Pyridopyrimidine kras inhibitors

Abstract

This disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (II-dd), (II-e), (II-ee), (II-f), (II-g), or (II-h)), or Formula (Aa)), 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 the compounds provided herein, or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

Description

[0001] Pyridopyrimidine KRas Inhibitors

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application Serial Nos. 63 / 398,737, filed on August 17, 2022; 63 / 426,885, filed on November 21, 2022; 63 / 456,316, filed on March 31, 2023; and 63 / 526,503, filed on July 13, 2023; each of which is incorporated by reference in its entirety herein.

[0004] DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0005] This application contains a Sequence Listing which has been submitted electronically in XML format. The Sequence Listing XML is incorporated herein by reference. Said XML file, created on August 14, 2023, is named TRLN-008-004W01_ST26_SL.xml and is 2,059 bytes in size.

[0006] TECHNICAL FIELD

[0007] This disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (La), (Laa), (Lb), (Lbb), (Lc), (Lee), (Ld), (Ldd), (Le), (Leel), (Lf), (Lg), or (Lh)), Formula (II) (e.g., (ILc), (ILcc), (ILd), (ILdd), (ILe), (ILee), (ILf), (ILg), or (ILh)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, that inhibit a KRas GTPase (e.g., a KRas GTPase that has a dysregulation (referred to herein as a dysregulated KRas protein)). In some embodiments, the KRas protein is a dysregulated KRas protein that has a mutation (referred to herein as a mutant KRas protein). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased and / or sustained (e.g., excessive) KRas activation, such as KRas activation associated with a mutant KRas protein, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (La), (Laa), (Lb), (I- bb), (Lc), (Lee), (Ld), (Ldd), (Le), (Lee), (Lf), (Lg), or (Lh)), Formula (II) (e.g., (ILc), (lice), (ILd), (ILdd), (ILe), (ILee), (ILf), (ILg), or (ILh)), or Formula (Aa)), 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), for example, due to a deficiency of intrinsic GTPase activity and / or insensitivity for GTPase-activating proteins (GAPs) and consequent increased KRas signaling. Specifically, some of the most common protein mutations include those at position 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.

[0010] 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.

[0011] In some embodiments, the KRas protein is a dysregulated KRas protein that has a mutation (referred to herein as a mutant KRas protein). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased and / or sustained (e.g., excessive) KRas activation, such as KRas activation associated with a mutant KRas protein, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.

[0012] SUMMARY

[0013] This disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, that inhibit a KRas protein (e.g., a dysregulated KRas protein, such as a mutant KRas protein). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased KRas activation, such as KRas activation associated with a mutant KRas protein or KRas activation associated with KRas amplification, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

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

[0015] Formula (A) or pharmaceutically acceptable salts thereof, wherein: m is 0, 1, or 2; each X1is independently selected from the group consisting of CH2, CHRa, C(Ra)2, O, N(Rd), C(=O), and S(0)o-2, provided that -(X4)m- does not include any O-O, O-N, N-S(0)o, or 0-S(0)o-2 bonds;

[0016] Ring C is selected from the group consisting of: C3-15 cycloalkylene, 4-15 membered heterocyclylene, 6-15 membered arylene, and 5-15 membered heteroarylene, each of which is optionally substituted with 1-4 R7, wherein: each R7is independently selected from the group consisting of Raand Rb; p is an integer from 3 to 10; each LAis independently selected from the group consisting of: LA1, LA2, LA3, and LA4, provided that 0-2 occurrences of LAare LA4, and 0-3 occurrences of LAare selected from the group consisting of LA2and LA3; each LA1is independently selected from the group consisting of: -CH2-, -CHRL-, and - C(RL)2-, wherein each RLis independently selected from the group consisting of: halo, cyano, -OH, -Ci-6 alkoxy, -Ci-6 haloalkoxy, -NRdRe, C(=0)N(Rf)2, and Ci-6 alkyl optionally substituted with 1-6 Rc; Aj^RL2 each LA2is independently selected from the group consisting of:rL2 wherein each RL2is independently selected from the group consisting of: H, halo, CN, and Ci-6 alkyl optionally substituted with 1-6 Rc; each LA3is independently selected from the group consisting of: -N(Rd)-, -O-, -S(0)o- 2-, and C(=O); each LA4is independently selected from the group consisting of: C3-10 cycloalkylene, 4-10 membered heterocyclylene, Ce-io arylene, and 5-10 membered heteroarylene, each of which is optionally substituted with 1-3 Rg;

[0017] Ring B is selected from the group consisting of: Ce-io arylene and 5-10 membered heteroarylene, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb;

[0018] Y1is selected from the group consisting of: a bond, -N(H)-, -N(CI-3 alkyl)-, -N(C3-6 cycloalkyl)-, -O-, and -S(0)o-2-; n is 0 or 1;

[0019] Y2is a straight-chain Ci-6 alkylene optionally substituted with 1-6 RY; each RYis independently selected from the group consisting of: halo, cyano, -OH, oxo, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 alkyl, and Ci-6 haloalkyl, or a pair of RYon the same or different carbon atom(s) taken together with the atom(s) connecting them form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring, each of which is optionally substituted with 1-3 independently selected C1.3 alkyl;

[0020] R3is selected from the group consisting of:

[0021] (a) -H;

[0022] (b) -halo;

[0023] (c) -NRdRe;

[0024] (d) C3-10 cycloalkyl or 3-15 membered heterocyclyl, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb; and (e) Ce-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb;

[0025] E1is N, CH, or CR6;

[0026] R4, R5, and R6are independently selected from the group consisting of:

[0027] (a) -H;

[0028] (b) halo;

[0029] (c) cyano;

[0030] (d) Ci-6 alkyl;

[0031] (e) Ci-6 haloalkyl;

[0032] (f) Ci-6 alkoxy;

[0033] (g) Ci-6 haloalkoxy;

[0034] (h) -(Co-3 alkylene)-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl portion is optionally substituted with 1-3 Rg; and

[0035] (i) -0-(Co-3 alkylene)-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl portion is optionally substituted with 1-3 Rg; each Rais independently selected from the group consisting of:

[0036] (a) halo;

[0037] (b) cyano;

[0038] (c) -OH;

[0039] (d) oxo;

[0040] (e) -Ci-6 alkoxy;

[0041] (f) -Ci-6 haloalkoxy;

[0042] (g) -NRdRe;

[0043] (h) C(=O)Ci-6alkyl;

[0044] (i) C(=O)Ci-6haloalkyl; a) C(=O)OH;

[0045] (k) C(=O)OCi-6alkyl;

[0046] (l) C(=O)OCi-6haloalkyl;

[0047] (m) C(=O)N(Rf)2;

[0048] (n) S(0)o-2(Ci-6 alkyl); (o) S(0)o-2(Ci-6 haloalkyl);

[0049] (p) S(O)i-2N(Rf)2; and

[0050] (q) Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rbland -Rbl, wherein: b is 1, 2, or 3; 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 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; each Rcis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NRdRe, C(=O)Ci-6 alkyl, C(=O)Ci-6 haloalkyl, C(=O)OCi-6 alkyl, C(=O)OCi-6 haloalkyl, C(=O)OH, C(=O)N(Rf)2, S(O)0.2(Ci.6alkyl), S(O)0.2(Ci.6haloalkyl), and S(O)i-2N(Rf)2; 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)i-2(Ci-6 alkyl), S(O)i-2(Ci-6 haloalkyl), S(O)i-2N(Rf)2, and Ci-6 alkyl optionally substituted with 1-3 Rb; each Rfis independently selected from the group consisting of: H and Ci-6 alkyl optionally substituted with 1-3 Rb; each Rgis independently selected from the group consisting of: Rb, C1.3 alkyl, and Ci- 3 haloalkyl; and each Rbis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NH2, -N(H)(CI-3 alkyl), and -N(CI-3 alkyl)2.

[0051] In some embodiments, the compounds of Formula (A) are compounds of Formula (I):

[0052] Formula (I) or pharmaceutically acceptable salts thereof.

[0053] In some embodiments, the compounds of Formula (A) are compounds of Formula (II):

[0054] Formula (II) or pharmaceutically acceptable salts thereof, wherein E1is CH or CR6.

[0055] Also provided herein are pharmaceutical compositions comprising a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0056] Provided herein are methods for treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0057] 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 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0058] 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 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0059] 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 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 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0060] Further provided herein are methods of treating a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., 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 G12D-associated cancer, a KRas G12R- associated cancer, or a KRas G12V-associated cancer)) a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (H-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0061] This disclosure also provides methods of treating a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., 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 mutation (e.g., a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation)); and administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H- ), or (n-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0062] 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.

[0063] 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.

[0064] DETAILED DESCRIPTION

[0065] This disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (Lee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (ILee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 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, for example, 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 compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, as provided herein as well as methods of using and making the same.

[0066] Ras family genes (e.g., KRAS, NRAS, and HRAS) were the first oncogenes identified and are some of the most commonly mutated of all discovered oncogenes. See, e.g., Hunter et al. Mol Cancer Res. 2015; 13(9): 1325-35. The Ras family are guanine nucleotide binding proteins generally found at the inner leaflet of the cell membrane. A wild type Ras protein becomes activated when bound to GTP, but it is inactive when bound to GDP. Normally, growth factors bind to extracellular receptors to induce nucleotide exchange with the help of guanine nucleotide exchange factors (GEF) (e.g., Son of sevenless homolog 1 (SOS 1)). 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.

[0067] 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.

