Spirocyclic dihydropyranopyrimidine KRAS inhibitors

Abstract

This disclosure provides compounds of Formula ( AA ), Formula ( A ) (e.g., Formula ( I-a1 )), or Formula ( B ), 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 ( AA ), Formula ( A ) (e.g., Formula ( I-a1 )), or Formula ( B ), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

Description

[0001] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0002] Spirocyclic Dihydropyranopyrimidine KRas Inhibitors CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims priority to U. S. Provisional Application Serial No. 63 / 759,842, filed February 18, 2025, which is incorporated by reference in its entirety herein.

[0004] SEQUENCE LISTING

[0005] This application contains a Sequence Listing that has been submitted electronically as an XML file named “TRLN-008-026W01_Sequence_Listing. XML.” The XML file, created on January 28, 2026, is 2 KB in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0006] TECHNICAL FIELD

[0007] This disclosure provides compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), 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 (AA), Formula (A) (e.g., Formula (I-a1)), 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 positionDocket No. TRLN-008-026W01 / 51379-0226WO1

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

[0011] 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.

[0012] SUMMARY

[0013] This disclosure provides compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), 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 (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

[0014] Provided herein are compounds of Formula (AA):

[0015] E1

[0016] O R3

[0017]

[0018] Formula (A A)

[0019] or pharmaceutically acceptable salts thereof or prodrugs thereof, wherein Ring B, *, M, R2a, R2b, R2c, R2d, R1, E1, E2, Y2, and R3are each as defined herein.

[0020] Also provided herein are compounds of Formula (A):Docket No. TRLN-008-026W01 / 51379-0226WO1

[0021] R3

[0022]

[0023] Formula (A)

[0024] or pharmaceutically acceptable salts thereof or prodrugs thereof, wherein Ring B, *, R2a, R2b, R2c, R2d, R1, E1, Y2, and R3are each as defined herein.

[0025] Also provided herein are compounds of Formula (B):

[0026]

[0027] Formula (B)

[0028] or pharmaceutically acceptable salts thereof or prodrugs thereof, wherein Ring B, R2a, R2b, R2c, R2d, R2e, R1, E1, Y2, and R3are each as defined herein.

[0029] Also provided herein are pharmaceutical compositions comprising a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0030] 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 (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0031] 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 G12C mutation, a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation)); and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0032] Provided herein are methods of treating a KRas-associated disease or disorder (e.g., a mutant KRas-associated disease or disorder (e.g., a KRas G12C-associated cancer, a KRasDocket No. TRLN-008-026W01 / 51379-0226WO1

[0033] G12D-associated cancer, a KRas G12R-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 (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0034] 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 G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer)) 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 G12C-associated disease or disorder, a KRas G12D-associated disease or disorder, a KRas G12R-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 (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0035] Further provided herein are methods of treating a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R-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 G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer)) a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0036] This disclosure also provides methods of treating a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R-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 G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer)); and administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.Docket No. TRLN-008-026W01 / 51379-0226WO1

[0037] 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.

[0038] 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.

[0039] DETAILED DESCRIPTION

[0040] This disclosure provides compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), 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 resistance mutation) confers intrinsic resistance to one or more KRas inhibitors (e.g., a KRas inhibitor selective 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.

[0041] 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,Docket No. TRLN-008-026W01 / 51379-0226WO1

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 2015; 13(9): 1325-35. These changes and other factors can contribute to increased KRas signaling in mutant KRas proteins.

[0046] Table 1

[0047] Raf Affinity

[0048] High Low

[0049] G12A G12R

[0050] Low

[0051] Intrinsic Q61L G12V

[0052] GTPase Wild type

[0053] activity High G12C G12D

[0054] G13D

[0055]

[0056] KRas inhibitors are described in, for example, International Publication Nos. WO 2025 / 038936; WO 2025 / 064848; WO 2025 / 245127; WO 2025 / 247153; WO 2025 / 255440; WO 2025 / 237091; 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.

[0057] 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;Docket No. TRLN-008-026W01 / 51379-0226WO1

[0058] 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 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.

[0059] Compound Embodiments

[0060] Provided herein are compounds of Formula (AA):

[0061] R2a. R2bR1

[0062]

[0063] Formula (A A)

[0064] or pharmaceutically acceptable salts thereof or prodrugs thereof, wherein:

[0065] E1and E2are independently selected from the group consisting of N, CH, and CR4, provided that at least one of E1and E2is N;

[0066] R4is selected from the group consisting of: CN, halo, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl;

[0067] M is selected from the group consisting of: O, S(0)o-2, C(R2eR2f), and N(R*);

[0068] R1is selected from the group consisting of:

[0069] (i) a chemical moiety that is capable of forming a covalent bond with the thiol group (SH) of cysteine 12 of a human KRas G12C mutant protein;

[0070] (ii) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7;

[0071] (iii) an 8-12 membered bicyclic heterocyclyl, wherein the heterocyclyl comprises an endocyclic group selected from the group consisting of C(=O)NH and S(O)2NH, and wherein the heterocyclyl is further optionally substituted with 1-3 R7at one or more ring carbon atoms;Docket No. TRLN-008-026W01 / 51379-0226WO1

[0072] ,N^

[0073] (

[0074]

[0075] iv), wherein b2 is 0, 1, 2, or 3; and A1and A2are independently selected from the group consisting of: N, CH, and CR7;

[0076] each R7is independently selected from the group consisting of Raand Rb;

[0077] R2aand R2bare independently selected from the group consisting of: H, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; or

[0078] R2aand R2btaken together with the ring carbon atom to which each is attached form a C3-6 cycloalkyl ring or a 4-6 membered heterocyclyl ring;

[0079] R2cand R2dare independently selected from the group consisting of: H, halo, CN, C1-3 alkyl, Ci-3 haloalkyl, and C3-6 cycloalkyl; or

[0080] R2cand R2dtaken together with the ring carbon atom to which each is attached form a C3-6 cycloalkyl ring or a 4-6 membered heterocyclyl ring;

[0081] R2eand R2fare independently selected from the group consisting of: H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; or

[0082] R2eand R2ftaken together with the ring carbon atom to which each is attached form a C3-6 cycloalkyl ring or a 4-6 membered heterocyclyl ring;

[0083] Ring B is selected from the group consisting of:

[0084]

[0085] b1^R)

[0086]

[0087] bi(R10), wherein:

[0088] the * marks the ring carbon atom common to both Ring B

[0089]

[0090] and X1is selected from the group consisting of a bond, S(0)o-2, CH2, CHRL, C(RL)2, and O;Docket No. TRLN-008-026W01 / 51379-0226WO1

[0091] X2and X3are independently selected from the group consisting of: CH2, CHR, C(RL)2, O, and S(0)o-2, provided that no more than one of X1, X2, and X3is selected from the group consisting of: O and S(0)o-2;

[0092] b1 is 0, 1, or 2;

[0093] R9is selected from the group consisting of: H, OH, NRdRe, and halo;

[0094] each R10is independently selected from the group consisting of Raand Rb;

[0095] 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

[0096] a pair of RLon the same or different ring carbon atom(s) taken together with the ring atom(s) connecting them form a C3-6 cycloalkyl ring;

[0097] 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,

[0098] R°

[0099] C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl, C1-6 haloalkyl, and

[0100]

[0101] ', or

[0102] a pair of RYon the same or different carbon atom(s) taken together 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;

[0103] R3is selected from the group consisting of:

[0104] (a) 4-15 membered heterocyclyl optionally substituted with 1-6 substituents R°

[0105] V^RO ^ROXindependently selected from the group consisting of: Ra, Rb,

[0106]

[0107] ', and '0; and (b) -NRdRe;

[0108] each R° is independently selected from the group consisting of: -H, -F, C1-3 alkyl, and C1-3 haloalkyl;

[0109] Roxis -H or C1-3 alkyl;

[0110] each Rais independently selected from the group consisting of:

[0111] (a) halo;Docket No. TRLN-008-026W01 / 51379-0226WO1

[0112] (b) cyano;

[0113] (c) -OH;

[0114] (d) oxo;

[0115] (e) -Ci-6 alkoxy;

[0116] (f) -Ci-6 haloalkoxy;

[0117] (g) -NRdRe;

[0118] (h) C(=O)Ci-6alkyl;

[0119] (i) C(=O)Ci-6haloalkyl;

[0120] (j) C(=O)OH;

[0121] (k) C(=O)OCi-6alkyl;

[0122] (l) C(=O)OCi-6haloalkyl;

[0123] (m) C(=O)N(Rf)2;

[0124] (n) S(0)o-2(Ci-6 alkyl);

[0125] (o) S(0)o-2(Ci-6 haloalkyl);

[0126] (p) S(O)i.2N(Rf)2; and

[0127] (q) Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc;

[0128] each Rbis independently selected from the group consisting of: -(Lb)b-Rbland -Rbl, wherein:

[0129] b is 1, 2, or 3;

[0130] each -Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(CI-3 alkyl)-, -S(0)o-2-, C(=O), and C1-3 alkylene; and

[0131] each Rblis independently selected from the group consisting of: C3-10 cycloalkyl, 4-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg;

[0132] 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;

[0133] each Rdand Reis independently selected from the group consisting of: H, C(=O)Ci-6 alkyl, C(=O)Ci-6haloalkyl, C(=O)OCi-6alkyl, C(=O)OCi-6haloalkyl, 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 withDocket No. TRLN-008-026W01 / 51379-0226WO1

[0134] 1-3 Rh;

[0135] each Rfis independently selected from the group consisting of: H and C1-6 alkyl optionally substituted with 1-3 Rh;

[0136] 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

[0137] 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-.

[0138] In some embodiments of Formula (AA), M is O.

[0139] In some embodiments of Formula (AA), M is N(Rf) (e.g., N(Me)).

[0140] In some embodiments of Formula (AA), M is C(R2eR2f) (e.g., CH2).

[0141] In some embodiments of Formula (AA), E2is N.

[0142] In some embodiments of Formula (AA), E2is N; and E1is N.

[0143] In some embodiments of Formula (AA), E2is CH or CR4(e.g., CH or C-CN); and E1is N.

