6 haloalkyl; (m) -C(=O)N(Rf)2; (n) -S(O)0-2(C1-6 alkyl); (o) -S(O)0-2(C1-6 haloalkyl); (p) -S(O)1-2N(Rf)2; and (q) C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1, 2, or 3; each Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3 alkyl)-, -S(O)0-2-, -C(=O) -, and C1-3 alkylene; and each Rb1is independently selected from the group consisting of: C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, cyano, -OH, C1-6 alkoxy, C1-6haloalkoxy, -NRdRe, -C(=O)C1-6alkyl, -C(=O)C1-6haloalkyl, -C(=O)OC1-6alkyl, -C(=O)OC1-6 haloalkyl, -C(=O)OH, -C(=O)N(Rf)2, -S(O)0-2(C1-6 alkyl), -S(O)0-2(C1-6 haloalkyl), and -S(O)1-2N(Rf)2; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6 alkyl, -C(=O)C1-6 haloalkyl, -C(=O)OC1-6 alkyl, -C(=O)OC1-6 haloalkyl, -C(=O)N(Rf)2, - S(O)1-2(C1-6 alkyl), -S(O)1-2(C1-6 haloalkyl), -S(O)1-2N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rh; each Rfis independently selected from the group consisting of: -H and C1-6 alkyloptionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, C1-3 alkyl, C1-3 haloalkyl, C3-5 cycloalkyl, and 4-5 membered heterocyclyl; and each Rhis independently selected from the group consisting of: halo, cyano, -OH, -C1- 6 alkoxy, -C1-6 haloalkoxy, -NH2, -N(H)(C1-3 alkyl), and -N(C1-3 alkyl)2.

2. The compound of claim 1, wherein RLis -CH3.

3. The compound of claim 1 or 2, wherein E1is CH. . The compound of any one of claims 1-3, wherein R3isoptionally substituted. The compound of any one of claims 1-4, wherein6. The compound of any one of claims 1-5, wherein R1is a 7-10 (e.g., 7) membered heterocyclyl having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, wherein the 7-10 membered heterocyclyl is optionally substituted with 1-4 R7.

7. The compound of any one of claims 1-6, wherein R1is a 7-10 (e.g., 7) membered monocyclic heterocyclyl having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, wherein the 7-10 membered monocyclic heterocyclyl is optionally substituted with 1-4 (e.g., 1-2) R7.1-4 R7at one or more ring carb9. The compound of any one of claims 6-8, wherein each R7is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 Rc, wherein each Rcpresent on R7is independently selected from the group consisting of: -F, -OH, and -CN.

10. The compound of any one of claims 1-9, wherein.

11. The compound of any one of claims 1-9, whereinwherein R7is a 5-membered heteroaryl optionally substituted with 1-3 Rg.

12. The compound of claim 11, wherein R7is pyrazolyl optionally substituted with 1-2 Rg(e.g., R7isoptionally substituted with one Rg); or wherein R7is oxazolyl optionally substituted with one Rg(e.g., R7isoptionally substituted with one Rg).

13. The compound of claim 11 or 12, wherein R7is.

14. The compound of any one of claims 1-6, wherein R1is a 7-10 (e.g., 7) membered spirocyclic bicyclic heterocyclyl having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, wherein the 7-10 membered spirocyclic bicyclic heterocyclyl is optionally substituted with 1-4 (e.g., 1-2) R7.

15. The compound of any one of claims 1-6 or 14, wherein, wherein: Ring A1 is a 4-7 membered heterocyclyl ring having one ring oxygen atom and no additional ring heteroatoms; n4 is 0, 1, or 2; and n5 is 0, 1, or 2, provided that n4 + n5 is 0, 1, .

16. The compound of any one of claims 1-6 or 14-15, wherein R1is, which is optionally substituted with 1-2 R7.

17. The compound of any one of claims 1-6 or 14-16, wherein R1is.

18. The compound of any one of claims 1-6 or 14-15, wherein R1is, each of which is optionally substituted with 1-2 R7.

19. The compound of any one of claims 1-6, 14-15, or 18, wherein R1is20. The compound of any one of claims 1-6, wherein R1is a 4-membered heterocyclyl optionally substituted with 1-4 (e.g., 1-2) R7.

21. The compound of any one of claims 1-6 or 20, wherein R1is optionally substituted with 1-4 (e.g., 1-2) R7.

22. The compound of any one of claims 1-6 or 20-21, wherein R1is (e.g.,23. The compound of any one of claims 20-22, wherein each R7is independently selected from the group consisting of: (a) -F, (b) cyano, (c) -OH, (d) Rb1, wherein the Rb1is a 5-6 membered heteroaryl optionally substituted with 1-2 Rg, (e) C1-3 alkyl optionally substituted with 1-3 F, (f) C1-3 alkyl substituted with -OH or C1-3 alkoxy, and (g) -C(=O)N(Rf)2.

24. The compound of any one of claims 1-6 or 20-22, wherein R1is (e.g., ), wherein R7is C1-3alkyl substituted with -OH or C1-3alkoxy (e.g., C1-3alkyl substituted with -OH).

25. The compound of any one of claims 1-6, 20-22, or 24, wherein R1is26. The compound of any one of claims 1-6 or 20-22, wherein, wherein each R7is independently selected from the group consisting of: (a) C1-3 alkyl optionally substituted with 1-3 -F; and (b) C1-3 alkyl substituted with OH or C1 3 alkoxy / Y-R7aN27. The compound of any one of claims 1-6, 20-22, or 26, wherein R1is -J—wherein R7ais C1-3 alkyl substituted with -OH (e.g., -CH2OH); andR7bis selected from the group consisting of:(a) C1-3 alkyl optionally substituted with 1-3 -F (e.g., methyl), and(b) C1-3 alkyl substituted with -OH or C1-3 alkoxy.