[0068] Mutant KRas proteins often have altered Raf affinity and / or altered intrinsic GTPase activity. See, for example, Table 1 reproduced from Hunter et al. Mol Cancer Res. 2015; 13(9): 1325-35. These changes and other factors can contribute to increased KRas signaling in mutant KRas proteins. Table 1

[0069] Compound Embodiments

[0070] Provided herein are compounds of Formula (A):

[0071] Formula (A) or pharmaceutically acceptable salts thereof, wherein: m is 0, 1, or 2; each X1is independently selected from the group consisting of CFb, CHRa, C(Ra)2, O, N(Rd), C(=O), and S(0)o-2, provided that -(X4)m- does not include any O-O, 0-N, N-S(0)o, or 0-S(0)o-2 bonds;

[0072] Ring C is selected from the group consisting of: C3-15 cycloalkylene, 4-15 membered heterocyclylene, 6-15 membered arylene, and 5-15 membered heteroarylene, each of which is optionally substituted with 1-4 R7, wherein: each R7is independently selected from the group consisting of Raand Rb; p is an integer from 3 to 10; each LAis independently selected from the group consisting of: LA1, LA2, LA3, and LA4, provided that 0-2 occurrences of LAare LA4, and 0-3 occurrences of LAare selected from the group consisting of LA2and LA3; each LA1is independently selected from the group consisting of: -CH2-, -CHRL-, and - C(RL)2-, wherein each RLis independently selected from the group consisting of: halo, cyano, -OH, -Ci-6 alkoxy, -Ci-6 haloalkoxy, -NRdRe, C(=0)N(Rf)2, and Ci-6 alkyl optionally substituted with 1-6 Rc; each LA2is independently selected from the group consisting of:rL2 wherein each RL2is independently selected from the group consisting of: H, halo, CN, and Ci-6 alkyl optionally substituted with 1-6 Rc; each LA3is independently selected from the group consisting of: -N(Rd)-, -O-, -S(0)o- 2-, and C(=O); each LA4is independently selected from the group consisting of: C3-10 cycloalkylene, 4-10 membered heterocyclylene, Ce-io arylene, and 5-10 membered heteroarylene, each of which is optionally substituted with 1-3 Rg;

[0073] Ring B is selected from the group consisting of: Ce-io arylene and 5-10 membered heteroarylene, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb;

[0074] Y1is selected from the group consisting of: a bond, -N(H)-, -N(CI-3 alkyl)-, -N(C3-6 cycloalkyl)-, -O-, and -S(0)o-2-; n is 0 or 1;

[0075] Y2is a straight-chain Ci-6 alkylene optionally substituted with 1-6 RY; each RYis independently selected from the group consisting of: halo, cyano, -OH, oxo, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 alkyl, and Ci-6 haloalkyl, or a pair of RYon the same or different carbon atom(s) taken together with the atom(s) connecting them form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring, each of which is optionally substituted with 1-3 independently selected C1.3 alkyl;

[0076] R3is selected from the group consisting of:

[0077] (a) -H;

[0078] (b) -halo; (c) -NRdRe;

[0079] (d) C3-10 cycloalkyl or 3-15 membered heterocyclyl, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb; and

[0080] (e) Ce-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb;

[0081] E1is N, CH, or CR6;

[0082] R4, R5, and R6are independently selected from the group consisting of:

[0083] (a) -H;

[0084] (b) halo;

[0085] (c) cyano;

[0086] (d) Ci-6 alkyl;

[0087] (e) Ci-6 haloalkyl;

[0088] (f) Ci-6 alkoxy;

[0089] (g) Ci-6 haloalkoxy;

[0090] (h) -(C0-3 alkylene)-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl portion is optionally substituted with 1-3 Rg; and

[0091] (i) -0-(Co-3 alkylene)-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl portion is optionally substituted with 1-3 Rg; each Rais independently selected from the group consisting of:

[0092] (a) halo;

[0093] (b) cyano;

[0094] (c) -OH;

[0095] (d) oxo;

[0096] (e) -Ci-6 alkoxy;

[0097] (f) -Ci-6 haloalkoxy;

[0098] (g) -NRdRe;

[0099] (h) C(=O)Ci-6alkyl;

[0100] (i) C(=O)Ci-6haloalkyl; a) C(=O)OH; (k) C(=O)OCi-6alkyl;

[0101] (l) C(=O)OCi-6haloalkyl;

[0102] (m) C(=O)N(Rf)2;

[0103] (n) S(0)o-2(Ci-6 alkyl);

[0104] (o) S(0)o-2(Ci-6 haloalkyl);

[0105] (p) S(O)i-2N(Rf)2; and

[0106] (q) Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rbland -Rbl, wherein: b is 1, 2, or 3; 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 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; each Rcis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NRdRe, C(=O)Ci-6 alkyl, C(=O)Ci-6 haloalkyl, C(=O)OCi-6 alkyl, C(=O)OCi-6 haloalkyl, C(=O)OH, C(=O)N(Rf)2, S(0)o.2(Ci-6 alkyl), S(0)o-2(Ci-6 haloalkyl), and S(O)i-2N(Rf)2; 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)i-2(Ci-6 alkyl), S(O)i-2(Ci-6 haloalkyl), S(O)i-2N(Rf)2, and Ci-6 alkyl optionally substituted with 1-3 Rb; each Rfis independently selected from the group consisting of: H and Ci-6 alkyl optionally substituted with 1-3 Rb; each Rgis independently selected from the group consisting of: Rb, C1.3 alkyl, and Ci- 3 haloalkyl; and each Rbis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NH2, -N(H)(CI-3 alkyl), and -N(CI-3 alkyl)2.

[0107] In some embodiments, the compounds of Formula (A) are compounds of Formula (I):

[0108] Formula (I) or pharmaceutically acceptable salts thereof, wherein: m is 0, 1, or 2; each X1is independently selected from the group consisting of CH2, CHRa, C(Ra)2, O, N(Rd), C(=O), and S(0)o-2, provided that -(X4)m- does not include any O-O, O-N, N-S(0)o, or 0-S(0)o-2 bonds;

[0109] Ring C is selected from the group consisting of: C3-15 cycloalkylene, 4-15 membered heterocyclylene, 6-15 membered arylene, and 5-15 membered heteroarylene, each of which is optionally substituted with 1-4 R7, wherein: each R7is independently selected from the group consisting of Raand Rb; p is an integer from 3 to 10; each LAis independently selected from the group consisting of: LA1, LA2, LA3, and LA4, provided that 0-2 occurrences of LAare LA4, and 0-3 occurrences of LAare selected from the group consisting of LA2and LA3; each LA1is independently selected from the group consisting of: -CH2-, -CHRL-, and - C(RL)2-, wherein each RLis independently selected from the group consisting of: halo, cyano, -OH, -Ci-6 alkoxy, -Ci-6 haloalkoxy, -NRdRe, C(=O)N(Rf)2, and Ci-6 alkyl optionally substituted with 1-6 Rc; each LA2is independently selected from the group consisting of:rL2 wherein each RL2is independently selected from the group consisting of: H, halo, CN, and Ci-6 alkyl optionally substituted with 1-6 Rc; each LA3is independently selected from the group consisting of: -N(Rd)-, -O-, -S(0)o- 2-, and C(=O); each LA4is independently selected from the group consisting of: C3-10 cycloalkylene, 4-10 membered heterocyclylene, Ce-io arylene, and 5-10 membered heteroarylene, each of which is optionally substituted with 1-3 Rg;

[0110] Ring B is selected from the group consisting of: Ce-io arylene and 5-10 membered heteroarylene, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb;

[0111] Y1is selected from the group consisting of: a bond, -N(H)-, -N(CI-3 alkyl)-, -N(C3-6 cycloalkyl)-, -O-, and -S(0)o-2-; n is 0 or 1;

[0112] Y2is a straight-chain Ci-6 alkylene optionally substituted with 1-6 RY; each RYis independently selected from the group consisting of: halo, cyano, -OH, oxo, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 alkyl, and Ci-6 haloalkyl, or a pair of RYon the same or different carbon atom(s) taken together with the atom(s) connecting them form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring, each of which is optionally substituted with 1-3 independently selected C1.3 alkyl;

[0113] R3is selected from the group consisting of:

[0114] (a) -H;

[0115] (b) -halo;

[0116] (c) -NRdRe;

[0117] (d) C3-10 cycloalkyl or 3-15 membered heterocyclyl, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb; and

[0118] (e) Ce-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb;

[0119] R4and R5are independently selected from the group consisting of:

[0120] (a) -H;

[0121] (b) halo; (c) cyano;

[0122] (d) Ci-6 alkyl;

[0123] (e) Ci-6 haloalkyl;

[0124] (f) Ci-6 alkoxy;

[0125] (g) Ci-6 haloalkoxy;

[0126] (h) -(Co-3 alkylene)-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl portion is optionally substituted with 1-3 Rg; and

[0127] (i) -0-(Co-3 alkylene)-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl portion is optionally substituted with 1-3 Rg; each Rais independently selected from the group consisting of:

[0128] (a) halo;

[0129] (b) cyano;

[0130] (c) -OH;

[0131] (d) oxo;

[0132] (e) -Ci-6 alkoxy;

[0133] (f) -Ci-6 haloalkoxy;

[0134] (g) -NRdRe;

[0135] (h) C(=O)Ci-6alkyl;

[0136] (i) C(=O)Ci-6haloalkyl; a) C(=O)OH;

[0137] (k) C(=O)OCi-6alkyl;

[0138] (l) C(=O)OCi-6haloalkyl;

[0139] (m) C(=O)N(Rf)2;

[0140] (n) S(0)o-2(Ci-6 alkyl);

[0141] (0) S(0)o-2(Ci-6 haloalkyl);

[0142] (p) S(O)i-2N(Rf)2; and

[0143] (q) Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rbland -Rbl, wherein: b is 1, 2, or 3; 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 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; each Rcis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NRdRe, C(=O)Ci-6 alkyl, C(=O)Ci-6 haloalkyl, C(=O)OCi-6 alkyl, C(=O)OCi-6 haloalkyl, C(=O)OH, C(=O)N(Rf)2, S(0)o-2(Ci-6 alkyl), S(0)o-2(Ci-6 haloalkyl), and S(O)i-2N(Rf)2; 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)i-2(Ci-6 alkyl), S(O)i-2(Ci-6 haloalkyl), S(O)i-2N(Rf)2, and Ci-6 alkyl optionally substituted with 1-3 Rb; each Rfis independently selected from the group consisting of: H and Ci-6 alkyl optionally substituted with 1-3 Rb; each Rgis independently selected from the group consisting of: Rb, C1.3 alkyl, and Ci- 3 haloalkyl; and each Rbis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NH2, -N(H)(CI-3 alkyl), and -N(CI-3 alkyl)2.

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

[0145] Formula (II) or pharmaceutically acceptable salts thereof, wherein E1is CH or CR6.

[0146] In some embodiments of Formula (A), Formula (I), or Formula (II), m is 0. In some embodiments of Formula (A), Formula (I), or Formula (II), Ring C is a 4-15 membered heterocyclylene optionally substituted with 1-4 R7. In some embodiments, Ring C is a 4-10 membered heterocyclylene optionally substituted with 1-4 R7, wherein Ring C has one ring nitrogen atom, 0-1 ring oxygen atom, and no additional ring heteroatoms.

[0147] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring C is a 4-6 membered heterocyclylene optionally substituted with 1-3 R7. In some embodiments, Ring C is a piperidinylene optionally substituted with 1-3 R7.

[0148] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring C is: wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; and cc represents the point of attachment to -(LA)P-. In some embodiments, cl is 0. In some embodiments, Ring some embodiments, Ring optionally substituted with

[0149] 1-3 F. In some embodiments, Ring

[0150] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring C is a 7-10 membered heterocyclylene optionally substituted with 1-3 R7. In some embodiments, Ring C has one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms.

[0151] In some embodiments of Formula (A), Formula (I) or Formula (II), Ring C is , wherein cl is 0, 1, or 2; and cc represents the point of attachment to - (LA)P-. In some embodiments, cl is 0.