[0144] In some embodiments, the compounds of Formula (AA) are compounds of Formula (A):

[0145] R2® R2bR1

[0146] (

[0147]

[0148] B7 R^2SCSX R^2d N^OXY'R3

[0149] Formula (A)

[0150] or pharmaceutically acceptable salts thereof or prodrugs thereof, wherein:

[0151] E1is selected from the group consisting of N, CH, and CR4, wherein R4is selected from the group consisting of: CN, halo, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl;

[0152] R1is selected from the group consisting of:

[0153] (i) a chemical moiety that is capable of forming a covalent bond with the thiol group (SH) of cysteine 12 of a human KRas G12C mutant protein;Docket No. TRLN-008-026W01 / 51379-0226WO1

[0154] (ii) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7;

[0155] (iii) an 8-12 membered bicyclic heterocyclyl, wherein the heterocyclyl comprises an endocyclic group selected from the group consisting of C(=O)NH and S(O)2NH, and wherein the heterocyclyl is further optionally substituted with 1-3 R7at one or more ring carbon atoms; and

[0156] ,N^

[0157] (

[0158]

[0159] iv), wherein b2 is 0, 1, 2, or 3; and A1and A2are independently selected from the group consisting of: N, CH, and CR7;

[0160] each R7is independently selected from the group consisting of Raand Rb;

[0161] R2aand R2bare independently selected from the group consisting of: H, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; or

[0162] R2aand R2btaken together with the ring carbon atom to which each is attached form a C3-6 cycloalkyl ring or a 4-6 membered heterocyclyl ring;

[0163] R2cand R2dare independently selected from the group consisting of: H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; or

[0164] R2cand R2dtaken together with the ring carbon atom to which each is attached form a C3-6 cycloalkyl ring or a 4-6 membered heterocyclyl ring;

[0165] Ring B is selected from the group consisting of:

[0166]

[0167] >>dR10) and

[0168]

[0169] b1(R10), wherein:

[0170] the * marks the ring carbon atom common to both Ring B

[0171]

[0172] andDocket No. TRLN-008-026W01 / 51379-0226WO1

[0173] X1is selected from the group consisting of a bond, S(0)o-2, CH2, CHRL, C(RL)2, and O;

[0174] X2and X3are independently selected from the group consisting of: CH2, CHRL, C(RL)2, O, and S(0)o-2, provided that no more than one of X1, X2, and X3is selected from the group consisting of: O and S(0)o-2;

[0175] b1 is 0, 1, or 2;

[0176] R9is selected from the group consisting of: H, OH, NRdRe, and halo;

[0177] each R10is independently selected from the group consisting of Raand Rb;

[0178] 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

[0179] a pair of RLon the same or different ring carbon atom(s) taken together with the ring atom(s) connecting them form a C3-6 cycloalkyl ring;

[0180] 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

[0181] a pair of RYon the same or different carbon atom(s) taken together 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 independently selected C1-3 alkyl;

[0182] R3is selected from the group consisting of:

[0183] (c) 4-15 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb; and

[0184] (d) -NRdRe;

[0185] each Rais independently selected from the group consisting of:

[0186] (a) halo;

[0187] (b) cyano;

[0188] (c) -OH;

[0189] (d) oxo;

[0190] (e) -C1-6 alkoxy;

[0191] (f) -C1-6 haloalkoxy;

[0192] (g) -NRdRe;Docket No. TRLN-008-026W01 / 51379-0226WO1

[0193] (h) C(=O)Ci-6 alkyl;

[0194] (i) C(=O)Ci-6haloalkyl;

[0195] (j) C(=O)OH;

[0196] (k) C(=O)OCi-6alkyl;

[0197] (l) C(=O)OCi-6haloalkyl;

[0198] (m) C(=O)N(Rf)2;

[0199] (n) S(0)o-2(Ci-6 alkyl);

[0200] (o) S(0)o-2(Ci-6 haloalkyl);

[0201] (p) S(O)i.2N(Rf)2; and

[0202] (q) Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc;

[0203] each Rbis independently selected from the group consisting of: -(Lb)b-Rbland -Rbl, wherein:

[0204] b is 1, 2, or 3;

[0205] each -Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(CI-3 alkyl)-, -S(0)o-2-, C(=O), and C1-3 alkylene; and

[0206] each Rblis independently selected from the group consisting of: C3-10 cycloalkyl, 4-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg;

[0207] 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;

[0208] each Rdand Reis independently selected from the group consisting of: H, C(=O)Ci-6 alkyl, C(=O)Ci-6haloalkyl, C(=O)OCi-6alkyl, C(=O)OCi-6haloalkyl, 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;

[0209] each Rfis independently selected from the group consisting of: H and C1-6 alkyl optionally substituted with 1-3 Rh;

[0210] 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

[0211] each Rhis independently selected from the group consisting of: halo, cyano, -OH, -Ci-Docket No. TRLN-008-026W01 / 51379-0226WO1

[0212] 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 (AA) (e.g., Formula (A)) which releases the Formula (AA) (e.g., Formula (A)) 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 Formula (AA) (e.g., Formula (A)) compounds 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 (AA) (e.g., Formula (A)) may form prodrugs at -NH2 (e.g., at R9when R9is -NH2) 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 1, 255-270 (2008), doi: 10.1038 / nrd246; Chem Biol Drug Des 82: 643-668 (2013), doi: 10.1111 / cbdd.12224; Prodrugs as Novel Delivery Systems, Vol.14, ACS Symposium Series; Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association.

[0213] CN

[0214] In some embodiments of Formula (AA) (e.g., Formula (A)), Ring B is:

[0215]

[0216] 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.

[0217] '2 XN

[0218] In some embodiments of Formula (AA) (e.g., Formula (A)), Ring B is:

[0219]

[0220] wherein X3is -CH2-, -CHRL-, or -C(RL)2-. In some embodiments, each RLis independently C1-3 alkyl optionally substituted with 1-3 F.

[0221] '2 XN

[0222] In some embodiments of Formula (AA) (e.g., Formula (A)), Ring

[0223]

[0224] B is For example, RLcan be methyl, ethyl, or CF3. For example, RLcan be methyl.Docket No. TRLN-008-026W01 / 51379-0226WO1

[0225] In some embodiments of Formula (AA) (e.g., Formula (A)), Ring

[0226]

[0227] B is

[0228] In some embodiments of Formula (AA) (e.g., Formula (A)), Ring

[0229]

[0230] B is

[0231] In some embodiments of Formula (AA) (e.g., Formula (A)), Ring

[0232]

[0233] B is

[0234] In some embodiments of Formula (AA) (e.g., Formula (A)), R2a, R2b, R2c, and R2dare each H.

[0235] In some embodiments, the compounds of Formula (A) are compounds of Formula (I-al):

[0236]

[0237] Formula (I-al)

[0238] or pharmaceutically acceptable salts thereof.

[0239] In some embodiments of Formula (I-al), X1is CH2; X2is CH2; and X3is CH2 or CHRL.

[0240] In some embodiments of Formula (I-al), the

[0241]

[0242] moiety isDocket No. TRLN-008-026W01 / 51379-0226WO1

[0243]

[0244] In some embodiments of Formula (I-al), the

[0245]

[0246] In some embodiments of Formula (I-al), X3is CHMe, CHEt, or CHCF3. For example, X3can be CHMe.

[0247] In some embodiments of Formula (I-al), X3is CH2.

[0248] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1is a chemical moiety that is capable of forming a covalent bond with the thiol group of cysteine 12 of a human KRas G12C mutant protein. Examples include chemical moieties disclosed in International Application Nos. WO 2019099524; WO 2021109737; WO 2021180181; WO 2018217651; WO 2017201161; WO 2020236940; WO 2021139748; WO 2022040469; WO 2022115439; WO 2022135546; WO 2022156761; WO 2023086383; WO 2022251576; WO 2022232320; WO 2022232318; WO 2022109487; WO 2022109485; WO 2021085653; WO 2021084765; WO 2021086833; WO 2020085493; WO 2024006445; WO 2023150394; WO 2023081840; WO 2023225252; WO 2023133181; WO 2023004102; WO 2021108683; WO 2021118877; WO 2021124222; WO 2020081282; and WO 2019155399.

[0249] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1is a chemical moiety having a Michael acceptor group, wherein the Michael acceptor group is capable of forming a covalent bond with the thiol group of cysteine 12 of a human KRas G12C mutant protein.

[0250] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0251] O R8bR

[0252]

[0253] 8CR8a is a chemical moiety having a group selected from the group consisting of:Docket No. TRLN-008-026W01 / 51379-0226WO1 O R8bO R8b

[0254]

[0255] -S(O)2F, wherein R8a, R8b, and R8care each independently selected from the group consisting of: H and

[0256] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0257] is a chemical moiety having a group selected from the group consisting of:

[0258]

[0259]

[0260] R8a, R8b, and R8care each independently selected from the group consisting of: H and R7.

[0261] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0262] is a chemical moiety having a group selected from the group consisting of:

[0263]

[0264] o

[0265]

[0266] R8a, and, wherein R8aand R8bare each independently selected R7. For example, R1can be a chemical moiety having a group selected from the group consisting of

[0267]

[0268] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1Docket No. TRLN-008-026W01 / 51379-0226WO1

[0269] R8R80

[0270] is a chemical moiety selected from the group consisting of: -J— and -J—, wherein X4is selected from the group consisting of: -O-, -N(R*)-, -CH2-, and a bond;

[0271] Ring Al is a 6-10 membered heterocyclylene optionally substituted with 1-4 R7;

[0272] Ring A2 is a 4-10 membered heterocyclylene optionally substituted with 1-4 R7; and

[0273] R8is selected from the group consisting of:

[0274]

[0275] RSb

[0276]

[0277] 0, and -S(O)2F, wherein R8a, R8b, and R8care each independently selected from the group consisting of: H and R7.

[0278] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0279] R8R80

[0280] is a chemical moiety selected from the group consisting of:

[0281]

[0282] and —1—, wherein X4is selected from the group consisting of: -O-, -N(R*)-, -CH2-, and a bond;

[0283] Ring Al is a 6-10 membered heterocyclylene optionally substituted with 1-4 R7;

[0284] Ring A2 is a 4-10 membered heterocyclylene optionally substituted with 1-4 R7; and

[0285] R8is selected from the group consisting of:

[0286]

[0287]

[0288] are each independently selected from the group consisting of: H and R7.

[0289] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1Docket No. TRLN-008-026W01 / 51379-0226WO1

[0290] R8

[0291]

[0292] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0293]

[0294] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R8

[0295] is selected from the group consisting of:

[0296]

[0297] R8aand R8bare each independently selected R7.

[0298] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R8o

[0299] is selected from the group consisting of:

[0300]

[0301] wherein the R8bis Rb(e g., R8bis Rbl, -CH2-NH-Rbl, or -CH2-Rbl).

[0302] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R8

[0303] is selected from the group consisting of:

[0304]

[0305]

[0306] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0307]

[0308] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R8

[0309]

[0310] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R8.

[0311] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0312] ted from the group consisting of:

[0313]

[0314]

[0315] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1Docket No. TRLN-008-026W01 / 51379-0226WO1

[0316] O'

[0317] is selected from the group consisting of:

[0318]

[0319] ,, and -J—

[0320] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1is a 6-10 membered heterocyclyl optionally substituted with 1-4 R7, wherein the heterocyclyl has two ring nitrogen atoms, 0-1 ring oxygen atom, and no additional ring heteroatoms.

[0321] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0322] i

[0323]

[0324] s, wherein Ring A3 is a 6-10 membered heterocyclylene optionally substituted with 1-4 R7at one or more ring carbon atoms.

[0325] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1H H H H

[0326] is selected from the group consisting of:

[0327]

[0328] , and

[0329] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), 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, each R7is independently selected from the group consisting of: -F, -OH, oxo, -Rbl, and C1-3 alkyl optionally substituted with 1-3 Rc, wherein the Rblis a 5-6 membered heteroaryl optionally substituted with 1-2 Rg.

[0330] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1(R7)n4

[0331] i

[0332]

[0333] s -J—, wherein: Ring Al is a 4-7 membered heterocyclyl ring having one ringDocket No. TRLN-008-026W01 / 51379-0226WO1

[0334] 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 = n5 = 0. In some embodiments, each R7is independently selected from the group consisting of: -F, -OH, oxo, -Rbl, and C1-3 alkyl optionally substituted with 1-3 Rc, wherein the Rblis a 5-6 membered heteroaryl optionally substituted with 1-2 Rg.

[0335] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0336]

[0337] 6 N 06—0' <6 N ( \0-0

[0338]

[0339] —J— or — J— ), each of which is optionally substituted with 1-2 R7.