28. The compound of any one of claims 1-6, 20-22, or 26-27, wherein R1is29. The compound of any one of claims 1-6, wherein R1is a 4-10 membered heterocyclyl substituted with -CN, -(C1-3 alkylene)-CN, or -(C3-6 cycloalkylene)-CN on a ring carbon atom, wherein the heterocyclyl is further optionally substituted with 1-3 R7.

30. The compound of any one of claims 1-6 or 29, wherein R1is a 6-8 membered heterocyclyl substituted with -CN or -(C1-3 alkylene)-CN on a ring carbon atom, wherein: the heterocyclyl has one ring nitrogen atom and 0-1 ring oxygen atom; and the heterocyclyl is further optionally substituted with 1-3 R7.

31. The compound of claim 29 or 30, wherein each R7is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 Rc(e.g., C1-3 alkyl optionally substituted with 1-3 -F).

32. The compound of any one of claims 1-6 or 29-31, whereinmpound of any one of claims 1-32, wherein the34. The compound of claim 1, wherein the compound of Formula (I-c) is a compound of Formula (I-c3) or (I-c4):Formula (I-c4) or a pharmaceutically acceptable salt thereof, wherein: E1is CH;R7is C 1-3 alkyl substituted with -OH; b4 is 0;R10is selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc;X1is -CH2-;X2is -CH2-; andX3is -CH2- or -CHRL-.

35. The compound of claim 34, wherein X2is -CH2-; and X3is -CH2-.

36. The compound of claim 34, wherein X2is -CH2-; and X3is -CHRL-.

37. The compound of claim 34 or 36, wherein X2is -CH2-; and X3is -CHMe-.

38. The compound of any one of claims 34-37, wherein the compound is aZS — R7^\->R7N N compound of Formula (I-c4); and the — 1— moiety is — J— •39. The compound of any one of claims 34-38, wherein R7is -CH2OH.

40. The compound of any one of claims 34-39, wherein Y2is -CH2-; and R3isoptionally substituted with 1-2 -F.

41. The compound of any one of claims 34-40, wherein42. The compound of any one of claims 34-41, wherein themoiety i43. The compound of claim 1, wherein the compound of Formula (I-c) is selected from the group consisting of Compound Nos. 101, 101a, 103, 103a, 107, 107a, 107b, 111, Illa, 121, 121a, 122, 122a, 136, 136a, 137, 137a, 140, 140a, 141, 141a, 142, 142a, 144, 144a, 146, 146a, 146b, 151, 151a, 151b, 151c, 152, 152a, 152b, 153, 153a, 153b, 155, 155a, 155b, 156, and 156a, as depicted in Table Cl, or a pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition comprising a compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

45. A method for treating cancer in a subj ect in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 44.

46. A method for treating cancer in a subj ect in need thereof, the method comprising (a) determining that the cancer in the subject has a KRas dysregulation; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim44.

47. A method of treating cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a cancer having a KRas dysregulation a therapeutically effective amount of a compound of any one of claims 1-43 or apharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 44.

48. The method of any one of claims 45-47, wherein the KRas dysregulation is a KRas mutation.

49. The method of claim 48, wherein the KRas mutation is a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, or a KRas G12V mutation.

50. The method of claim 49, wherein the KRas mutation is a KRas G12C mutation, a KRas G12D mutation or a KRas G12V mutation.

51. The method of claim 46, wherein the step of determining that the cancer in the subject has a KRas dysregulation includes performing an assay to detect the KRas dysregulation (e.g., a KRas mutation) in a tumor sample from the subject.

52. The method of claim 51, wherein detecting the KRas dysregulation includes detecting a KRAS gene having a mutation corresponding to a substitution of glycine 12 in a KRas protein and / or a KRas protein having a substitution of glycine 12.

53. The method of claim 52, wherein the substitution of glycine 12 is a substitution to alanine, cysteine, aspartic acid, arginine, serine, or valine.

54. The method of any one of claims 45-53, wherein the cancer is selected from the group consisting of: a hematological cancer, a soft tissue cancer, bile duct cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer (e.g., colon cancer or rectal cancer), endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, urothelial cancer, uterine cancer, and a combination thereof.

55. The method of claim 54, wherein the cancer is selected from the group consisting of: colon cancer, endometrial cancer, lung cancer, pancreatic cancer, and uterine cancer.

56. The method of claim 54, wherein the cancer is selected from the group consisting of: colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), ovarian cancer, and pancreatic cancer.

57. The method of any one of claims 45-56, comprising administering an additional therapy or therapeutic agent to the subject.

58. The method of claim 57, wherein the additional therapy or therapeutic agent is selected from the group consisting of Ras pathway targeted therapeutic agents, kinase-targeted therapeutics, mTORCl inhibitors or degraders, YAP inhibitors or degraders, proteasome inhibitors or degraders, HSP90 inhibitors or degraders, farnesyl transferase inhibitors or degraders, PTEN inhibitors or degraders, signal transduction pathway inhibitors or degraders, checkpoint inhibitors, modulators of the apoptosis pathway, chemotherapeutics, angiogenesis- targeted therapies, immune-targeted agents, radiotherapy, and combinations thereof.

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