[0152] In some embodiments of Formula (A), Formula (I), or Formula (II), p is 4, 5, or 6.

[0153] In some embodiments of Formula (A), Formula (I), or Formula (II), p is 6, 7, or 8. In some embodiments of Formula (A), Formula (I), or Formula (II), each LAis independently selected from the group consisting of: LA1, LA3, and LA4.

[0154] In some embodiments of Formula (A), Formula (I), or Formula (II), 0-1 occurrence of LAis LA4; and each remaining LAis independently selected from the group consisting of LA1and LA3.

[0155] In some embodiments of Formula (A), Formula (I), or Formula (II), one occurrence of LAis LA4; and each remaining LAis independently LA1.

[0156] In some embodiments of Formula (A), Formula (I), or Formula (II), each LAis independently LA1.

[0157] In some embodiments of Formula (A), Formula (I), or Formula (II), 1-2 occurrence of LAis independently LA3; and each remaining LAis independently LA1.

[0158] In some embodiments of Formula (A), Formula (I), or Formula (II), p is 4, 5, or 6; one occurrence of LAis LA4; and each remaining LAis independently LA1. In some embodiments, -(LA)P- is - (LA1)o-5-LA4-(LA1)o-5, wherein p is 4, 5, or 6. In some embodiments, LA4is phenylene or 5-6 membered heteroarylene, each of which is optionally substituted with 1-3 Rg. In some embodiments, LA4is a 5-membered heteroarylene optionally substituted with 1-2 Rg. For example, LA4can be triazolylene or oxadiazolylene (e.g., 1,2,4-oxadiazolylene). In some embodiments, LA1is CHz.

[0159] In some embodiments of Formula (A), Formula (I), or Formula (II), -(LA)P- is: - (LAla)aia-LA4-(LAlb)aib-ii, wherein: ala and alb are independently integers from 0 to 5, provided that ala + alb is 3, 4, or 5; each LAlaand LAlbis an independently selected LA1; LA4is phenylene or 5-6 membered heteroarylene, each of which is optionally substituted with 1-3 Rg; and bb represents the point of attachment to Ring C. In some embodiments, LA4is 5- membered heteroarylene optionally substituted with 1-2 Rg. In some embodiments, LA4is selected from the group consisting of: wherein dd represents the point of attachment to -(LAlb)aib-. For example, LA4can be , wherein dd represents the point of attachment to -(LAlb)aib-. In some embodiments, alb is 1; and ala is 2, 3, or 4. In some embodiments, each of LAlaand LAlbis CH2. In some embodiments, p is 6, 7, or 8; and each LAis independently LA1. In some embodiments, each LAis -CH2-.

[0160] In some embodiments of Formula (A), Formula (I), or Formula (II), p is 6, 7, or 8; one occurrence of LAis C(=O); a second occurrence of LAis N(Rd); and each remaining LAis independently LA1.

[0161] In some embodiments of Formula (A), Formula (I), or Formula (II), -(LA)P- is: - (LAla)aia-C(=O)NH-(LAl h)aib-M), wherein: ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1; and bb represents the point of attachment to Ring C. In some embodiments, alb is 2; and ala is 2, 3, or 4. In some embodiments, alb is 1; and ala is 3, 4, or 5. In some embodiments, each of LAlaand LAlbis CH2.

[0162] In some embodiments of Formula (A), Formula (I), or Formula (II), m is 0; Ring C is: wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; and cc represents the point of attachment to -(LA)P-; -(LA)P- is: - (LAla)aia-LA4-(LAlb)aib-AA, wherein: ala and alb are independently integers from 0 to 5, provided that ala + alb is 3, 4, or 5; each LAlaand LAlbis an independently selected LA1; LA4is phenylene or 5-6 membered heteroarylene, each of which is optionally substituted with 1-3 Rg; and bb represents the point of attachment to Ring C. In some embodiments, LA4is 5- membered heteroarylene optionally substituted with 1-2 Rg. In some embodiments, LA4is , wherein dd represents the point of attachment to -(LAlb)aib-. In some embodiments, alb is 1; and ala is 2, 3, or 4. In some embodiments, each of LAlaand LAlbis

[0163] CH2. In some embodiments, Ring some embodiments, Ring C is some embodiments, cl is 0. In some embodiments of Formula (A), Formula (I), or Formula (II), m is 0; Ring C is: wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; and cc represents the point of attachment to -(LA)P-; p is 6, 7, or 8; and each LAis an independently selected LA1. In some embodiments, each LAis -CH2-. In some embodiments, Ring In some embodiments, Ring C is some embodiments, cl is 0. In some embodiments, cl is 0.

[0164] In some embodiments of Formula (A), Formula (I), or Formula (II), m is 0; Ring C is: wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; and cc represents the point of attachment to -(LA)P-; -(LA)P- is: - (LAla)aia-C(=O)NH-(LAl b)aib-M), wherein: ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis independently selected LA1; and bb represents the point of attachment to Ring C. In some embodiments, alb is 2; and ala is 2, 3, or 4. In some embodiments, alb is 1; and ala is 3, 4, or 5. In some embodiments, each of LAlaand LAlbis CH2. In some embodiments, Ring some embodiments,

[0165] Ring some embodiments, cl is 0. In some embodiments, cl is 0. In some embodiments of Formula (A), Formula (I), or Formula (II), m is 0; Ring C is: , wherein: cl is 0, 1, or 2; cc represents the point of attachment to -(LA)P-

[0166] ; and (LA)p- is: -(LAla)aia-C(=O)NH-(LAlb)aib-ii, wherein: ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis independently selected LA1; and bb represents the point of attachment to Ring C. In some embodiments, alb is 2; and ala is 2, 3, or 4. In some embodiments, alb is 1; and ala is 3, 4, or 5. In some embodiments, each of LAlaand LAlbis CH2. In some embodiments, cl is 0.

[0167] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is Ce-io arylene optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb.

[0168] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is naphthylene optionally substituted with 1-4 Ra.

[0169] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is , wherein R2aand R2care independently H or Ra; and aa represents the point of attachment to -(LA)P-. In some embodiments, R2ais -OH. In some embodiments, R2ais -NH2.

[0170] In some embodiments, R2ais -H. In some embodiments, R2cis halo (e.g., F) or H.

[0171] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is , wherein aa represents the point of attachment to -(LA)P-. In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is , wherein aa represents the point of attachment to -(LA)P-.

[0172] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is phenylene optionally substituted with 1-4 Ra.

[0173] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is , wherein R2a, R2b, and R2care independently H or Ra; and aa represents the point of attachment to -(LA)P-. In some embodiments, R2ais -OH. In some embodiments, R2ais - NH2. In some embodiments, R2cis halo (e.g., -Cl).

[0174] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is , wherein R2aand R2care independently H or Ra; and aa represents the point of attachment to -(LA)P-. In some embodiments, R2ais -OH. In some embodiments, R2ais -NH2. In some embodiments, R2cis halo (e.g., -Cl).

[0175] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is a 5-10 membered heteroarylene, which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb. In some embodiments, Ring B is a 9-10 membered heteroarylene having 1-2 ring nitrogen atoms and 0-1 additional ring heteroatom selected from the group consisting of: O and S, wherein the heteroarylene is optionally substituted with 1-3 Ra. In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is , wherein R2cis H or Ra; and aa represents the point of attachment to -(LA)P-. In some embodiments, R2cis halo. For example, R2ccan be -Cl. For example, Ring B can be , wherein aa represents the point of attachment to -(LA)P-.

[0176] In some embodiments of Formula (A), Formula (I), or Formula (II), Y1is -O-.

[0177] In some embodiments of Formula (A), Formula (I), or Formula (II), n is 1.

[0178] In some embodiments of Formula (A), Formula (I), or Formula (II), Y2is a straightchain Ci-3 alkylene optionally substituted with 1-3 RY.

[0179] In some embodiments of Formula (A), Formula (I), or Formula (II), Y2is -CH2-.

[0180] In some embodiments of Formula (A), Formula (I), or Formula (II), Y2is

[0181] In some embodiments of Formula (A), Formula (I), or Formula (II), R3is a 4-10 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb.

[0182] In some embodiments of Formula (A), Formula (I), or Formula (II), R3is a monocyclic 4-6 membered heterocyclyl optionally substituted with 1-3 Ra, wherein the heterocyclyl includes at least one ring nitrogen atom.

[0183] In some embodiments of Formula (A), Formula (I), or Formula (II), R3is optionally substituted with 1-3 Raon one or more ring carbon atoms. In some embodiments of Formula (A), Formula (I), or Formula (II), R3is optionally substituted with 1-3 Raon one or more ring carbon atoms.

[0184] In some embodiments of Formula (A), Formula (I), or Formula (II), R3is a bicyclic 7- 10 membered heterocyclyl optionally substituted with 1-6 Ra.

[0185] In some embodiments of Formula (A), Formula (I), or Formula optionally substituted with 1-3 Ra.

[0186] In some embodiments of Formula (A), Formula (I), or Formula (II), R3is selected from the group consisting of: example, R3can

[0187] In some embodiments of Formula (A), Formula (I), or Formula (II), R3is selected from the group consisting of: , , each of which is optionally substituted with 1-3 Ra.

[0188] In some embodiments of Formula (A), Formula (I), or Formula (II), Y1is -O-; n is 1; optionally substituted with 1-3 Ra. In some embodiments, R3is selected from the group consisting of: example, R3can In some embodiments of Formula (A), Formula (I), or Formula (II), Y1is -O-; n is 1; ; and R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra. In some embodiments, R3is selected from the group consisting of: , each of which is optionally substituted with 1-3

[0189] Ra

[0190] In some embodiments of Formula (A), Formula (I), or Formula (II), Y1is -O-; n is 1; example, R3can be -NMe2.

[0191] In some embodiments of Formula (A), Formula (I), or Formula (II), R4is H.

[0192] In some embodiments of Formula (A), Formula (I), or Formula (II), R5is -F.

[0193] In some embodiments of Formula (A), Formula (I), or Formula (II), R4is H; and R5is -F.

[0194] In some embodiments of Formula (A), Formula (I), or Formula (II), E1is CR6. In some embodiments, R6is halo (e.g., -F, or -Cl).

[0195] In some embodiments of Formula (A), Formula (I), or Formula (II), E1is CH.

[0196] In some embodiments of Formula (A), the compounds are compounds of Formula (Aa):

[0197] Formula (Aa) or a pharmaceutically acceptable salt thereof, wherein: Ring C is a 4-10 membered heterocyclylene optionally substituted with 1-4 R7, wherein Ring C has one ring nitrogen atom, 0-1 ring oxygen atom, and no additional ring heteroatoms;

[0198] Ring B is selected from the group consisting of: Ce-io arylene and 5-10 membered heteroarylene, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: Raand Rb; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;

[0199] R3is: a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra, or

[0200] -NRdRe; and

[0201] R5is H or halo.