[0340] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1is a 4-membered heterocyclyl optionally substituted with 1-4 R7. In some embodiments, each R7is independently selected from the group consisting of: -F, -OH, oxo, -Rbl, and C1-3 alkyl optionally substituted with 1-3 Rc, wherein the Rblis a 5-6 membered heteroaryl optionally substituted with 1-2 Rg.

[0341] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0342]

[0343] N

[0344] is 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, -Rbl, and C1-3 alkyl optionally substituted with 1-3 Rc, wherein the Rblis a 5-6 membered heteroaryl optionally substituted with 1-2 Rg.

[0345] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0346] / \. R7

[0347] < >— R7<

[0348] N N R7

[0349] is selected from the group consisting of: — 1— and —*•. In some embodiments, each R7is independently selected from the group consisting of:

[0350] -Rbl, wherein the Rblis a 5-6 membered heteroaryl optionally substituted with 1-2 Rg;

[0351] C1-3 alkyl optionally substituted with 1-3 F; and

[0352] C1-3 alkyl substituted with -OH or C1-3 alkoxy.

[0353] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1Docket No. TRLN-008-026W01 / 51379-0226WO1

[0354] < -R7< > " R7

[0355] N N

[0356] is — L- (

[0357]

[0358] e g-, —I— ), wherein R7is Ci-3 alkyl substituted with -OH or Ci-3 alkoxy (e.g.,

[0359] C1-3 alkyl substituted with -OH). In some embodiments, R1is

[0360]

[0361] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1 / \ / R7byv R7b

[0362] < / -R7a

[0363] N N 'R73

[0364] i

[0365]

[0366] s -J— (e.g., — 1— ), 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 C1-3 alkyl substituted with -OH or C1-3 alkoxy. For example, R1can be

[0367]

[0368] ). For example, R1can be

[0369] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0370]

[0371] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0372] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0373]

[0374] ), 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

[0375]

[0376] N

[0377] optionally substituted with one Rg). For example, R7can be

[0378]

[0379] N. In some embodiments,Docket No. TRLN-008-026W01 / 51379-0226WO1

[0380] R7is oxazolyl optionally substituted with one Rg(e.g., R7is

[0381]

[0382] ' ° optionally substituted

[0383] with one Rg). For example, R7can

[0384]

[0385] be

[0386] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1 / N 1

[0387] is

[0388]

[0389] -J—, wherein b2 is 0, 1, or 2, and A1and A2are independently selected from the group consisting of: N, CH, and CR7.

[0390] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1R7

[0391] R7

[0392]

[0393] is or

[0394] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R1

[0395] R7a

[0396] R7b

[0397] i

[0398]

[0399] s or, wherein:

[0400] R7ais selected from the group consisting of: C(=O)N(Rf)2, C(O)N(CI-3 alkyl)Rbl, C(O)N(H)Rbl, Rbl, and C(O)Rbl; and

[0401] R7bis -halo, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc.

[0402] In some embodiments, R7ais selected from the group consisting of:

[0403] (a) C(=O)N(Rf)2, wherein each Rfis independently H or C1-3 alkyl optionally substituted with 1-3 Rh;

[0404] (b) C(O)N(C1-3 alkyl)Rblor -C(O)N(H)Rbl, wherein: Rblis C3-6 cycloalkyl or 4-6 membered heterocyclyl, each of which is optionally substituted with 1-3 Rg; and

[0405] (c) C(O)Rbl, wherein Rblis 4-10 membered heterocyclyl optionally substituted with 1-3 Rg, wherein Rblis attached to the C(O) via a ring nitrogen atom.

[0406] In some embodiments, R7bis selected from the group consisting of: -halo, -CN, and C1-3 alkyl optionally substituted with 1-3 -F. In some embodiments, R7bis halo (e.g., -Cl).Docket No. TRLN-008-026W01 / 51379-0226WO1

[0407] In some embodiments, R7ais -C(=O)N(Rf)2, wherein each Rfis independently H or C1-3 alkyl optionally substituted with 1-3 Rh(e.g., each Rfpresent on R7ais an independently selected C1-3 alkyl) (e.g., R7ais C(=0)N(Me)2); and R7bis -Cl, -F, or methyl. For example, R7acan be C(=0)N(Me)2; and R7bcan be -Cl. For example, R7acan be C(=0)N(Me)2; and R7bcan be -F. For example, R7acan be C(=0)N(Me)2; and R7bcan be methyl.

[0408]

[0409] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), E1is N.

[0410] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), Y2

[0411] i

[0412]

[0413] s CH2 or

[0414] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), Y2is CH2.

[0415] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), R3

[0416]

[0417] optionally substituted with 1-2 substituents each independently selected from the

[0418] group consisting of: -F, -C1-3 alkoxy, and -C1-3 haloalkoxy. For example, R3can

[0419]

[0420] be In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), Y2

[0421] is CH2; and R3is

[0422]

[0423] optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F, -C1-3 alkoxy, and -C1-3 haloalkoxy. For example, R3

[0424] can b

[0425]

[0426] eDocket No. TRLN-008-026W01 / 51379-0226WO1

[0427] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), 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, R°

[0428] R°

[0429] and

[0430]

[0431] . 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

[0432] Ci-3 alkoxy. For example, R3can be selected from the group consisting

[0433]

[0434]

[0435] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), Y2is -CH2- or -CD2- (e.g., -CH2-); and R3is an 8-12 membered heterocyclyl substituted with 1-2 R°

[0436]

[0437] R°

[0438] and further optionally substituted with 1-2 independently selected Ra. In some

[0439]

[0440] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0441]

[0442] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), 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

[0443] R°

[0444] consisting of: Raand

[0445]

[0446] . In some embodiments, R is selected from the group consisting

[0447]

[0448] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0449]

[0450] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), Y2-CH2- or -CD2- (e.g., -CH2-); and R3is selected from the group consisting of:

[0451]

[0452]

[0453] Ra3) orRa3(e.g.,Ra3), wherein each Ra3is an independently selected C1-3 alkyl optionally substituted with 1-3 F. For example, R3can be selected from the groupDocket No. TRLN-008-026W01 / 51379-0226WO1

[0454]

[0455] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), Y2

[0456]

[0457] is -CH2- or -CD2- (e.g., -CH2-); and R3is selected from the group consisting of: (F)°-2

[0458]

[0459] independently selected C1-3 alkyl optionally substituted with 1-3 F. For example, R3can be

[0460] selected from the group consisting of:

[0461]

[0462]

[0463] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), Y2is a straight-chain C3-6 alkylene optionally substituted with 1-6 RY. In some embodiments, Y2

[0464] F F

[0465] V7F\ / \ / Fis selected from the group consisting of:

[0466]

[0467] , / \Z N / \, Xs* —,anc[

[0468]

[0469] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), Y2is a straight-chain C3-6 alkylene optionally substituted with 1-6 RY; and R3is -NRdRe. In someDocket No. TRLN-008-026W01 / 51379-0226WO1

[0470] embodiments, Y2is selected from the group consisting of:

[0471]

[0472]

[0473] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), 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

[0474] consisting of: Ra,

[0475]

[0476] ', and \0. In some embodiments, Y2is selected from the

[0477] group consisting of:

[0478]

[0479] In some embodiments of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))), the ring carbon atom labelled with * has (S)-stereochemical configuration.Docket No. TRLN-008-026W01 / 51379-0226WO1

[0480] In some embodiments, the compounds of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))) are selected from the group consisting of:

[0481]

[0482] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0483] or pharmaceutically acceptable salts thereof.

[0484] In some embodiments, the compounds of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))) are selected from the group consisting of the compounds depicted in Table Cl, or pharmaceutically acceptable salts thereof.

[0485] Table Cl

[0486] No. Compound Structure

[0487] CK JL F

[0488] T ]

[0489] H, N k >

[0490] 101 \ N

[0491] r- / F

[0492] \N

[0493] CK JL

[0494] y F

[0495] A'

[0496] 101a

[0497] T = — /

[0498] CK JL

[0499] F

[0500] . X’X.z'N's

[0501] T ]

[0502] H, N < >

[0503] 101b VN

[0504] (J1

[0505]

[0506] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0507]

[0508] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0509]

[0510] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0511]

[0512] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0513]

[0514] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0515]

[0516] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0517]

[0518] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0519]

[0520] In some embodiments, the compounds of Formula (AA) (e.g., Formula (A) (e.g., Formula (I-a1))) are selected from the group consisting of the compounds depicted in Table Cl of U. S. Provisional Application Serial No. 63 / 759,842, filed February 18, 2025, wherein the Table Cl is incorporated by reference in its entirety herein.

[0521] Also provided herein are compounds of Formula (B):Docket No. TRLN-008-026W01 / 51379-0226WO1

[0522]

[0523] Formula (B)

[0524] or pharmaceutically acceptable salts thereof or prodrugs thereof, wherein:

[0525] E1is selected from the group consisting of N, CH, and CR4, wherein R4is selected from the group consisting of: CN, halo, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl;

[0526] R1is selected from the group consisting of:

[0527] (i) a chemical moiety that is capable of forming a covalent bond with the thiol group (SH) of cysteine 12 of a human KRas G12C mutant protein;

[0528] (ii) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7;

[0529] (iii) an 8-12 membered bicyclic heterocyclyl, wherein the heterocyclyl comprises an endocyclic group selected from the group consisting of C(=O)NH and S(O)2NH, and wherein the heterocyclyl is further optionally substituted with 1-3 R7at one or more ring carbon atoms; and

[0530] ,N^

[0531] (

[0532]

[0533] iv) — L-, wherein b2 is 0, 1, 2, or 3; and A1and A2are independently selected from the group consisting of: N, CH, and CR7;

[0534] each R7is independently selected from the group consisting of Raand Rb;

[0535] R2aand R2bare independently selected from the group consisting of: H, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; or

[0536] R2aand R2btaken together with the ring carbon atom to which each is attached form a C3-6 cycloalkyl ring or a 4-6 membered heterocyclyl ring;

[0537] R2Cand R2dare independently selected from the group consisting of: H, halo, CN, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; or

[0538] R2cand R2dtaken together with the ring carbon atom to which each is attached form a C3-6 cycloalkyl ring or a 4-6 membered heterocyclyl ring;

[0539] R2eis selected from the group consisting of: H, C1-3 alkyl, and C1-3 haloalkyl;Docket No. TRLN-008-026W01 / 51379-0226WO1

[0540] CN

[0541] Ring B is selected from the group consisting of:

[0542]

[0543] wherein:

[0544] R9is -NRdRe;

[0545] b1 is 0, 1, or 2;

[0546] Ring B2 is a phenyl ring or a 6-membered heteroaryl ring, each of which is optionally substituted with 1-2 R10;

[0547] each R10is independently selected from the group consisting of: Raand Rb;

[0548] 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,

[0549] R°

[0550] RO

[0551] C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkyl, C1-6 haloalkyl, and

[0552]

[0553] , or

[0554] a pair of RYon the same or different carbon atom(s) taken together 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;

[0555] R3is selected from the group consisting of:

[0556] (a) 4-15 membered heterocyclyl optionally substituted with 1-6 substituents R°

[0557] .R°* independently selected from the group consisting of: Ra, Rb,

[0558]

[0559] ', and '0; and (b) -NRdRe;

[0560] each R° is independently selected from the group consisting of: -H, -F, C1-3 alkyl, and C1-3 haloalkyl;

[0561] Roxis -H or C1-3 alkyl;

[0562] each Rais independently selected from the group consisting of:

[0563] (a) halo;

[0564] (b) cyano;Docket No. TRLN-008-026W01 / 51379-0226WO1

[0565] (c) -OH;

[0566] (d) oxo;

[0567] (e) -Ci-6 alkoxy;

[0568] (f) -Ci-6 haloalkoxy;

[0569] (g) -NRdRe;

[0570] (h) C(=O)Ci-6alkyl;

[0571] (i) C(=O)Ci-6haloalkyl;

[0572] (j) C(=O)OH;

[0573] (k) C(=O)OCi-6alkyl;

[0574] (l) C(=O)OCi-6haloalkyl;

[0575] (m) C(=O)N(Rf)2;

[0576] (n) S(0)o-2(Ci-6 alkyl);

[0577] (o) S(0)o-2(Ci-6 haloalkyl);

[0578] (p) S(O)i.2N(Rf)2; and

[0579] (q) Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc;

[0580] each Rbis independently selected from the group consisting of: -(Lb)b-Rbland -Rbl, wherein:

[0581] b is 1, 2, or 3;

[0582] each -Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(CI-3 alkyl)-, -S(0)o-2-, C(=O), and C1-3 alkylene; and

[0583] each Rblis independently selected from the group consisting of: C3-10 cycloalkyl, 4-12 (e.g., 4-10) membered heterocyclyl, Ce-ioaryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg;

[0584] 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;

[0585] each Rdand Reis independently selected from the group consisting of: H, C(=O)Ci-6 alkyl, C(=O)Ci-6haloalkyl, C(=O)OCi-6alkyl, C(=O)OCi-6haloalkyl, 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;Docket No. TRLN-008-026W01 / 51379-0226WO1

[0586] each Rfis independently selected from the group consisting of: H and Ci-6 alkyl optionally substituted with 1-3 Rh;

[0587] 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

[0588] each Rhis independently selected from the group consisting of: halo, cyano, -OH, -Cn 6 alkoxy, -C1-6 haloalkoxy, -NH2, -N(H)(CI-3 alkyl), and -N(CI-3 alkyl)?-.

[0589] In some embodiments of Formula (B), Ring

[0590]

[0591] B is (R°)bi jnsome embodiments, bl is 1 or 2 (e.g., 2). In some embodiments, R9is -NH2. In some embodiments, each R10is independently selected from the group consisting of: halo; C2-4 alkynyl; and C1-3 alkyl optionally substituted with 1-3 F.

[0592] CN

[0593] H2N

[0594] In some embodiments of Formula (B), Ring B

[0595]

[0596] is (Rl0)bi, wherein bl is 1 or CN

[0597] 2. In some embodiments, Ring

[0598]

[0599] B is In some embodiments, each R10is independently selected from the group consisting of: halo; C2-4 alkynyl; and C1-3 alkyl

[0600] optionally substituted with 1-3 F. For example, Ring B can

[0601]

[0602] be

[0603] In some embodiments of Formula (B), Ring

[0604]

[0605] B is In some embodiments, R9is -NH2. In some embodiments, Ring B2 is a phenyl ring or pyridyl ring, each of which is substituted with 1-2 R10. In some embodiments, each R10is independently selected from theDocket No. TRLN-008-026W01 / 51379-0226WO1

[0606] group consisting of: halo and C1-3 alkyl optionally substituted with 1-3 F.

[0607] In some embodiments of Formula (B), Ring

[0608]

[0609] B is. In some embodiments, each R10is independently selected from the group consisting of: halo CN

[0610] and Ci-3 alkyl optionally substituted with 1-3 F. For example, Ring B can

[0611]

[0612] be

[0613] o

[0614]

[0615] r

[0616] In some embodiments of Formula (B), E1is N.

[0617] In some embodiments of Formula (B), R2aand R2bare each H.

[0618] In some embodiments of Formula (B), R2cand R2dare each H.

[0619] In some embodiments of Formula (B), R2eis H.

[0620] In some embodiments of Formula (B), E1is N; and R2a, R2b, R2c, R2d, and R2eare each H.

[0621] In some embodiments of Formula (B), R1is a 4-10 membered heterocyclyl optionally substituted with 1-4 R7.

[0622] In some embodiments of Formula (B), 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, each R7is independently selected from the group consisting of: -F, -OH, oxo, -Rbl, and C1-3 alkyl optionally substituted with 1-3 Rc, wherein the Rblis a 5-6 membered heteroaryl optionally substituted with 1-2 Rg.

[0623] (R7)n4

[0624] In some embodiments of Formula

[0625]

[0626] (B), R1is —, wherein: Ring Al is aDocket No. TRLN-008-026W01 / 51379-0226WO1

[0627] 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 = n5 = 0. In some embodiments, each R7is independently selected from the group consisting of: -F, -OH, oxo, -Rbl, and C1-3 alkyl optionally substituted with 1-3 Rc, wherein the Rblis a 5-6 membered heteroaryl optionally substituted with 1-2 Rg.

[0628] In some embodiments of Formula (B), R1is selected from the group consisting of:

[0629]

[0630]

[0631] ), each of which is optionally substituted with 1-2 R7.

[0632] In some embodiments of Formula (B), R1is a 4-membered heterocyclyl optionally substituted with 1-4 R7. In some embodiments, each R7is independently selected from the group consisting of: -F, -OH, oxo, -Rbl, and C1-3 alkyl optionally substituted with 1-3 Rc, wherein the Rblis a 5-6 membered heteroaryl optionally substituted with 1-2 Rg.

[0633]

[0634] In some embodiments of Formula (B), R1is — 1— 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, -Rbl, and C1-3 alkyl optionally substituted with 1-3 Rc, wherein the Rblis a 5-6 membered heteroaryl optionally substituted with 1-2 Rg.

[0635] In some embodiments of Formula (B), R1is selected from the group consisting of:

[0636]

[0637] In some embodiments, each R7is independently selected from the group consisting of:

[0638] -Rbl, wherein the Rblis a 5-6 membered heteroaryl optionally substituted with 1-2 Rg; C1-3 alkyl optionally substituted with 1-3 F; and

[0639] C1-3 alkyl substituted with -OH or C1-3 alkoxy.

[0640] \ z Nr7In some embodiments of Formula (B), R1is -J— (e.g., ), wherein R7is

[0641]

[0642] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0643] C1-3 alkyl substituted with -OH or C1-3 alkoxy (e.g., C1-3 alkyl substituted with -OH). In some

[0644] embodiments, R

[0645]

[0646] 1is

[0647] R7b

[0648] N *R7a

[0649] In some embodiments of Formula (B

[0650]

[0651] ), R1is ■J— ), wherein R7ais Ci-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 C1-3 alkyl substituted with -

[0652] OH or Ci -3 alkoxy. For example, R1can be

[0653]

[0654] ). For example, R1

[0655] can b

[0656]

[0657] e

[0658] In some embodiments of Formula (B

[0659]

[0660] ), R1is

[0661] In some embodiments of Formula (B

[0662]

[0663] ), R1is

[0664] In some embodiments of Formula

[0665]

[0666] (B), R1is (e.g., — ), 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

[0667] Rg(e.g., R7is

[0668]

[0669] Noptionally substituted with one Rg). For example, R7can be

[0670]

[0671] N

[0672] . In some embodiments, R7is oxazolyl optionally substituted with one Rg(e.g., R7is y '-0

[0673] optionally substituted with one Rg). For example, R7can be y '-O0Docket No. TRLN-008-026W01 / 51379-0226WO1

[0674] In some embodiments of Formula (B), R1is

[0675]

[0676] , wherein b2 is 0, 1, or 2, and A1and A2are independently selected from the group consisting of: N, CH, and CR7.

[0677] In some embodiments of Formula (B

[0678]

[0679] ), R1is

[0680] In some embodiments of Formula (B

[0681]

[0682] ), R1is, wherein: R7ais selected from the group consisting of: C(=0)N(Rf)2, C(O)N(CI-3 alkyl)Rbl, C(O)N(H)Rbl, Rbl, and C(O)Rbl; and

[0683] R7bis -halo, -CN, and C1-3 alkyl optionally substituted with 1-3 Rc.

[0684] In some embodiments, R7ais selected from the group consisting of:

[0685] (a) C(=0)N(Rf)2, wherein each Rfis independently H or C1-3 alkyl optionally substituted with 1-3 Rh;

[0686] (b) C(O)N(C1-3 alkyl)Rblor -C(O)N(H)Rbl, wherein: Rblis C3-6 cycloalkyl or 4-6 membered heterocyclyl, each of which is optionally substituted with 1-3 Rg; and

[0687] (c) C(O)Rbl, wherein Rblis 4-10 membered heterocyclyl optionally substituted with 1-3 Rg, wherein Rblis attached to the C(O) via a ring nitrogen atom.

[0688] In some embodiments, R7bis selected from the group consisting of: -halo, -CN, and C1-3 alkyl optionally substituted with 1-3 -F. In some embodiments, R7bis halo (e.g., -Cl).

[0689] In some embodiments, R7ais -C(=O)N(Rf)2, wherein each Rfis independently H or Cn 3 alkyl optionally substituted with 1-3 Rh(e.g., each Rfpresent on R7ais an independently selected C1-3 alkyl) (e.g., R7ais C(=O)N(Me)2); and R7bis -Cl, -F, or methyl. For example, R7acan be C(=O)N(Me)2; and R7bcan be -Cl. For example, R7acan be C(=O)N(Me)2; and R7bcan be -F. For example, R7acan be C(=O)N(Me)2; and R7bcan be methyl.Docket No. TRLN-008-026W01 / 51379-0226WO1

[0690]

[0691] In some embodiments of Formula (B), Y2is -CH2- or -CD2- (e.g., -CH2-).

[0692] In some embodiments of Formula (B), Y2is -CH2- or -CD2- (e.g., -CH2-); and R3is

[0693]

[0694] optionally substituted with 1-2 substituents each independently selected from the

[0695] group consisting of: -F, -C1-3 alkoxy, and -C1-3 haloalkoxy. For example, R3can

[0696]

[0697] be 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 R°

[0698] R° independently selected from the group consisting of: Ra, Rb, and

[0699]

[0700] . 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

[0701] example, R3can be selected from the group consisting of:

[0702]

[0703]

[0704] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0705]

[0706] In some embodiments of Formula (B), Y2is -CH2- or -CD2- (e.g., -CH2-); and R3is an R°

[0707] R°

[0708] 8-12 membered heterocyclyl substituted with 1-2

[0709]

[0710] and further optionally substituted with 1-2 independently selected Ra. In some embodiments, R3is selected from the group

[0711]

[0712] . For

[0713] example, R3can be selected from the group consisting of:

[0714]

[0715]

[0716] 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

[0717] R°

[0718] RO

[0719] substituents independently selected from the group consisting of: Raand

[0720]

[0721] . In some

[0722] embodiments, R3is selected from the group consisting of:

[0723]

[0724]

[0725] andR0. For example, R3can be selected from the group consistingDocket No. TRLN-008-026W01 / 51379-0226WO1

[0726]

[0727] In some embodiments of Formula (B), Y2is -CH2- or -CD2- (e.g., -CH2-); and R3isDocket No. TRLN-008-026W01 / 51379-0226WO1

[0728]

[0729]

[0730] Ra3), wherein each Ra3is an independently selected C1-3 alkyl optionally substituted

[0731] with 1-3 F. For example, R3can be selected from the group consisting of:

[0732]

[0733]

[0734] In some embodiments of Formula (B), Y2is -CH2- or -CD2- (e.g., -CH2-); and R3is

[0735]

[0736]

[0737] , wherein each Ra3is an independently selected C1-3 alkyl optionally substituted with 1-3 F. For example, R3can be selected from the group consisting o

[0738]

[0739] f:Docket No. TRLN-008-026W01 / 51379-0226WO1

[0740]

[0741] 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:

[0742]

[0743] 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

[0744]

[0745] 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- R° X^^^R0

[0746] 3 substituents independently selected from the group consisting of: Ra, ', and ’ '-N”h"0'ROX. In some embodiments, Y2is selected from the group consisting of:

[0747]

[0748] ' z A

[0749]

[0750] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0751]

[0752] Chemical definitions

[0753] The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0754] 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.