[0202] In some embodiments of Formula (Aa), E1is N, CH, or C-halo;

[0203] Ring C is selected from the group consisting of: wherein: cl is 0, 1, or 2; cc represents the point of attachment to -(LAlb)aib-; each R7aand R7bis an independently selected R7; and

[0204] Ring B is selected from the group consisting of: wherein R2ais -OH or -NH2; R2band R2care independently H or halo (e.g., -Cl); and aa represents the point of attachment to -(LAla)aia-. In some embodiments, cl is 0. In some embodiments, R7a, when present, is OH.

[0205] In some embodiments of Formula (Aa), alb is 2; and ala is 2, 3, or 4. In some embodiments of Formula (Aa), alb is 1; and ala is 3, 4, or 5.

[0206] In some embodiments of Formula (Aa), each of LAlaand LAlbis CH2.

[0207] In some embodiments of Formula R5is F.

[0208] In some embodiments of Formula (Aa), Y2is

[0209] For example, R3can be -NMe2.

[0210] In some embodiments of Formula (Aa), R6is -F or -Cl; and R5is -F. In some embodiments of Formula (I), the compounds are compounds of Formula (I-a) or (I-aa):

[0211]

[0212] Formula (I-aa) or pharmaceutically acceptable salts thereof, wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 3, 4, or 5; each LAlaand LAlbis an independently selected LA1;

[0213] LA4is phenylene or 5-6 membered heteroarylene, each of which is optionally substituted with 1-3 Rg;

[0214] R2aand R2care independently H or Ra;

[0215] R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; and R5is H or halo. In some embodiments of Formula (I-a) or (I-aa), LA4is a 5-membered heteroarylene optionally substituted with 1-2 Rg. In some embodiments of Formula (I-a) or (I-aa), LA4is , wherein dd represents the point of attachment to -(LAlb)aib-.

[0216] In some embodiments of Formula (I-a) or (I-aa), alb is 1; and ala is 2, 3, or 4. In some embodiments of Formula (I-a), each of LAlaand LAlbis CH2.

[0217] In some embodiments of Formula (I), the compounds are compounds of Formula (I-b) or (I-bb):

[0218] Formula (I-bb) or pharmaceutically acceptable salts thereof, wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; p is 6, 7, or 8;

[0219] R2aand R2care independently H or Ra;

[0220] R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; and

[0221] R5is H or halo.

[0222] In some embodiments of Formula (I-b) or (I-bb), each LA1is CH2.

[0223] In some embodiments of Formula (I), the compounds are compounds of Formula (I-c) or (I-cc):

[0224] Formula (I-cc) or pharmaceutically acceptable salts thereof, wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;

[0225] R2aand R2care independently H or Ra;

[0226] R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; and

[0227] R5is H or halo.

[0228] In some embodiments of Formula (I-c) or (I-cc), alb is 2; and ala is 2, 3, or 4.

[0229] In some embodiments of Formula (I-c) or (I-cc), each of LAlaand LAlbis CH2.

[0230] In some embodiments of Formula (II), the compounds are compounds of Formula (Il¬-cc):

[0231] Formula (II-c)

[0232] Formula (II-cc) or pharmaceutically acceptable salts thereof, wherein: E1is CH or CR6; cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;

[0233] R2aand R2care independently H or Ra;

[0234] R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; and

[0235] R5is H or halo.

[0236] In some embodiments of Formula (I), the compounds are compounds of Formula (I-d) or (I-dd):

[0237]

[0238] Formula (I-dd) or pharmaceutically acceptable salts thereof, wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;

[0239] R2aand R2care independently Ra;

[0240] R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; and R5is H or halo.

[0241] In some embodiments of Formula (II), the compounds are compounds of Formula (II- d) or (Il-dd):

[0242]

[0243] Formula (Il-dd) or pharmaceutically acceptable salts thereof, wherein:

[0244] E1is CH or CR6; cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or

[0245] 6; each LAlaand LAlbis an independently selected LA1;

[0246] R2aand R2care independently Ra; R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; and

[0247] R5is H or halo.

[0248] In some embodiments of Formula (I), the compounds are compounds of Formula (I-e) or (I-ee):

[0249] or pharmaceutically acceptable salts thereof, wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;

[0250] R2cis H or Ra;

[0251] R3is: a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra, or

[0252] -NRdRe(e.g., -NMe2); and

[0253] R5is H or halo. In some embodiments of Formula (II), the compounds are compounds of Formula (II- e) or (Il-ee): or pharmaceutically acceptable salts thereof, wherein:

[0254] E1is CH or CR6; cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1; R2cis H or Ra;

[0255] R3is: a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra, or

[0256] -NRdRe(e.g., -NMe2); and R5is H or halo. in some embodiments of Formula (I), the compounds are compounds of Formula (I-f):

[0257] Formula (I-f) or pharmaceutically acceptable salts thereof, wherein: cl is 0, 1, or 2; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;

[0258] R2aand R2care independently Ra;

[0259] R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; and

[0260] R5is H or halo.

[0261] In some embodiments of Formula (II), the compounds are compounds of Formula (Ilf):

[0262] Formula (Il-f) or pharmaceutically acceptable salts thereof, wherein: cl is 0, 1, or 2; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;

[0263] R2aand R2care independently Ra;

[0264] R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; and

[0265] R5is H or halo.

[0266] In some embodiments of Formula (I), the compounds are compounds of Formula (I-g):

[0267] Formula (I-g) or pharmaceutically acceptable salts thereof, wherein: cl is 0, 1, or 2; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;

[0268] R2aand R2care independently H or Ra;

[0269] R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; and R5is H or halo. In some embodiments of Formula (II), the compounds are compounds of Formula (II- g): or pharmaceutically acceptable salts thereof, wherein:

[0270] E1is CH or CR6; cl is 0, 1, or 2; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;

[0271] R2aand R2care independently H or Ra;

[0272] R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; and R5is H or halo.

[0273] In some embodiments of Formula (I), the compounds are compounds of Formula (I-h): or pharmaceutically acceptable salts thereof, wherein: cl is 0, 1, or 2; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or

[0274] 6; each LAlaand LAlbis an independently selected LA1;

[0275] R2cis H or Ra;

[0276] R3is: a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra, or

[0277] -NRdRe(e.g., -NMe2); and

[0278] R5is H or halo.

[0279] In some embodiments of Formula (II), the compounds are compounds of Formula (II- h):

[0280] Formula (Il-h) or pharmaceutically acceptable salts thereof, wherein:

[0281] E1is CH or CR6; cl is 0, 1, or 2; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;

[0282] R2cis H or Ra;

[0283] R3is: a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra, or

[0284] -NRdRe(e.g., -NMe2); and

[0285] R5is H or halo.

[0286] In some embodiments of Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (II-c), (lice), (I-d), (I-dd), (Il-d), (Il-dd), (I-e), (I-ee), (Il-e), (Il-ee), (I-f), (Il-f), (I-g), (Il-g), (I-h), or (Il-h), alb is 2; and ala is 2, 3, or 4.

[0287] In some embodiments of Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (II-c), (lice), (I-d), (I-dd), (Il-d), (Il-dd), (I-e), (I-ee), (Il-e), (Il-ee), (I-f), (Il-f), (I-g), (Il-g), (I-h), or (Il-h), alb is 1; and ala is 3, 4, or 5.

[0288] In some embodiments of Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (II-c), (lice), (I-d), (I-dd), (Il-d), (Il-dd), (I-e), (I-ee), (Il-e), (Il-ee), (I-f), (Il-f), (I-g), (Il-g), (I-h), or (Il-h), each of LAlaand LAlbis CH2.

[0289] In some embodiments of Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (II-c), (lice), (I-d), (I-dd), (Il-d), (Il-dd), (I-f), (Il-f), (I-g), or (Il-g), R2ais -NH2.

[0290] In some embodiments of Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (II-c), (lice), (I-d), (I-dd), (Il-d), (Il-dd), (I-e), (I-ee), (Il-e), (Il-ee), (I-f), (Il-f), (I-g), (Il-g), (I-h), or (Il-h), R2cis -F. In some embodiments of Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (II- c), (II-cc), (I-d), (I-dd), (Il-d), (Il-dd), (I-e), (I-ee), (Il-e), (Il-ee), (I-f), (Il-f), (I-g), (Il-g), (I-h), or (Il-h), R2cis -Cl.

[0291] In some embodiments of Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (II-c), (II- cc), (I-d), (I-dd), (Il-d), (Il-dd), (I-e), (I-ee), (Il-e), (Il-ee), (I-f), (Il-f), (I-g), (Il-g), (I-h), or (Il-h), cl is 0.

[0292] In some embodiments of Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (II-c), (II- cc), (I-d), (I-dd), (H-d), (Il-dd), (I-e), (I-ee), (Il-e), or (Il-ee), R7a, when present, is OH. In some embodiments of Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (II-c), (II-

[0293] In some embodiments of Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (II-c), (lice), (I-d), (I-dd), (II-d), (Il-dd), (I-e), (I-ee), (Il-e), or (Il-ee), R6is -F or -Cl; and R5is -F.

[0294] In some embodiments, the compounds are selected from the group consisting of the compounds in Table Cl, or pharmaceutically acceptable salts thereof.

[0295] Table Cl

[0296]

[0297] Note: When a stereogenic center (e.g., a chiral carbon or a center of axial chirality) is denoted with a this stereogenic center has been resolved, but its absolute configuration is not assigned.

[0298] Exemplary compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)) also include those depicted in Table Cl of U.S. Provisional Application Serial No. 63 / 398,737, filed on August 17, 2022; Table Cl of U.S. Provisional Application Serial No. 63 / 426,885, filed on November 21, 2022; Table Cl of U.S. Provisional Application Serial No. 63 / 456,316, filed on March 31, 2023; and Table Cl of U.S. Provisional Application Serial No. 63 / 526,503, filed on July 13, 2023; or pharmaceutically acceptable salts thereof, wherein each Table Cl is incorporated herein by reference in its entirety.