[0755] 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, n-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.

[0756] 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).

[0757] 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).

[0758] The term “alkylene” refers to a divalent alkyl (e.g., -CH2-). Similarly, terms such as “cycloalkylene” and “heterocyclylene” refer to divalent cycloalkyl and heterocyclyl respectively. For avoidance of doubt, in “cycloalkylene” and “heterocyclylene”, the two

[0759] radicals can be on the same ring carbon atom (e.g., a geminal diradical such

[0760]

[0761] as or

[0762]

[0763] ) or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ringDocket No. TRLN-008-026W01 / 51379-0226WO1

[0764] carbon and / or nitrogen atoms))

[0765]

[0766] (e.g., 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.

[0767] The term “alkynyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl 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.

[0768] 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.

[0769] 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 of fused / 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,Docket No. TRLN-008-026W01 / 51379-0226WO1

[0770] bicyclo[3.2. l]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.

[0771] 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

[0772] consisting of N, O, S (inclusive of oxidized forms such as:

[0773]

[0774] or ), and P (inclusive o n^ xX

[0775] of oxidized forms such as:

[0776]

[0777] ' ) 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-Z>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-Z>]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-hydrogen substituents), such as one or more of pyridonyl (e.g.,

[0778]

[0779] Docket No. TRLN-008-026W01 / 51379-0226WO1

[0780]

[0781] imidazolonyl (e.g.,

[0782]

[0783] ), 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).

[0784] 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 o

[0785] from O, N, S (inclusive of oxidized forms such as:

[0786]

[0787] ), and P (inclusive of

[0788] oxidized forms such as:

[0789]

[0790] ) (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.

[0791] Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyl includes: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2- azabicy clo[ 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, 2-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, 5- oxabicyclo[2.1.1 ]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 7Docket No. TRLN-008-026W01 / 51379-0226WO1

[0792] 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, l-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2-azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, l,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, l,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.

[0793] 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.

[0794] 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 order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x. O] ring systems, in which 0 represents a zero atom

[0795] bridge (e.g., )); (ii) a single ring atom (spiro-fused ring systems) (e.g.,

[0796]

[0797]

[0798] , or ), or (iii) a contiguous array of ring atoms (bridged ring systems

[0799] having all bridge lengths > 0) (e.g., 00, or

[0800]

[0801] f© ’—^"'' 7.

[0802] 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 withoutDocket No. TRLN-008-026W01 / 51379-0226WO1

[0803] limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0804] 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:

[0805]

[0806] * encompasses the tautomeric form containing the moiety:

[0807]

[0808] HSimilarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0809] 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.

[0810] 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(0)o-2-halo bonds. Accordingly, such compounds are less preferred. As used herein, “acyclic bonds” mean

[0811] chemical bonds that are not part of a ring. Examples include the N-0 bond i

[0812]

[0813] n0HandOH. For avoidance of doubt, acyclic N-O, N-N, or N-S(0)o bonds (i.e., those bonds that are not i H

[0814] FN

[0815] part of a ring (e.g., in

[0816]

[0817] HorH)) are less preferred, but compounds provided herein can include N-O, N-N, or N-S(0)o bonds that form part of a ring (e.g., the N-N bond in IT \ —

[0818]

[0819] )Docket No. TRLN-008-026W01 / 51379-0226WO1

[0820] Methods of Treatment

[0821] Indications

[0822] 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 G12C mutant protein, 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).

[0823] 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 / sl3073-020-0714-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.

[0824] 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). Nonlimiting 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 / sl3073-020-0714-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.Docket No. TRLN-008-026W01 / 51379-0226WO1

[0825] The phrase “dysregulation of a KRAS gene, a KRas protein, or the expression or activity or level of any of the same” refers to (i) 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); (ii) 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 (iii) 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, a KRas amplification is an amplification of the wild type KRas. In some embodiments, a KRas amplification is an amplification of a mutant KRas.

[0826] 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)Docket No. TRLN-008-026W01 / 51379-0226WO1

[0827] 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.

[0828] 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).

[0829] 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).

[0830] 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).

[0831] 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).

[0832] 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).

[0833] 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).

[0834] A “KRas G12S mutant protein” as used herein refers to a KRas protein including a glycine to serine substitution at the twelfth amino acid position (relative to SEQ ID NO: 1).

[0835] 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).

[0836] 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).

[0837] 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).

[0838] 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).Docket No. TRLN-008-026W01 / 51379-0226WO1

[0839] 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).

[0840] 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).

[0841] 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).

[0842] 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).

[0843] 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).

[0844] 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).

[0845] 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).

[0846] 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).

[0847] 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 theDocket No. TRLN-008-026W01 / 51379-0226WO1

[0848] 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 termed a “KRas G13D inhibitor”. In some embodiments, a KRas inhibitor can inhibit a KRas protein having 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.

[0849] Compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts thereof, are KRas inhibitors. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a mutant KRas inhibitor. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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, aDocket No. TRLN-008-026W01 / 51379-0226WO1

[0850] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12V mutant protein, or a combination thereof. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein, a KRas G12V mutant protein, or both. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12R mutant protein, a KRas G12V mutant protein, or both. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12C mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12R mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12V mutant protein.

[0851] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12X inhibitor. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12DDocket No. TRLN-008-026W01 / 51379-0226WO1

[0852] mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptableDocket No. TRLN-008-026W01 / 51379-0226WO1

[0853] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein, a KRAS G12V mutant protein, or both. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12A mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12C mutant protein In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, does not inhibit a KRas G12D mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12R mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12S mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12V mutant protein.

[0854] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G13X inhibitor. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G13C mutant protein, a KRas G13D mutant protein, and a KRas G13VDocket No. TRLN-008-026W01 / 51379-0226WO1

[0855] mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G13C mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G13D mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G13V mutant protein.

[0856] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas Q61X inhibitor. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits five or more mutant KRas proteins selected from the group consisting of: a KRas Q61EDocket No. TRLN-008-026W01 / 51379-0226WO1

[0857] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61E mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61H mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61K mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61L mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61P mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61R mutant protein.

[0858] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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, aDocket No. TRLN-008-026W01 / 51379-0226WO1

[0859] compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 mutantDocket No. TRLN-008-026W01 / 51379-0226WO1

[0860] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein.

[0861] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or FormulaDocket No. TRLN-008-026W01 / 51379-0226WO1

[0862] (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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, the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts thereof, are useful for treating a bladder cancer.

[0863] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or FormulaDocket No. TRLN-008-026W01 / 51379-0226WO1

[0864] (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts thereof, are useful for treating a cervical cancer.

[0865] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutantDocket No. TRLN-008-026W01 / 51379-0226WO1

[0866] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts thereof, are useful for treating a colorectal cancer.

[0867] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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,Docket No. TRLN-008-026W01 / 51379-0226WO1

[0868] a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G13V mutant protein, a KRas Q61H mutant protein, and a KRas Q61L mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts thereof, are useful for treating an endometrial cancer.

[0869] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits one or more mutantDocket No. TRLN-008-026W01 / 51379-0226WO1

[0870] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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, a KRas G13D mutant protein, and a KRas Q61H mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts thereof, are useful for treating an esophageal or stomach cancer.

[0871] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 KRasDocket No. TRLN-008-026W01 / 51379-0226WO1

[0872] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 mutantDocket No. TRLN-008-026W01 / 51379-0226WO1

[0873] protein, and a KRas G12V mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts thereof, are useful for treating a leukemia.

[0874] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G13D mutant protein, a KRas G13V mutant protein, a KRas a KRas Q61K mutant protein, a KRas Q61L mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 a KRas Q61K mutant protein, a KRas Q61L mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 a KRas Q61K mutant protein, a KRas Q61L mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteinsDocket No. TRLN-008-026W01 / 51379-0226WO1

[0875] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein, and a KRas G12R mutant protein, or both. In some such embodiments, the compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts thereof, are useful for treating a melanoma.

[0876] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 Q6 IL mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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, aDocket No. TRLN-008-026W01 / 51379-0226WO1

[0877] KRas G12D mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts thereof, are useful for treating a lung cancer (e.g., non-small cell lung cancer).

[0878] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 Q61RDocket No. TRLN-008-026W01 / 51379-0226WO1

[0879] mutant protein. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceuticallyDocket No. TRLN-008-026W01 / 51379-0226WO1

[0880] acceptable salts thereof, are useful for treating a pancreatic cancer.

[0881] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof,Docket No. TRLN-008-026W01 / 51379-0226WO1

[0882] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts thereof, are useful for treating a testicular cancer (e.g., seminoma).

[0883] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, can bind to a KRas protein in the GTP -bound state. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, can bind selectively to a KRas protein in the GTP -bound state.

[0884] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, can bind to a KRas protein in the GDP -bound state. In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, can bind selectively to a KRas protein in the GDP -bound state.

[0885] An exemplary sequence of mature human KRas protein is shown below (UniProtKB entry P01116) (SEQ ID NO: 1)

[0886] MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ RVEDAFYTLV REIRQYRLKK ISKEEKTPGC VKIKKCIIM

[0887] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or aDocket No. TRLN-008-026W01 / 51379-0226WO1

[0888] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, “selectively” reduces the viability 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) EC50 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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.

[0889] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C 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 KRasDocket No. TRLN-008-026W01 / 51379-0226WO1

[0890] 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 of the two cell lines. For example, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 it does not inhibit (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 it does not inhibit (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).

[0891] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein and a KRas G12V mutant protein. In some such embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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).Docket No. TRLN-008-026W01 / 51379-0226WO1

[0892] For example, if the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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-Docket No. TRLN-008-026W01 / 51379-0226WO1

[0893] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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.

[0894] In some such embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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).

[0895] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 aboutDocket No. TRLN-008-026W01 / 51379-0226WO1

[0896] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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).

[0897] For example, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 someDocket No. TRLN-008-026W01 / 51379-0226WO1

[0898] embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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).

[0899] For example, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, can inhibit ERK phosphorylation in a GP2d cell line 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 SW620 cell line, wherein the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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).Docket No. TRLN-008-026W01 / 51379-0226WO1

[0900] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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).

[0901] For example, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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).Docket No. TRLN-008-026W01 / 51379-0226WO1

[0902] The ability of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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.

[0903] In some cases, binding affinities (e.g., as measured by dissociation constant KD) of the compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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).

[0904] Another exemplary assay for determining the potency of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, includes measuring the effect of the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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,Docket No. TRLN-008-026W01 / 51379-0226WO1

[0905] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B)). 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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.

[0906] As another example, the potency and / or efficacy of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 SW620or a patient-derived xenograft (PDX) model). See, e.g., U. S. Publication No. US 2021 / 0179633.

[0907] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or aDocket No. TRLN-008-026W01 / 51379-0226WO1

[0908] 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 G12C mutant protein, 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 G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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.

[0909] In some embodiments, potency of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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).

[0910] In some embodiments, potency of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, as provided herein can also be determined by IC50 value. A compound with a lower IC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC50 value. In some embodiments, an IC50 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,Docket No. TRLN-008-026W01 / 51379-0226WO1

[0911] 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).

[0912] In some embodiments, measuring the potency of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 (e.g., AGS, A375, A427, ASPC1, H727, H441, RKN, and / or SW620)). For example, cells can be contacted with a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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® Phospho-ERK (Thr202 / Tyr204) cellular kit (CisBio)). In some embodiments, multiple concentrations of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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.

[0913] 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, opaque-bottom Perkin Elmer CulturPlate-384 (product number 6007680)), cells are seeded at the desired concentration one day prior to treatment with compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 MIAPACA2 (KRas G12C), H358 (KRas G12C), AGS (KRas G12D), ASPC1 (KRas G12D), GP2D (KRas G12D), LSI 80 (KRas G12D), Panc04.03 (KRas G12D),Docket No. TRLN-008-026W01 / 51379-0226WO1

[0914] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 µM 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

[0915]

[0916] 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.

[0917] 615nm Signal (pERKl / 2)

[0918] Ratio pERKl / 2 = — - 545nm Signal (Total ERK1 / 2)

[0919] 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.

[0920] In some embodiments, the compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, 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 G12C mutant protein, aDocket No. TRLN-008-026W01 / 51379-0226WO1

[0921] 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 G12C mutant protein, 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.

[0922] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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.

[0923] In some embodiments, the potency of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 proteinbound 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 beDocket No. TRLN-008-026W01 / 51379-0226WO1

[0924] measured via the increase in fluorescence of an incubated mixture of KRas protein-bound GDP and a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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., SOS1) can be added to accelerate nucleotide exchange.

[0925] Inhibition of SOS 1 -catalyzed exchange of GDP for GTP on the KRas protein by compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, 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.

[0926] An exemplary SO SI -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. lOpL of the 1.5x KRas-Ab solution is added to wells of aDocket No. TRLN-008-026W01 / 51379-0226WO1

[0927] black, low-volume 384-well assay plate, compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 pM 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 pL of the SOS 1 -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], IC50 values are calculated using a four-parameter, variable response sigmoidal dose response curve fit in Graphpad Prism software.

[0928] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits SOS 1 -catalyzed exchange of GDP for GTP on the KRas 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 SOS 1 -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 compounds 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.

[0929] Additional assays for evaluating the potency of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof). For example, FLAG tagged KRas protein can be preloaded with the GTP analogue 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.,Docket No. TRLN-008-026W01 / 51379-0226WO1

[0930] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts thereof, that may bind selectively to the GTP-state, His-tagged KRas protein can be preloaded with the GTP analogue GppNHp and then incubated with a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 IC50 value. 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 ofDocket No. TRLN-008-026W01 / 51379-0226WO1

[0931] 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 the two parts of the enzyme can be tuned, for example, to reduce or eliminate signal based on proximity 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, 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.

[0932] Inhibition of the interaction between the KRas protein and Raf-RBD by compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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)).

[0933] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, modulates the interaction between the KRas protein and one or more Raf proteins. In some embodiments, the compounds inhibit the interaction between the KRas protein and Raf-RBD 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 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 compounds inhibit the interaction between the KRas protein and Raf-RBD with an IC50 from 0.001 nM toDocket No. TRLN-008-026W01 / 51379-0226WO1

[0934] 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.

[0935] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, inhibits the interaction between the KRas protein and Raf-RBD with an IC50 of less than 1 pM 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 1 nM, 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.

[0936] Another exemplary assay for evaluating the potency of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 ERK1ZERK2 (Phospho) [pT202 / pY204] / [pT185 / pY187] ELISA or MesoScale Discovery p / t ERK1 / 2). In some embodiments, multiple concentrations of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, can be used to construct a dose response curve. In some embodiments, the compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12RDocket No. TRLN-008-026W01 / 51379-0226WO1

[0937] 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 a KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12C mutant protein, 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 G12C mutant protein, 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.

[0938] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt 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 G12C mutation, 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 pM, 3 pM, 1.1 pM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and an EC50 is calculated.

[0939] 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.

[0940] The pharmacokinetic parameters of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 (Va), maximum plasma concentration (Cmax), time of maximum plasma concentration (tmax), half-life (ti / 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.Docket No. TRLN-008-026W01 / 51379-0226WO1

[0941] Certain pharmacokinetic parameters of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 (ti / 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.

[0942] In some embodiments, the compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or pharmaceutically acceptable salts 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, a KRas G12D mutant protein and / or a KRas G12V mutant protein))). In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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).

[0943] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceuticallyDocket No. TRLN-008-026W01 / 51379-0226WO1

[0944] 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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).

[0945] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative inhibition of aDocket No. TRLN-008-026W01 / 51379-0226WO1

[0946] related GTPase (e.g., wild type NRas protein, and / or wild type HRas protein). In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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).

[0947] In some embodiments, the compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, a KRas G12D mutant protein and / or a KRas G12V mutant protein))). In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, can selectively inhibit a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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).

[0948] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of a mutant KRas protein (e.g., a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 greaterDocket No. TRLN-008-026W01 / 51379-0226WO1

[0949] inhibition of a mutant KRas protein (e.g., a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, can exhibit up to 10000-fold greater inhibition of a mutant KRas protein (e.g., a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild type KRas protein.

[0950] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild type KRas protein.Docket No. TRLN-008-026W01 / 51379-0226WO1

[0951] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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.

[0952] In some embodiments, a compound of Formula (AA), Formula (A) (e.g., Formula (I-Docket No. TRLN-008-026W01 / 51379-0226WO1

[0953] al)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12C mutant protein, 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.

[0954] Compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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), and proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced solid tumors). In some embodiments, the diseases and disorders are KRas-associated diseases and disordersDocket No. TRLN-008-026W01 / 51379-0226WO1

[0955] (e.g., mutant KRas-associated diseases or disorders (e.g., KRas G12C-, KRas G12D-, KRas G12R-, or G12V-associated diseases or disorders)).

[0956] In certain embodiments, compounds of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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).

[0957] 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.

[0958] 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 a regulatory agency -approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject 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).

[0959] 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 consistingDocket No. TRLN-008-026W01 / 51379-0226WO1

[0960] 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.

[0961] In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, or KRas G12V mutation (e.g., a KRas G12C mutation, 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 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 G12V mutation.

[0962] 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). Nonlimiting examples of a KRas-associated cancer are described herein.

[0963] 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.

[0964] 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). Nonlimiting examples of a KRas G12X-associated cancer are described herein.

[0965] 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). Nonlimiting examples of a KRas G12A-associated cancer are described herein.

[0966] 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-Docket No. TRLN-008-026W01 / 51379-0226WO1

[0967] limiting examples of a KRas G12C-associated cancer are described herein.

[0968] 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). Nonlimiting examples of a KRas G12D -associated cancer are described herein.

[0969] 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). Nonlimiting examples of a KRas G12R-associated cancer are described herein.

[0970] 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). Nonlimiting examples of a KRas G12S-associated cancer are described herein.

[0971] 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). Nonlimiting examples of a KRas G12V-associated cancer are described herein.

[0972] 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). Nonlimiting examples of a KRas G13X-associated cancer are described herein.

[0973] 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). Nonlimiting examples of a KRas G13C-associated cancer are described herein.

[0974] 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). Nonlimiting examples of a KRas G13D-associated cancer are described herein.

[0975] 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). Nonlimiting examples of a KRas G13V-associated cancer are described herein.Docket No. TRLN-008-026W01 / 51379-0226WO1

[0976] 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). Nonlimiting examples of a KRas Q61X-associated cancer are described herein.

[0977] The term “KRas Q6 IE-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). Nonlimiting examples of a KRas Q6 IE-associated cancer are described herein.

[0978] 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). Nonlimiting examples of a KRas Q61H-associated cancer are described herein.

[0979] 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). Nonlimiting examples of a KRas Q61K-associated cancer are described herein.

[0980] The term “KRas Q61L-associated cancer” as used herein refers to cancers associated with 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). Nonlimiting examples of a KRas Q61L-associated cancer are described herein.

[0981] The term “KRas Q6 IP-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). Nonlimiting examples of a KRas Q61P-associated cancer are described herein.

[0982] 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). Nonlimiting examples of a KRas Q61R-associated cancer are described herein.

[0983] 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.

[0984] 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 aDocket No. TRLN-008-026W01 / 51379-0226WO1

[0985] compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is treatment naive with respect to the cancer. In some embodiments, the subject has received one or more lines of previous therapy for the cancer.

[0986] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy. In some embodiments, the subject is treatment naive with respect to the cancer. In some embodiments, the subject has received one or more lines of previous therapy for the cancer.

[0987] Provided herein is use of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of cancer, for example, any of the cancers provided herein.

[0988] Provided herein is use of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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.

[0989] Provided herein is use of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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.

[0990] Provided herein is a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament. Also provided herein is a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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.

[0991] Provided herein is a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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.

[0992] As used herein, “monotherapy”, when referring to a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable saltDocket No. TRLN-008-026W01 / 51379-0226WO1

[0993] thereof, means that the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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). Monotherapy does not exclude the co-administration of medicaments (including, for example, over the counter or prescription medications, vitamins, and / or herbal supplements) for the treatment of side effects (e.g., adverse events), concurrent illnesses, or general symptoms associated with the cancer or treatment, such as pain, rash, edema, photosensitivity, pruritus, 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. These types of medicaments are sometimes referred to as “supportive care” or “supportive therapy”. In some embodiments, transfusion with blood products and / or administration of granulocyte colony-stimulating factor (G-CSF) is considered to be supportive care.

[0994] As used herein, “the subject has previously received one or more therapeutic agents or therapies for the cancer” or “the subject has received one or more lines of therapy for the cancer” means that the subj ect has been previously administered one or more therapeutic agents or therapies (e.g., anticancer agent or therapy (e.g., systemic therapies)) for the cancer other than a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, during a prior treatment cycle. In some embodiments, at least one of the one or more therapeutic agents or therapies was administered systemically. 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 subj ect has stopped responding to the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, a response, 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, the Lugano 2014 criteria (Cheson, Bruce D., et al. Journal of Clinical Oncology 32.27 (2014): 3059-3067; doi: 10.1200 / JC0.2013.54.8800) or the Global Response Criteria (Olsen, Elise A., et al. Blood, The Journal of the AmericanDocket No. TRLN-008-026W01 / 51379-0226WO1

[0995] Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057)). In some embodiments, a response, a lack of response, an inadequate response, or a discontinued response can be determined by the subject’s physician.

[0996] As used herein, “the subject is treatment naive with respect to the cancer”, “the subject is treatment-naive”, or that the subject was “previously untreated” for the cancer means that the subject has not been previously administered one or more therapeutic agents or therapies for the cancer. Treatment of a subject who is treatment naive with respect to the cancer is often referred to as “first-line” therapy.

[0997] 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.

[0998] Provided herein is a method of treating a cancer in a 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 G12C mutation, a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation (e.g., a KRas G12C mutation, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer (e.g., a KRas G12C-associated cancer, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12C-Docket No. TRLN-008-026W01 / 51379-0226WO1

[0999] associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer (e.g., a KRas G12C-associated cancer, 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 G12C mutation, a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation (e.g., a KRas G12C mutation, 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof.