[0299] Exemplary compounds of Formula (A) include compounds: 101, 101a, 102, 102a, 103, 103a, 104, 104a, 105, 105a, 106, 106a, 107, 107a, 108, 108a, 109, 109a, 110, 110a, 111, Illa, 112, 112a, 113, 113a, 114, 114a, 115, 115a, 115b, 115c, 116, 116a, 117, 117a, 118, 118a, 119, 119a, 120, 120a, 121, 121a, 122, 122a, 123, 123a, 124, 124a, 125, 125a, 126, 126a, 127, 127a, 128, 128a, 129, 129a, 130, 130a, 131, 131a, 132, 132a, 133, 133a, 134, 134a, 135, 135a, 136, 136a, 137, 137a, 138, 138a, 139, 139a, 140, 140a, 140b, 140c, 141, 141a, 143, 143a, 151, 151a, 152, 152a, 153, 153a, 154, 154a, 155, 155a, 156, 156a, 157, 157a, 158, 158a, 159, 159a, 159b, 159c, 160, 160a, 161, 161a, 162, 162a, 163, 163a, 164, 164a, 165, 165a, 166, 166a, 167, 167a, 170, 170a, 171, 171a, 172, 172a, 173, 173a, 174, 174a, 175, 175a, 176, 176a, 177, 178, 179, 179a, 180, 180a, 181, 181a, 182, 182a, 183, 183a, 184, 184a, 185, 185a, 186, 186a, 187, 187a, 188, 188a, 188b, 189, 189a, 190, 190a, 191, 191a, 192, 192a, 193, 193a, 194, 194a, 195, 195a, 196, 196a, 197, 197a, 197b, 198, 198a, 199, 199a, 200, 200a, 201, 201a, 202, 202a, 202b, 203, and 203a.

[0300] Exemplary compounds of Formula (Aa) include compounds: 113, 113a, 114, 114a, 115, 115a, 115b, 115c, 117, 117a, 118, 118a, 135, 135a, 136, 136a, 137, 137a, 138, 138a, 139, 139a, 140, 140a, 140b, 140c, 141, 141a, 154, 154a, 155, 155a, 156, 156a, 158, 158a, 162, 162a, 165, 165a, 166, 166a, 167, 167a, 170, 170a, 171, 171a, 173, 173a, 175, 175a, 177, 179, 179a, 181, 181a, 189, 189a, 190, 190a, 191, 191a, 192, 192a, 193, 193a, 194, 194a, 195, 195a, 196, 196a, 197a, 197b, 198, 198a, 199, 199a, 200, 200a, 201, 201a, 202, 202a, 202b, 203, and 203a.

[0301] Exemplary compounds of Formula (I) include compounds: 101, 101a, 102, 102a, 103, 103a, 104, 104a, 105, 105a, 106, 106a, 107, 107a, 108, 108a, 109, 109a, 110, 110a, 111, Illa, 112, 112a, 113, 113a, 114, 114a, 115, 115a, 115b, 115c, 116, 116a, 117, 117a, 118, 118a, 119, 119a, 120, 120a, 121, 121a, 122, 122a, 123, 123a, 124, 124a, 125, 125a, 126, 126a, 127, 127a, 128, 128a, 129, 129a, 130, 130a, 131, 131a, 132, 132a, 133, 133a, 134, 134a, 135, 135a, 136, 136a, 137, 137a, 138, 138a, 139, 139a, 140, 140a, 140b, 140c, 141, 141a, 143, 143a, 151, 151a, 152, 152a, 153, 153a, 154, 154a, 156, 156a, 157, 157a, 159, 159a, 159b, 159c, 160, 160a, 161, 161a, 162, 162a, 164, 164a, 167, 167a, 170, 170a, 171, 171a, 172, 172a, 173, 173a, 176, 176a, 177, 178, 179, 179a, 181, 181a, 182, 182a, 185, 185a, 186, 186a, 189, 189a, 192, 192a, 193, 193a, 194, 194a, 196, 196a, 201, 201a, 203, and 203a.

[0302] Exemplary compounds of Formula (I-a) include compounds: 126, 126a, 127, 127a, 128, and 128a.

[0303] Exemplary compounds of Formula (I-aa) include compounds: 101, 101a, 102, 102a, 103, 103a, 119, 119a, 120, and 120a.

[0304] Exemplary compounds of Formula (I-b) include compounds: 130, 130a, 131, and 131a.

[0305] Exemplary compounds of Formula (I-bb) include compounds: 111, Illa, 112, and 112a.

[0306] Exemplary compounds of Formula (I-c) include compounds: 136, and 136a. Exemplary compounds of Formula (I-cc) include compounds: 117, 117a, 118, 118a, 135, 135a, 170, 170a, 189, and 189a.

[0307] Exemplary compounds of Formula (I-d) include compounds: 138, 138a, 140, 140a, 140b, 140c, 156, and 156a.

[0308] Exemplary compounds of Formula (I-dd) include compounds: 113, 113a, 114, 114a, 115, 115a, 115b, 115c, 137, 137a, 139, 139a, 141, 141a, 154, 154a, 171, 171a, 177, 179, 179a, 181, 181a, 201, and 201a.

[0309] Exemplary compounds of Formula (I-ee) include compounds: 167, 167a, 196, and 196a.

[0310] Exemplary compounds of Formula (I-f) include compounds: 162, and 162a.

[0311] Exemplary compounds of Formula (I-g) include compounds: 173, 173a, 192, 192a, 193, 193a, 194, and 194a.

[0312] Exemplary compounds of Formula (I-h) include compounds: 203, and 203a.

[0313] Exemplary compounds of Formula (II) include compounds: 155, 155a, 158, 158a, 163, 163a, 165, 165a, 166, 166a, 174, 174a, 175, 175a, 180, 180a, 183, 183a, 184, 184a, 187, 187a, 188, 188a, 188b, 190, 190a, 191, 191a, 195, 195a, 197, 197a, 197b, 198, 198a, 199, 199a, 200, 200a, 202, 202a, and 202b.

[0314] Exemplary compounds of Formula (II-c) include compounds: 175, 175a, 190, 190a, 191, and 191a.

[0315] Exemplary compounds of Formula (Il-d) include compounds: 158, and 158a.

[0316] Exemplary compounds of Formula (Il-dd) include compounds: 155, 155a, 165, and 165a.

[0317] Exemplary compounds of Formula (Il-e) include compounds: 199, and 199a.

[0318] Exemplary compounds of Formula (Il-ee) include compounds: 166, 166a, 197a, 197b, 202, 202a, and 202b.

[0319] Exemplary compounds of Formula (Il-g) include compounds: 195, and 195a.

[0320] Exemplary compounds of Formula (Il-h) include compounds: 198, 198a, 200, and 200a.

[0321] Certain examples of Formula (A) (e.g., Formula (I) or (II)) compounds were synthesized using methods involving resolution of stereoisomeric mixture(s) (e.g., SFC separation of stereoisomers). In Table Cl, the resolved stereogenic centers in these compounds are labelled with an asterisk (i.e., “*”). In some instances, the stereoisomeric resolutions were performed during the last step of the synthesis, thereby providing the individual stereoisomers of the Formula (A) (e.g., Formula (I) or (II)) compounds. Alternatively, in some other instances, the resolutions were performed on an intermediate or starting material, wherein each of the constituent stereoisomers of the intermediate or starting material could be separately subjected to the subsequent steps of the synthesis to provide the respective Formula (A) (e.g., Formula (I) or (II)) compounds as separate stereoisomers. Methods of resolution and correlation between resolved intermediates and Formula (A) (e.g., Formula (I) or (II)) compounds are disclosed in the examples herein (e.g., in Examples 65, 66, 68, 69, 76, 77, 78, 79, 84, and 85). A person of ordinary skill in the art would understand that, under either approach for stereoisomeric resolution, stereoisomers having both (R)- and (^-configurations at a resolved stereogenic center are provided. See Table C2, wherein Table Cl compounds whose stereoisomers contain the asterisk stereochemical notations are provided in non- stereogenic form, followed by the respective stereoisomers having the (R)- and (S)- configurations.

[0322] Table C2

[0323]

[0324] Also provided herein is a KRas protein (e.g., a dysregulated KRas protein (e.g., a mutated KRas protein)) non-covalently bound with a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (H-g), or (II- h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof. In some embodiments, GlylO of the KRas protein interacts non-covalently with the Ring C of the compound of Formula (A) (e.g., Formula (I)), or a pharmaceutically acceptable salt thereof, (e.g., via a hydrogen bond between the carbonyl of Gly 10 and an OH present on Ring C and / or via a water mediated interaction between the NH group of GlylO and an OH present on Ring C). Without wishing to be bound by theory, in some embodiments, the interaction between GlylO of the KRas protein and the Ring C of the compound of Formula (A) (e.g., Formula (I)), or a pharmaceutically acceptable salt thereof, facilitates the inhibition of interaction between the KRas protein and Raf-RBD. In some embodiments, Arg68 of the KRas protein interacts non- covalently with the Ring C of the compound of Formula (A) (e.g., Formula (I)), or a pharmaceutically acceptable salt thereof, (e.g., via a hydrogen bond between the guanidine of Arg68 and a CN group present on Ring C). Without wishing to be bound by theory, in some embodiments, the interaction between Arg68 of the KRas protein and the Ring C of the compound of Formula (A) (e.g., Formula (I)), or a pharmaceutically acceptable salt thereof, facilitates the inhibition of interaction between the KRas protein and Raf-RBD.

[0325] Chemical definitions

[0326] The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0327] 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.

[0328] 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, Ci-io 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, z.w-propyl, tert-butyl, zz-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.

[0329] 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).

[0330] The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).

[0331] 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 radicals can be on the same ring carbon atom (e.g., a geminal diradical such different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring 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.

[0332] 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.

[0333] 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.

[0334] 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[l.l. l]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2. 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.

[0335] 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

[0336] 0 0 consisting of N, O, S (inclusive of oxidized forms such as: or ), and P (inclusive o \

[0337] II A

[0338] \^P. ' of oxidized forms such as: ' ) and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotri azolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-t ]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[Z>][l,4]dioxinyl, benzo[ ][l,3]dioxolyl, 2,3- dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[Z>][l,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., o imidazolonyl (e.g., wherein each ring nitrogen adjacent to a carbonyl is tertiary

[0339] (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).

[0340] 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, the heteroatoms selected from O, N, S (inclusive of oxidized forms such as: and P (inclusive of

[0341] O \ II A p\ oxidized forms such as: ' ) (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O,

[0342] 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.

[0343] Examples of partially unsaturated heterocyclyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl.

[0344] Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2- 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[l .1 ,0]butyl, oxabicyclo[2.1 ,0]pentyl, 2-oxabicyclo[l .1.1 ]pentyl, 3-oxabicyclo[3.1 ,0]hexyl oxabicyclo[2.1.1 ]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3 -oxabi cy cl o [4.1.0] heptyl oxabicyclo[2.2.1 jheptyl, 6-oxabicyclo[3.1.1 ]heptyl, 7-oxabicyclo[4.2.0]octyl, 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.

[0345] As used herein, when a ring is described as being “partially unsaturated”, it means the 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.

[0346] 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

[0347] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses thetautomeric form containing the moiety: . Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0348] 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.