[1000] 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 G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer (e.g., a KRas G12C-associated cancer, 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., cervicalDocket No. TRLN-008-026W01 / 51379-0226WO1

[1001] 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.

[1002] 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. 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.Docket No. TRLN-008-026W01 / 51379-0226WO1

[1003] In some embodiments, the cancer is a hematological cancer, cervical cancer, colon cancer, endometrial cancer, liver cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), pancreatic cancer, rectal cancer, testicular cancer (e.g., seminoma), skin cancer, stomach cancer, urothelial cancer, or uterine cancer. In some embodiments, the cancer is a KRas G12C-associated cancer.

[1004] 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, 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.

[1005] 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.

[1006] 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.

[1007] 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.

[1008] 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,Docket No. TRLN-008-026W01 / 51379-0226WO1

[1009] 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.

[1010] In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., mutant KRas-associated cancer)) is advanced-stage lung adenocarcinoma.

[1011] 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 G12C mutation, 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 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 G12V mutation.

[1012] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 aDocket No. TRLN-008-026W01 / 51379-0226WO1

[1013] sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[1014] 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. 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 G12D mutation. In some embodiments, the bladder cancer has a KRas G12R mutation. In some embodiments, the bladder cancer has a KRas G12V mutation.

[1015] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceuticalDocket No. TRLN-008-026W01 / 51379-0226WO1

[1016] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12R mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), 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 G12V mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[1017] In some embodiments, the cancer is a cervical cancer. In some embodiments, the cervical cancer has a KRas dysregulation (e.g., a KRas mutation or amplification). ForDocket No. TRLN-008-026W01 / 51379-0226WO1

[1018] example, the cervical cancer has a KRas mutation selected from the group consisting of: a KRas G12C mutation, a KRas G12D mutation, a KRas G12V mutation, and a KRas G13D mutation. In some embodiments, the cervical cancer has a KRas G12D mutation or a KRas G12V mutation. In some embodiments, the cervical cancer has a KRas G12D mutation. In some embodiments, the cervical cancer has a KRas G12V mutation.

[1019] Also provided herein is a method of treating a cervical 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating a cervical cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12C mutation, a KRas G12D mutation, a KRas G12V mutation, or a KRas G13D mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a cervical 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a cervical cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12D 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a cervical cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a cervical cancer 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 theDocket No. TRLN-008-026W01 / 51379-0226WO1

[1020] subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[1021] In some embodiments, the cancer is a colorectal cancer. In some embodiments, the colorectal cancer has a KRas dysregulation (e.g., a KRas mutation or amplification). For example, the colorectal cancer 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, 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, the colorectal cancer has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation. In some embodiments, the colorectal cancer has a KRas G12D mutation or a KRas G12V mutation. In some embodiments, the colorectal cancer has a KRas G12D mutation. In some embodiments, the colorectal cancer has a KRas G12V mutation.

[1022] Also provided herein is a method of treating a colorectal 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating a colorectal cancer 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, 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, or a KRas Q61R mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a colorectal 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceuticallyDocket No. TRLN-008-026W01 / 51379-0226WO1

[1023] acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a colorectal cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12D 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a colorectal cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a colorectal cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a colorectal cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[1024] In some embodiments, the cancer is an endometrial cancer. In some embodiments, the endometrial cancer has a KRas dysregulation (e.g., a KRas mutation or amplification). For example, the endometrial cancer has a KRas mutation selected from the group consisting of: a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12S mutation, a KRas G12V mutation, a KRas G13C mutation, a KRas G13D mutation, a KRas G13V mutation, a KRas Q61H mutation, and a KRas Q61L mutation. In some embodiments, the endometrial cancer has a KRas G12D mutation or a KRas G12V mutation. In some embodiments, the endometrial cancer has a KRas G12D mutation. In some embodiments, the endometrial cancer has a KRas G12V mutation.

[1025] Also provided herein is a method of treating an endometrial 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 aDocket No. TRLN-008-026W01 / 51379-0226WO1

[1026] therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating an endometrial cancer 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 G12S mutation, a KRas G12V mutation, a KRas G13C mutation, a KRas G13D mutation, a KRas G13V mutation, a KRas Q61H mutation, or a KRas Q61L mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an endometrial 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an endometrial cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12D 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an endometrial cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an endometrial cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[1027] In some embodiments, the cancer is an esophageal or stomach cancer. In some embodiments, the esophageal or stomach cancer has a KRas dysregulation (e.g., a KRas mutation or amplification). For example, the esophageal or stomach cancer has a KRasDocket No. TRLN-008-026W01 / 51379-0226WO1

[1028] mutation selected from the group consisting of: a KRas G12C mutation, a KRas G12D mutation, a KRas G12S mutation, a KRas G12V mutation, a KRas G13C mutation, a KRas G13D mutation, and a KRas Q61H mutation. In some embodiments, the esophageal or stomach cancer has a KRas G12D mutation or a KRas G12V mutation. In some embodiments, the esophageal or stomach cancer has a KRas G12D mutation. In some embodiments, the esophageal or stomach cancer has a KRas G12V mutation.

[1029] Also provided herein is a method of treating an esophageal or stomach 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating an esophageal or stomach cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12C mutation, a KRas G12D mutation, a KRas G12S mutation, a KRas G12V mutation, a KRas G13C 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an esophageal or stomach cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an esophageal or stomach cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12D 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating an esophageal or stomach cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceuticalDocket No. TRLN-008-026W01 / 51379-0226WO1

[1030] composition as described herein. Additionally provided herein is a method of treating an esophageal or stomach cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[1031] In some embodiments, the cancer is a leukemia. In some embodiments, the leukemia has a KRas dysregulation (e.g., a KRas mutation or amplification). For example, the leukemia 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, 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, the leukemia has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation. In some embodiments, the leukemia has a KRas G12D mutation or a KRas G12V mutation. In some embodiments, the leukemia has a KRas G12D mutation. In some embodiments, the leukemia has a KRas G12R mutation. In some embodiments, the leukemia has a KRas G12V mutation.

[1032] Also provided herein is a method of treating a leukemia 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating a leukemia 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, 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, or a KRas Q61R mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a leukemia in a subject in need thereof, the methodDocket No. TRLN-008-026W01 / 51379-0226WO1

[1033] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a leukemia in a subject in need thereof, the method comprising: (a) detecting a KRas G12D 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a leukemia 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a leukemia 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a leukemia 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[1034] In some embodiments, the cancer is a melanoma. In some embodiments, the melanoma has a KRas dysregulation (e.g., a KRas mutation or amplification). For example, the melanoma has a KRas mutation selected from the group consisting of: a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G13D mutation, a KRas G13V mutation, a KRas a KRas Q61K mutation, a KRas Q61L mutation, and a KRas Q61R mutation. In some embodiments, the melanoma has a KRas G12D mutation or a KRas G12R mutation. In some embodiments, the melanoma has a KRas G12D mutation. In some embodiments, the melanoma has a KRas G12R mutation.

[1035] Also provided herein is a method of treating a melanoma in a subject in need thereof,Docket No. TRLN-008-026W01 / 51379-0226WO1

[1036] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating a melanoma 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 G13D mutation, a KRas G13V mutation, a KRas a KRas Q61K mutation, a KRas Q61L mutation, or a KRas Q61R mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a melanoma 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a melanoma 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a melanoma 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[1037] In some embodiments, the cancer is a lung cancer (e.g., non-small cell lung cancer). In some embodiments, the lung cancer (e.g., non-small cell lung cancer) has a KRas dysregulation (e.g., a KRas mutation or amplification). For example, the lung cancer (e.g., non-small cell lung cancer) has a KRas mutation selected from the group consisting of: a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12S mutation, a KRas G12V mutation, a KRas G13C mutation, a KRas G13D mutation, a KRas Q61H mutation, and a KRas Q61L mutation. In some embodiments, the lung cancer has a KRas G12D mutation orDocket No. TRLN-008-026W01 / 51379-0226WO1

[1038] a KRas G12V mutation. In some embodiments, the lung cancer has a KRas G12D mutation. In some embodiments, the lung cancer has a KRas G12V mutation.

[1039] Also provided herein is a method of treating a lung cancer (e.g., non-small cell lung 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating a lung cancer (e.g., non-small cell lung cancer) 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 G12S mutation, a KRas G12V mutation, a KRas G13C mutation, a KRas G13D mutation, a KRas Q61H mutation, or a KRas Q61L mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a lung 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a lung cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12D 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a lung cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a lung cancer 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 of Formula (AA), Formula (A) (e.g., FormulaDocket No. TRLN-008-026W01 / 51379-0226WO1

[1040] (I-al)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[1041] In some embodiments, the cancer is a pancreatic cancer. In some embodiments, the pancreatic cancer has a KRas dysregulation (e.g., a KRas mutation or amplification). For example, the pancreatic cancer 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, a KRas G12V mutation, a KRas G13C mutation, a KRas Q61H mutation, and a KRas Q61R mutation. In some embodiments, the pancreatic cancer has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation. In some embodiments, the pancreatic cancer has a KRas G12D mutation or a KRas G12V mutation. In some embodiments, the pancreatic cancer has a KRas G12D mutation. In some embodiments, the pancreatic cancer has a KRas G12R mutation. In some embodiments, the pancreatic cancer has a KRas G12V mutation.

[1042] Also provided herein is a method of treating a pancreatic 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating a pancreatic cancer 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, a KRas G12V mutation, a KRas G13C mutation, a KRas Q61H mutation, or a KRas Q61R mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a pancreatic cancer in a subject in need thereof, the method comprising: (a) detecting 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a pancreatic cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12C mutation in a sample from the subject, and (b)Docket No. TRLN-008-026W01 / 51379-0226WO1

[1043] administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a pancreatic cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12D 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a pancreatic cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a pancreatic cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a pancreatic cancer 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[1044] In some embodiments, the cancer is a testicular cancer (e.g., seminoma). In some embodiments, the testicular cancer (e.g., seminoma) has a KRas dysregulation (e.g., a KRas mutation or amplification). For example, the testicular cancer (e.g., seminoma) has a KRas mutation selected from the group consisting of: a KRas G12A mutation, a KRas G12R mutation, a KRas G12S mutation, a KRas G12V mutation, a KRas Q61L mutation, a KRas Q61P mutation, and a KRas Q61R mutation. In some embodiments, the testicular cancer (e.g., seminoma) cancer has a KRas G12R mutation or a KRas G12V mutation. In some embodiments, the testicular cancer (e.g., seminoma) cancer has a KRas G12R mutation. In some embodiments, the testicular cancer (e.g., seminoma) cancer has a KRas G12V mutation.

[1045] Also provided herein is a method of treating a testicular cancer (e.g., seminoma) in aDocket No. TRLN-008-026W01 / 51379-0226WO1

[1046] 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating a testicular cancer (e.g., seminoma) in a subject in need thereof, the method comprising: (a) detecting a KRas G12A mutation, a KRas G12R mutation, a KRas G12S mutation, a KRas G12V mutation, a KRas Q61L mutation, a KRas Q61P mutation, or a KRas Q61R mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a testicular cancer (e.g., seminoma) 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a testicular cancer (e.g., seminoma) 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a testicular cancer (e.g., seminoma) 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 of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[1047] Also provided herein is a method of treating a bladder cancer in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. In some embodiments, the method further comprises determining that 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 G13DDocket No. TRLN-008-026W01 / 51379-0226WO1

[1048] mutation, and a KRas Q61H mutation. In some such embodiments, the cancer is a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, a KRas G12V-associated cancer, a KRas G13D-associated cancer, or a KRas Q61H-associated cancer. In some aspects of this embodiment, the cancer is a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer. In some embodiments, the cancer is a KRas G12C-associated cancer. In some embodiments, the cancer is a KRas G12D-associated cancer. In some embodiments, the cancer is a KRas G12R-associated cancer. In some embodiments, the cancer is a KRas G12V-associated cancer. In some embodiments, the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12C inhibitor, a KRas G12D inhibitor, a KRas G12R inhibitor, a KRas G12V inhibitor, a KRas G13D inhibitor, a KRas Q61H inhibitor, or two or more thereof. In some aspects of this embodiment, the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12C inhibitor, a KRas G12D inhibitor, a KRas G12R inhibitor, and / or a KRas G12V inhibitor. In some aspects of this embodiment, the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12D inhibitor, a KRas G12V inhibitor, or both.

[1049] Also provided herein is a method of treating a cervical cancer in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. In some embodiments, the method further comprises determining that the cervical cancer has a KRas mutation selected from the group consisting of: a KRas G12C mutation, a KRas G12D mutation, a KRas G12V mutation, and a KRas G13D mutation. In some embodiments, the cancer is a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12V-associated cancer, or a KRas G13D-associated cancer. In some embodiments, the cancer is a KRas G12C-associated cancer. In some embodiments, the cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer. In some embodiments, the cancer is a KRas G12D-associated cancer. In some embodiments, the cancer is a KRas G12V-associated cancer. In some such embodiments, the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12C inhibitor, a KRas G12D inhibitor, a KRas G12V inhibitor, a KRas G13D inhibitor, or two or more thereof. In some aspects of this embodiment, the compound of Formula (AA),Docket No. TRLN-008-026W01 / 51379-0226WO1

[1050] Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12D inhibitor, a KRas G12V inhibitor, or both.

[1051] Also provided herein is a method of treating a colorectal cancer in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. In some embodiments, the method further comprises determining that the colorectal cancer 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, 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, the cancer is 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, a KRas G12V-associated cancer, a KRas G13C-associated cancer, a KRas G13D-associated cancer, a KRas G13V-associated cancer, a KRas Q61E-associated cancer, a KRas Q61H-associated cancer, a KRas Q61K-associated cancer, a KRas Q61L-associated cancer, a KRas Q61P-associated cancer, or a KRas Q61R-associated cancer. In some aspects of this embodiment, the cancer is a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer. In some embodiments, the cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer. In some embodiments, the cancer is a KRas G12C-associated cancer. In some embodiments, the cancer is a KRas G12D-associated cancer. In some embodiments, the cancer is a KRas G12R-associated cancer. In some embodiments, the cancer is a KRas G12V-associated cancer. In some embodiments, the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12A inhibitor, a KRas G12C inhibitor, a KRas G12D inhibitor, a KRas G12R inhibitor, a KRas G12S inhibitor, a KRas G12V inhibitor, a KRas G13C inhibitor, a KRas G13D inhibitor, a KRas G13V inhibitor, a KRas Q61E inhibitor, a KRas Q61H inhibitor, a KRas Q61K inhibitor, a KRas Q61L inhibitor, a KRas Q61P inhibitor, a KRas Q61R inhibitor, or two or more thereof. In some aspects of this embodiment, the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12C inhibitor, a KRas G12D inhibitor, a KRas G12R inhibitor, and / or a KRas G12V inhibitor. In some aspects of this embodiment, the compoundDocket No. TRLN-008-026W01 / 51379-0226WO1

[1052] of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12D inhibitor, a KRas G12V inhibitor, or both.

[1053] Also provided herein is a method of treating an endometrial cancer in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. In some embodiments, the method further comprises determining that the endometrial cancer has a KRas mutation selected from the group consisting of: a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12S mutation, a KRas G12V mutation, a KRas G13C mutation, a KRas G13D mutation, a KRas G13V mutation, a KRas Q61H mutation, and a KRas Q61L mutation. In some embodiments, the cancer is a KRas G12A-associated cancer, a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12S-associated cancer, a KRas G12V-associated cancer, a KRas G13C-associated cancer, a KRas G13D-associated cancer, a KRas G13V-associated cancer, a KRas Q61H-associated cancer, or a KRas Q61L-associated cancer. In some embodiments, the cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer. In some embodiments, the cancer is a KRas G12C-associated cancer. In some embodiments, the cancer is a KRas G12D-associated cancer. In some embodiments, the cancer is a KRas G12V-associated cancer. In some such embodiments, the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12A inhibitor, a KRas G12C inhibitor, a KRas G12D inhibitor, a KRas G12S inhibitor, a KRas G12V inhibitor, a KRas G13C inhibitor, a KRas G13D inhibitor, a KRas G13V inhibitor, a KRas Q61H inhibitor, a KRas Q61L inhibitor, or two or more thereof. In some aspects of this embodiment, the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12C inhibitor, a KRas G12D inhibitor, and / or a KRas G12V inhibitor. In some aspects of this embodiment, the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12D inhibitor, a KRas G12V inhibitor, or both.

[1054] Also provided herein is a method of treating an esophageal or stomach cancer in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. In some embodiments, the method further comprisesDocket No. TRLN-008-026W01 / 51379-0226WO1

[1055] determining that the esophageal or stomach cancer has a KRas mutation selected from the group consisting of: a KRas G12C mutation, a KRas G12D mutation, a KRas G12S mutation, a KRas G12V mutation, a KRas G13C mutation, a KRas G13D mutation, and a KRas Q61H mutation. In some embodiments, the cancer is a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12S-associated cancer, a KRas G12V-associated cancer, a KRas G13C-associated cancer, a KRas G13D-associated cancer, or a KRas Q61H-associated cancer. In some embodiments, the cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer. In some embodiments, the cancer is a KRas G12C-associated cancer. In some embodiments, the cancer is a KRas G12D-associated cancer. In some embodiments, the cancer is a KRas G12V-associated cancer. In some embodiments, the compound of Formula (AA), Formula (A) (e.g., Formula (I-a1)), or Formula (B), or a pharmaceutically acceptable salt thereof, is a KRas G12C inhibitor, a KRas G12D inhibitor, a KRas G12S inhibitor, a KRas G12V inhibitor, a KRas G13C inhibitor, a KRas G13D in...

Claims

Docket No. TRLN-008-026W01 / 51379-0226WO1WHAT IS CLAIMED IS:

1. A compound of Formula (A):Formula (A)or a pharmaceutically acceptable salt thereof, wherein:E1isN;Docket No. TRLN-008-026W01 / 51379-0226WO1R2a, R2b, R2C, and R2dare each H;, wherein X3is -CH2-, -CHRL-, or -C(RL)2-;each RLis independently C1-3 alkyl optionally substituted with 1-3 F;the * marks the ring carbon atom common to both Ring BandY2is CH2; andR3isoptionally substituted with 1-2 substituents each independently selected from the group consisting of: -F, -C1-3 alkoxy, and -C1-3 haloalkoxy.The compound of claim 1, wherein Ring Bis3. The compound of claim 2, wherein RLis methyl, ethyl, or CF3.The compound of any one of claims 1-3, wherein RingB isDocket No. TRLN-008-026W01 / 51379-0226WO15. The compound of claim 1, wherein RingB is6. The compound of any one of claims 1-5, wherein R1is selected from the groupN Nconsisting of:-J—, and -J-The compound of any one of claims 1-6, whereinR1isN8. The compound of any one of claims 1-7, whereinR3is9. The compound of any one of claims 1-8, wherein the ring carbon atom labelled with * has (5)- stereochemical configuration.

10. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds depicted in Table Cl, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. A dysregulated KRas protein covalently or non-covalently bound with a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof.

13. A method for treating a KRas-associated 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 1-10, or a pharmaceutically acceptable salt thereof, or aDocket No. TRLN-008-026W01 / 51379-0226WO1pharmaceutical composition according to claim 11.

14. A method for treating a KRas-associated 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 1-10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11.

15. A method of treating a KRas-associated 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 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11.

16. A method of treating a KRas-associated cancer in a subject, 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 1-10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11.

17. The method of any one of claims 13-16, wherein the KRas-associated cancer is a mutant KRas-associated cancer.

18. The method of claim 17, wherein the mutant KRas-associated cancer is a KRas G12C-associated cancer or a KRas G12D -associated cancer.

19. The method of any one of claims 14 or 16, 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.

20. The method of claim 19, 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.Docket No. TRLN-008-026W01 / 51379-0226WO121. The method of claim 20, wherein the substitution of glycine 12 is a substitution to cysteine.

22. The method of claim 20, wherein the substitution of glycine 12 is a substitution to aspartic acid.

23. The method of any one of claims 19-22, comprising obtaining a tumor sample from the subject.

24. The method of claim 23, wherein the tumor sample is a biopsy sample.

25. The method of any one of claims 19-24, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, and enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

26. The method of claim 25, wherein the sequencing is pyrosequencing or next generation sequencing.

27. The method of any one of claims 13-26, wherein the KRas-associated cancer is selected from the group consisting of: a hematological cancer, cervical cancer, colon cancer, endometrial cancer, liver cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), pancreatic cancer, rectal cancer, testicular cancer (e.g., seminoma), skin cancer, stomach cancer, urothelial cancer, uterine cancer, and a combination thereof.

28. The method of claim 27, wherein the KRas-associated cancer is NSCLC.

29. The method of claim 27, wherein the KRas-associated cancer is selected from the group consisting of: colon cancer, rectal cancer, or a combination thereof.

30. The method of any one of claims 13-26, wherein the KRas-associated 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, 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,Docket No. TRLN-008-026W01 / 51379-0226WO1testicular cancer, thymus cancer, thyroid cancer, urothelial cancer, uterine cancer, and a combination thereof.

31. The method of claim 30, wherein the KRas-associated cancer is pancreatic cancer.

32. The method of claim 30, wherein the KRas-associated cancer is selected from the group consisting of: a hematological cancer, brain cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, thymus cancer, urothelial cancer, and uterine cancer.

33. The method of claim 30, wherein the KRas-associated cancer is selected from the group consisting of: 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, and uterine cancer.

34. The method of claim 30, wherein the KRas-associated cancer is selected from the group consisting of: bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal or stomach cancer, leukemia, lung cancer (e.g., NSCLC), pancreatic cancer, and kidney cancer.

35. The method of any one of claims 13-34, comprising administering an additional therapy or therapeutic agent to the subject.

36. The method of claim 35, 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, famesyl 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.Docket No. TRLN-008-026W01 / 51379-0226WO1 37. A method for modulating KRas protein activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof.

38. The method of claim 37, wherein the contacting occurs in vivo.

39. The method of claim 37, wherein the contacting occurs in vitro.

40. The method of claim 37, wherein the contacting occurs ex vivo.

41. The method of any one of claims 37-40, wherein the mammalian cell is a mammalian cancer cell.

42. The method of any one of claims 37-41, wherein the KRas protein is a mutant KRas protein.

43. The method of claim 42, wherein the mutant KRas protein is a mutant KRas protein selected from the group consisting of: a KRas G12C mutant protein and a KRas G12D mutant protein.

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