[0349] Methods of Treatment

[0350] Indications

[0351] Provided herein are methods for inhibiting a KRas protein. For example, provided herein are inhibitors of a KRas protein (e.g., a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein))) useful for treating or preventing diseases or disorders associated with the KRas dysregulation (i.e., a KRas-associated disease or disorder), such as a cardiovascular disease, an inflammatory and / or autoimmune disease, or a cancer (e.g., a KRas-associated cancer).

[0352] 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; Niemela et al. Blood. 2011; 117(10):2883-6; Nosan et al. Croat Med J. 2013; 54(6): 574-578; and Messina et al. Small GTPases 11.5 (2020): 312-319. 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; Niemela et al. Blood. 2011; 117(10):2883-6; Nosan et al. Croat Med J. 2013; 54(6): 574-578; and Messina et al. Small GTPases 11.5 (2020): 312-319.

[0353] The phrase “dysregulation of a KRAS gene, a KRas protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a KRAS gene that results in the expression of a KRas protein that includes a deletion of at least one amino acid as compared to a wild type KRas protein, a mutation in a KRAS gene that results in the expression of a KRas protein with one or more point mutations as compared to a wild type KRas protein, a mutation in a KRAS gene that results in the expression of a KRas protein with at least one inserted amino acid as compared to a wild type KRas protein, a gene duplication that results in an increased level of KRas protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of KRas protein in a cell); an alternative spliced version of a KRas mRNA that results in a KRas protein having a deletion of at least one amino acid in the KRas protein as compared to the wild type KRas protein; or increased expression (e.g., increased levels) of a wild type KRas protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non-cancerous cell). As an example, a dysregulation of a KRAS gene, a KRas protein, or expression or activity, or level of any of the same, can be a mutation in a KRAS gene that encodes a KRas protein that has low GTPase activity and / or has increased signaling activity as compared to a protein encoded by a KRAS gene that does not include the mutation. As another example, a dysregulation of a KRAS gene, a KRas protein, or expression or activity, or level of any of the same, can be a KRas amplification. In some embodiments, a KRas amplification is an amplification of the wild type KRas. In some embodiments, a KRas amplification is an amplification of a mutant KRas.

[0354] 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, an insertion of at least one amino acid as compared to a wild type KRas protein); (ii) a KRas protein resulting from a gene duplication event, e.g., of the gene encoding the KRas protein (e.g., the wild type KRas protein), thus resulting in an increased level and / or activity of the KRas protein (e.g., the wild type KRas protein) in a cell; (iii) a KRas protein resulting from a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that can also result in an increased level and / or activity of the KRas protein (e.g., the wild type KRas protein) in a cell);, (iv) a KRas protein resulting from an alternative spliced version of a KRas mRNA that results in a KRas protein having a deletion of at least one amino acid in the KRas protein as compared to the wild type KRas protein); or (v) a KRas protein resulting from increased expression (e.g., increased levels) of a wild type KRas protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non-cancerous cell). In some embodiments, a dysregulated KRas protein is a dysregulated human KRas protein.

[0355] 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).

[0356] 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).

[0357] 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).

[0358] 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).

[0359] 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).

[0360] 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).

[0361] 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).

[0362] A “KRas G12V mutant protein” as used herein refers to a KRas protein including a glycine to valine substitution at the twelfth amino acid position (relative to SEQ ID NO: 1). A “KRas G13X mutant protein” as used herein refers to a KRas protein including substitution of a glycine to any other amino acid at the thirteenth amino acid position (relative to SEQ ID NO: 1).

[0363] 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).

[0364] 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).

[0365] 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).

[0366] 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).

[0367] 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).

[0368] 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).

[0369] 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).

[0370] 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).

[0371] 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).

[0372] 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).

[0373] A “KRas inhibitor” as used herein includes any compound exhibiting KRas protein inactivation activity (e.g., inhibiting or decreasing KRas signaling activity). A KRas inhibitor as described herein has an IC50 value of 1 pM or less in a nucleotide exchange assay as described herein, an IC50 value of 1 pM or less in a Raf kinase interaction assay as described herein, or both. In some embodiments, a KRas inhibitor inhibits the signaling activity of a wild type KRas protein. In some embodiments, a KRas inhibitor inhibits the signaling activity of a dysregulated KRas protein, for example, resulting in a decrease in activated Raf or other downstream effectors, such as ERK. In some embodiments, a KRas inhibitor inhibits the signaling activity of a mutant KRas protein. In some embodiments, a KRas inhibitor inhibits both the signaling activity of a wild-type KRas protein and the signaling activity of one or more mutant KRas proteins and can be termed a “pan KRas inhibitor”. In some embodiments, a KRas inhibitor inhibits one or more mutant KRas proteins, and such a KRas inhibitor can be termed a “mutant KRas inhibitor”, and also termed by the mutant(s) it inhibits. For example, a KRas inhibitor that inhibits KRas G12R mutant protein could be termed a “KRas G12R inhibitor”. As another example, a KRas inhibitor that inhibits both KRas G12C mutant protein and KRas G12D mutant protein could be termed a “KRas G12C inhibitor” and / or a “KRas G12D inhibitor”. In some embodiments, a “mutant KRas inhibitor” inhibits two or more mutant KRas proteins and can be termed a “pan mutant KRas inhibitor”. In some embodiments, a pan mutant KRas inhibitor inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. For example, a “KRas G12X inhibitor” can inhibit two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. As yet another example, a KRas inhibitor that inhibits a KRas G13D mutant protein could be 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.

[0374] Compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, are KRas inhibitors. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I- e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (n-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, is a mutant KRas inhibitor. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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

[0375] G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas

[0376] G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas

[0377] Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas

[0378] Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (II- e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12V mutant protein.

[0379] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, is a KRas G12X inhibitor. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (II- e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I- aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (II- e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I- aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits four or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12A mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12C mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, does not inhibit a KRas G12C mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12D mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, does not inhibit a KRas G12D mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12S mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12V mutant protein.

[0380] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, is a KRas G13X inhibitor. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 G13V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G13C mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G13D mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G13V mutant protein.

[0381] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, is a KRas Q61X inhibitor. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II- h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (II-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II- h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits five or more mutant KRas proteins selected from the group consisting of: a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula

[0382] (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II- h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61E mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61H mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula

[0383] (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61K mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61L mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61P mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas Q61R mutant protein.

[0384] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 Q6 IX mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (n-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 Q6 IX mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (n-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits a KRas G12X mutant protein, a KRas G13X mutant protein, and a KRas Q61X mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I- aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (II- e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, five or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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.

[0385] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H- ), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (H-h)), or Formula (Aa)), 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, compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, are useful for treating a bladder cancer.

[0386] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (H-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, are useful for treating a cervical cancer.

[0387] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (II- e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, are useful for treating a colorectal cancer.

[0388] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 Q6 IL mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61H mutant protein, and a KRas Q61L mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 G13 V mutant protein, a KRas Q61H mutant protein, and a KRas Q61L mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (II- e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I- aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, are useful for treating an endometrial cancer.

[0389] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, and a KRas Q61H mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- 0, (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- 0, (U S), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I- c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II- d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, are useful for treating an esophageal or stomach cancer.

[0390] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (II-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, are useful for treating a leukemia.

[0391] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 G13 V 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of: a KRas G12C mutant protein, a KRas G12D mutant protein, and a KRas G12R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, are useful for treating a melanoma.

[0392] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (II-h)), or Formula (Aa)), 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 Q6 IL mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (ILf), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas Q61H mutant protein, and a KRas Q61L mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (II- e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I- aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, are useful for treating a lung cancer (e.g., non-small cell lung cancer).

[0393] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (H-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (n-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas Q61H mutant protein, and a KRas Q61R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (II- e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, are useful for treating a pancreatic cancer.

[0394] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of: a KRas G12A mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I- aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, are useful for treating a testicular cancer (e.g., seminoma).

[0395] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can bind to a KRas protein in the GTP- bound state. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can bind selectively to a KRas protein in the GTP -bound state.

[0396] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can bind to a KRas protein in the GDP- bound state. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can bind selectively to a KRas protein in the GDP -bound state.

[0397] An exemplary sequence of mature human KRas protein is shown below (UniProtKB entry P01116) (SEQ ID NO: 1)

[0398] MTEYKLVWG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQWIDGET

[0399] CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI

[0400] KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ

[0401] RVEDAFYTLV REIRQYRLKK ISKEEKTPGC VKIKKCI IM

[0402] 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (II- e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, has at least a 5-fold (e.g., at least a 10-fold, at least a 25-fold, at least a 50-fold, or at least a 100-fold) smaller KD value for any one or more KRas mutant proteins selected from the group consisting of the KRas G12X mutant proteins than for the wild type KRas protein when measured by the SPR assay. As a further example, if a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II- h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II- h)), or Formula (Aa)), 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 (A) (e.g., Formula

[0403] (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II- h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I- aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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.

[0404] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula

[0405] (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, is a pan mutant KRas inhibitor (i.e., can inhibit two or more mutant KRas proteins (e.g., two or more of a KRas G12A mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein)). For example, such a compound can inhibit each mutant KRas protein (e.g., two or more mutant KRas proteins) with an IC50 of less than 1 pM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). As another example, such a compound can inhibit ERK phosphorylation in cell lines each expressing a mutant KRas protein with an independent IC50 of less than 1 pM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM) in at least of the two cell lines. For example, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (II- e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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).

[0406] The ability of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I- aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II- h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (II- e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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.

[0407] In some cases, binding affinities (e.g., as measured by dissociation constant KD) of the compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 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). 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).

[0408] Another exemplary assay for determining the potency of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (n-g), or (H-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, includes measuring the effect of the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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, PSN1, HUPT3, KP2, CAL62, TCCPAN2, PK8, PATC50, H358, MIAPaCa-2, CALU1, AGS, A427, ASPC1, HKA1, KMS20, A549, LS123, HTK, H727, H441, HCT116, H460, A375, NCI-H1993, PC9, MKN1, NCI-H211, NCI-H424, and / or NCI-H526. In some embodiments, the cell line can be AGS, A427, ASPC1, H727, and / or H441. 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (n-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa))). 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (n-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof). 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. 2021 / 0179633, 2021 / 0230142, and 2019 / 0284144.

[0409] As another example, the potency and / or efficacy of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 H727, H441, AGS, A427 and / or ASPC1 or a patient-derived xenograft (PDX) model). See, e.g., U.S. Publication No. 2021 / 0179633.

[0410] 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof) stabilizes the GTP -bound state or GDP -bound state of a KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)). In such assays, the rate of hydrogen exchange of the backbone amide hydrogens can be measured for a KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) bound to a non-hydrolyzable GTP mimic (GMPPNP), GDP, or a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II- h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof. See, e.g., Lim et al. Angew Chem Int Ed Engl. 2014; 53(1): 199-204.

[0411] In some embodiments, potency of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, as provided herein can be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC50 value. In some embodiments, an EC50 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 PSN1, HUPT3, KP2, CAL62, TCCPAN2, PK8, PATC50, H358, MIAPaCa-2, CALU1 AGS, A427, ASPC1, HKA1, KMS20, A549, LS123, HTK, H727, HCT116, H460, A375, NCI-H1993, PC9, MKN1, NCI-H211, NCI-H424, and / or NCI-H526) 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).

[0412] In some embodiments, potency of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 PSN1, HUPT3, KP2, CAL62, TCCPAN2, PK8, PATC50, H358, MIAPaCa-2, CALU1 AGS, A427, ASPC1, HKA1, KMS20, A549, LS123, HTK, H727, HCT116, H460, A375, NCI-H1993, PC9, MKN1, NCI-H211, NCI-H424, and / or NCI-H526) 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).

[0413] In some embodiments, measuring the potency of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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., PSN1, HUPT3, KP2, CAL62, TCCPAN2, PK8, PATC50, H358, MIAPaCa-2, CALU1 AGS, A427, ASPC1, HKA1, KMS20, A549, LS123, HTK, H727, H441, HCT116, H460, A375, NCI-H1993, PC9, MKN1, NCI-H211, NCI-H424, and / or NCI- H526 (e.g., AGS, A427, ASPC1, H727, and / or H441)). For example, cells can be contacted with a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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, 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof can be used to construct a dose response curve. See, e.g., International Publication No. WO 2021 / 041671, U.S. Publication Nos. 2021 / 0122764, 2018 / 0334454, 2021 / 0179633, 2018 / 0334454, and 2019 / 0144444.

[0414] An exemplary ERK phosphorylation protocol follows. In some embodiments, an ERK phosphorylation assay can be carried out using the AlphaLisa SUREFIRE® Ultra Multiplex Phospho / Total ERK1 / 2 (Thr202 / Tyr204) Assay Kit. In a plate (e.g., a white, opaquebottom Perkin Elmer CulturPlate-384 (product number 6007680)), cells are seeded at the desired concentration one day prior to treatment with compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II- h)), or Formula (Aa)), 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), HPAFII (KRas G12D), Panc02.03 (KRas G12D), A427 (KRas G12D), HPAC (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), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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- .M top concentration, in triplicate). Treatment plates are then returned to a standard 37 °C, 5% CO2 humidified incubator for the pre-determined treatment time. Following compound treatment, all media is removed from the treatment plate(s), and the cells are subsequently lysed (e.g., using IX Lysis Buffer in accordance with manufacturer protocol). Next, the Acceptor Mix (prepared in accordance with manufacturer’s protocol) is added to each well of the assay plate and incubated on an orbital shaker at room temperature for 2 hours. Following incubation with the Acceptor Mix, the Donor Mix (prepared in accordance with manufacturer protocol) is added to each well of the assay plate, covered to protect from light, and incubated on an orbital shaker at room temperature overnight. Assay plates are read the following day (e.g., on a BMG Labtech PHERAstar FSX microplate reader). Data are then analyzed by calculating the ratio of ERKl / 2-phosphorylation relative to Total ERK1 / 2 for each individual well.

[0415] 615nm Signal (pERKl / 2)

[0416] Ratio pERKl / 2 = — -

[0417] 545nm Signal (Total ERK1 / 2)

[0418] 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.

[0419] In some embodiments, the compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, inhibit ERK phosphorylation in a cell line expressing a KRas protein (e.g., a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein))) with an IC50 of less than 1 pM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compounds inhibit ERK phosphorylation in a cell line expressing the KRas protein (e.g., a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein))) with an IC50 of less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM). For example, the compounds can inhibit ERK phosphorylation in a cell line expressing the KRas protein (e.g., a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein))) with an IC50 of 0.1 nM to 100 nM, 0.1 nM to 50 nM, 1 nM to 50 nM, or 1 nM to 20 nM.

[0420] 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (n-h)), or Formula (Aa)), 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; Lu, et al. Biochemistry 57.3 (2018): 324-333; Lim, et al. bioRxiv (2021) (doi:

[0421] 10.1101 / 2021.09.11.459913).

[0422] In some embodiments, the potency of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, as a KRas inhibitor can be evaluated by its effect on the nucleotide exchange of GDP for GTP. For example, nucleotide exchange can be measured via the increase in fluorescence of protein-bound N- methylanthraniloyl (MANT)-GDP upon the addition of an excess amount of a non- hydrolyzable GTP analog such as guanosine-5'-[(P,y)-imido]triphosphate (GppNHp, sometimes also referred to as GMPPNP), when exchange is inhibited. See, e.g., Kanie and Jackson, Bio Protoc. 2018; 8(7): e2795. 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, followed by treatment with unlabeled GTP. In such an assay, an exchange of fluorophore- tagged GDP (e.g., Bodipy-GDP) for unlabeled GTP results in a reduced TR-FRET signal. As another example, nucleotide exchange can be measured via the increase in fluorescence of an incubated mixture of KRas protein-bound GDP and a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II- h)), or Formula (Aa)), 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. 2021 / 0122764, 2021 / 0269434, and 2018 / 0334454. In some embodiments of nucleotide exchange assays, a guanine nucleotide exchange factor (e.g., S0S1) can be added to accelerate nucleotide exchange.

[0423] Inhibition of SOS 1 -catalyzed exchange of GDP for GTP on the KRas protein by compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (n-g), or (n-h)), or Formula (Aa)), 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. In some embodiments, an enzyme-linked immunosorbent assay (ELISA) can be used to measure the effect of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II- h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, on the GTPase activity of a KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)), for example, by detecting a change in the amount of GST-Ras-RBD that binds to the KRas protein following pull-down and antibody detection of the complex. See, e.g., US 2021 / 0179633.

[0424] 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 MgCb, 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 a black, low-volume 384-well assay plate. Compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 S0S1 (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 S0S1 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.

[0425] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 SOS 1 -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.

[0426] Additional assays for evaluating the potency of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), 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 KRasmucleotide complexes for the Ras Binding Domain (RBD) of a RAF protein kinase (e.g., as impacted by a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I- aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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., Hunter et al. Mol Cancer Res. 2015; 13(9): 1325-35; Lim et al. Angew Chem Int Ed Engl. 2014; 53(1): 199-204; and Durrant, et al. Molecular Cancer Therapeutics 20.9 (2021): 1743-1754. As another example, for compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (H-e), (Il-ee), (Il-f), (H-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can be incubated with a KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) and GDP, then GTP (and optionally, a GEF such as SOS1) can be introduced. Then, RAF (e.g., cRAF) acceptor beads (e.g., GST-tagged acceptor beads) can be incubated with the KRas mixture, followed by introduction of donor beads (e.g., glutathione donor beads) and measurement using ALPHASCREEN® technology. As an alternative to ALPHASCREEN® technology, any appropriate FRET pair can be used to perform homogenous time resolved fluorescence. See, e.g., U.S. Publication Nos. 2018 / 0334454 and 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I- bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (lice), (H-d), (Il-dd), (H-e), (H-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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. 2019 / 0233440. As another example, the effect of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I- aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, on the interaction between KRas and Raf-RBD can be evaluated using HiBiT and / or NANOBIT™ technology, wherein two parts of an enzyme are fused to or inserted into two proteins of interest (e.g., KRas and Raf-RBD); when the two proteins of interest are in proximity, the two parts of the enzyme complement each other to complete an enzyme that has signaling activity (e.g., that produces luminescence). In some such assays, the affinity of 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. Similarly, the effect of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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. In some embodiments, a RAF kinase interaction assay can be used to determine if a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (n-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, is selective for a KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) in the GDP -bound state or the GTP -bound state.

[0427] Inhibition of the interaction between the KRas protein and Raf-RBD by compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 herein)).

[0428] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (H-g), or (II-h)), or Formula (Aa)), 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 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.

[0429] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (H-g), or (II-h)), or Formula (Aa)), 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.

[0430] Another exemplary assay for evaluating the potency of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (n-h)), or Formula (Aa)), 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., PSN1, HUPT3, KP2, CAL62, TCCPAN2, PK8, PATC50, H358, MIAPaCa-2, CALU1 AGS, A427, ASPC1, HKA1, KMS20, A549, LS123, HTK, H727, HCT116, H460, A375, NCI-H1993, PC9, MKN1, NCI-H211, NCI-H424, and / or NCI-H526). For example, cells can be contacted with a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, for a period of time, then lysed or permeabilized, and total ERK or MEK and phosphoERK or phosphoMEK content can be determined (e.g., using antibodies, or a kit, such as Invitrogen InstantOne ERK1 / ERK2 (Phospho) [pT202 / pY204] / [pT185 / pY187] ELISA or MesoScale Discovery p / t ERK1 / 2). In some embodiments, multiple concentrations of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can be used to construct a dose response curve. In some embodiments, the compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, inhibit ERK phosphorylation in a cell line expressing a KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) with an IC50 of less than 1 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 G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) with an IC50 of less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM). For example, the compounds can inhibit ERK phosphorylation in a cell line expressing a KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) with an IC50 from 0.1 nM to 100 nM, from 0.1 nM to 50 nM, from 1 nM to 50 nM, or from 1 nM to 20 nM.

[0431] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 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.

[0432] 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.

[0433] The pharmacokinetic parameters of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, for instance, a mouse model, a rat model, a dog model, or a nonhuman primate (e.g., cynomolgus monkey) model. Pharmacokinetics parameters, including clearance (CL), volume of distribution (Vd), maximum plasma concentration (Cmax), time of maximum plasma concentration (tmax), half-life (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.

[0434] Certain pharmacokinetic parameters of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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.

[0435] In some embodiments, the compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))). In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) over another GTPase or non-GTPase target. In some embodiments, the compounds provided herein can exhibit nanomolar potency against a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) with minimal activity against related GTPases (e.g., wild type NRas protein, and / or wild type HRas protein).

[0436] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (H-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of a related GTPase (e.g., wild type NRas protein, and / or wild type HRas protein). In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25- fold, 50-fold, or 100-fold greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of a related GTPase (e.g., wild type NRas protein, and / or wild type HRas protein). In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit up to lOOOO-fold greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of a related GTPase (e.g., wild type NRas protein, and / or wild type HRas protein).

[0437] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10- fold greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of a related GTPase (e.g., wild type NRas protein, and / or wild type HRas protein). In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (H-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of a related GTPase (e.g., wild type NRas protein, and / or wild type HRas protein). In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative inhibition of a related GTPase (e.g., wild type NRas protein, and / or wild type HRas protein). In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about lOOOO-fold greater inhibition of a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of a related GTPase (e.g., wild type NRas protein, and / or wild type HRas protein).

[0438] In some embodiments, the compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or pharmaceutically acceptable salts thereof, can exhibit potent and selective inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))). In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I- e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (H-h)), or Formula (Aa)), 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 G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) over another GTPase or non-GTPase target. In some embodiments, the compounds provided herein can exhibit nanomolar potency against a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) with minimal activity against related GTPases (e.g., wild type KRas protein, wild type NRas protein, and / or wild type HRas protein).

[0439] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild type KRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I- e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild type KRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit up to lOOOO-fold greater inhibition of a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild type KRas protein.

[0440] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10- fold greater inhibition of a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild type KRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild type KRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1000-fold greater inhibition of a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild type KRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I- b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II- c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about lOOOO-fold greater inhibition of a mutant KRas protein (e.ga KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein)) relative to inhibition of wild type KRas protein.

[0441] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit nanomolar potency against a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) with minimal activity against wild type NRas protein, and / or wild type HRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild type NRas protein, and / or wild type HRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild type NRas protein, and / or wild type HRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit up to 1000-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild type NRas protein, and / or wild type HRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit up to lOOOO-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild type NRas protein, and / or wild type HRas protein.

[0442] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I- a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10- fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild type NRas protein, and / or wild type HRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I- dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild type HRas protein and / or wild type NRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1000-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild type NRas protein, and / or wild type HRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about lOOOO-fold greater inhibition of a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and / or a KRas G12V mutant protein (e.g., a KRas G12D mutant protein and / or a KRas G12V mutant protein))) relative to inhibition of wild type NRas protein, and / or wild type HRas protein.

[0443] Compounds Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (H-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 disorders (e.g., mutant KRas- associated diseases or disorders (e.g., KRas G12D-, KRas G12R-, or G12V-associated diseases or disorders)).

[0444] In certain embodiments, compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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).

[0445] 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.

[0446] 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).

[0447] In some such embodiments, the cancer (e.g., a tumor sample) has a KRas mutation selected from the group consisting of: a KRas G12X mutation, a KRas G13X mutation, and a KRas Q61X mutation. In some embodiments, a KRas mutation is selected from the group consisting of: a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, a KRas G12V mutation, a KRas G13C mutation, a KRas G13D mutation, a KRas G13V mutation, a KRas Q61E mutation, a KRas Q61H mutation, a KRas Q61K mutation, a KRas Q61L mutation, a KRas Q61P mutation, and a KRas Q61R mutation. In some embodiments, a KRas mutation is selected from the group consisting of: a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, and a KRas G12V mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas mutation selected from the group consisting of: a KRas G12A mutation, a KRas G12D mutation, a KRas G12R mutation, and a KRas G12V mutation.

[0448] In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12D mutation, a KRas G12R mutation, or KRas G12V mutation (e.g., a KRas G12D mutation or a KRas G12V mutation). In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12D mutation or a KRas G12V mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12D mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12R mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12V mutation.

[0449] 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.

[0450] 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.

[0451] 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.

[0452] The term “KRas G12A-associated cancer” as used herein refers to cancers associated with or having a KRas G12A mutation (e.g., a KRAS gene having a mutation corresponding to a G12A mutation in a KRas protein and / or a KRas protein having a G12A mutation). Non- limiting examples of a KRas G12A-associated cancer are described herein.

[0453] 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). Nonlimiting examples of a KRas G12C-associated cancer are described herein.

[0454] 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.

[0455] 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.

[0456] 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 G12 S -associated cancer are described herein.

[0457] 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.

[0458] 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.

[0459] 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.

[0460] 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. The term “KRas G13V-associated cancer” as used herein refers to cancers associated with or having a KRas G13 V 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.

[0461] 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.

[0462] 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.

[0463] 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.

[0464] 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.

[0465] 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.

[0466] 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 Q6 IP-associated cancer are described herein.

[0467] 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.

[0468] 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.

[0469] Provided herein are methods of treating a cancer in a subject in need of such treatment, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (H-e), (Il-ee), (Il-f), (Il-g), or (n-h)), or Formula (Aa)), 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.

[0470] 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (H-e), (Il-ee), (Il-f), (Il-g), or (n-h)), or Formula (Aa)), 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.

[0471] Provided herein is use of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of cancer, for example, any of the cancers provided herein.

[0472] Provided herein is use of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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.

[0473] Provided herein is use of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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.

[0474] Provided herein is a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament. Also provided herein is a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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.

[0475] Provided herein is a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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.

[0476] As used herein, “monotherapy”, when referring to a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II- g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, means that the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, is the only therapeutic agent or therapy (e.g., anticancer agent or therapy) administered to the subject during the treatment cycle (e.g., no additional targeted therapeutics, anticancer agents, chemotherapeutics, or checkpoint inhibitors are administered to the subject during the treatment cycle). As a person of ordinary skill in the art would understand, monotherapy does not exclude the co-administration of medicaments for the treatment of side effects or general symptoms associated with the cancer or treatment, such as pain, rash, edema, photosensitivity, pruritis, skin discoloration, hair brittleness, hair loss, brittle nails, cracked nails, discolored nails, swollen cuticles, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms, including nausea, diarrhea, and lack of appetite.

[0477] As used herein, “the subject has previously received one or more therapeutic agents or therapies for the cancer” means that the subject has been previously administered one or more therapeutic agents or therapies (e.g., anticancer agent or therapy) for the cancer other than a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (n-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, during a prior treatment cycle. In some embodiments, the subj ect cannot tolerate the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject did not respond to the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject did not adequately respond to one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject has stopped responding to the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, a lack of response, an inadequate response, or a discontinued response can be determined by objective criteria (e.g., tumor volume, or by criteria such as RECIST 1.1). In some embodiments, a lack of response, an inadequate response, or a discontinued response can be determined by the subject’s physician.

[0478] As used herein, “the subject is treatment naive with respect to the cancer” means that the subject has not been previously administered one or more therapeutic agents or therapies for the cancer.

[0479] 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.

[0480] 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 G12D mutation, a KRas G12R mutation, or a KRas G12V mutation (e.g., a KRas G12D mutation or a KRas G12V mutation)) or amplification) in a sample from the subject (e.g., detecting a KRAS gene having a mutation corresponding to a mutation in KRas protein and / or detecting a KRas protein having a mutation, a KRAS gene copy number increase, and / or an increase in KRas mRNA or protein expression); and b) administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer (e.g., a KRas G12D-associated cancer or a KRas G12V-associated cancer))) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I- bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II- cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer (e.g., a KRas G12D-associated cancer or a KRas G12V-associated cancer))) in a subject in need of such treatment, the methods comprising a) detecting a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation (e.g., a KRas G12D mutation or a KRas G12V mutation)) or amplification) in a sample from the subject (e.g., detecting a KRAS gene having a mutation corresponding to a mutation in KRas protein and / or detecting a KRas protein having a mutation, a KRAS gene copy number increase, and / or an increase in KRas mRNA or protein expression); and b) administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I- e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof.

[0481] 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 G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer (e.g., a KRas G12D-associated cancer or a KRas G12V-associated cancer)))) is breast cancer (e.g., breast invasive carcinoma, breast invasive ductal carcinoma), central or peripheral nervous system tissue cancer (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligoastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), multiple neuroendocrine type I and type II tumors, parathyroid cancer, pituitary tumors, thyroid cancer (e.g., papillary thyroid cancer)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer, bile duct cancer (e.g., cholangiocarcinoma), colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, liver cancer (e.g., hepatocellular carcinoma, intrahepatic bile duct cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic islet cell cancer), small intestine cancer, or stomach cancer (e.g., stomach adenocarcinoma, signet ring cell carcinoma of the stomach)), genitourinary cancer (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., renal clear cell carcinoma, renal papillary cell carcinoma, kidney chromophobe), prostate cancer (e.g., prostate adenocarcinoma), testicular cancer (e.g., testicular germ cell tumors, seminoma), or ureter cancer), gynecologic cancer (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, endocervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinosarcoma, uterine endometrioid carcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, uterine corpus endometrial carcinoma), or vulvar cancer), head and neck cancer (e.g., ear cancer (e.g., middle ear cancer), head and neck squamous cell carcinoma, nasal cavity cancer, oral cancer, pharynx cancer (e.g., hypopharynx cancer, nasopharynx cancer, oropharyngeal cancer), hematological cancer (e.g., leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) (e.g., Philadelphia chromosome positive ALL), acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia (APL)), chronic myeloid leukemia (CML)), lymphoma (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)), non -Hodgkin lymphoma (e.g., Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), diffuse histiocytic lymphoma (DHL), follicular lymphoma (FL), intravascular large B-cell lymphoma (IVLBCL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL))), or myeloma (e.g., multiple myeloma)), Li-Fraumeni tumors, mesentery cancer (e.g., omentum cancer, peritoneal cancer), pleural cancer, respiratory cancer (e.g., larynx cancer, lung cancer (e.g., lung squamous cell carcinoma, lung adenocarcinoma, mesothelioma, non-small cell lung cancer (NSCLC)), tracheal cancer), sarcoma (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcoma (Ewing sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), skin cancer (e.g., melanoma), thymus cancer (e.g., thymoma), or a combination thereof. 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.

[0482] 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.

[0483] 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.

[0484] 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.

[0485] 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.

[0486] In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., mutant KRas- associated cancer)) is pancreatic cancer or metastatic pancreatic cancer. In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., mutant KRas-associated cancer)) is pancreatic ductal adenocarcinoma (PDAC). In some such embodiments, the pancreatic cancer is a KRas G12R-associated cancer.

[0487] In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., mutant KRas- associated cancer)) is advanced-stage lung adenocarcinoma.

[0488] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor has a KRas dysregulation (e.g., a KRas mutation or amplification). For example, the solid tumor has a KRas mutation selected from the group consisting of a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, and a KRas G12V mutation. In some embodiments, the solid tumor has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation. In some embodiments, the solid tumor has a KRas G12D mutation or a KRas G12V mutation. In some embodiments, the solid tumor has a KRas G12D mutation. In some embodiments, the solid tumor has a KRas G12R mutation. In some embodiments, the solid tumor has a KRas G12V mutation.

[0489] 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Additionally provided herein is a method of treating a solid tumor in a subject in need thereof, the method comprising: (a) detecting a KRas G12D or a KRas G12V mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I- e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (H-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I- c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II- d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (H-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0490] 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.

[0491] 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein. Also provided herein is a method of treating a bladder cancer in a subject in need thereof, the method comprising: (a) detecting a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12V mutation, a KRas G13D mutation, or a KRas Q61H mutation in a sample from the subject, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (II- e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (H-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0492] 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). For 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.

[0493] 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I- e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (H-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (II-h)), or Formula (Aa)), 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 the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I- c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II- d), (Il-dd), (Il-e), (Il-ee), (Il-f), (II-g), or (n-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0494] 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.

[0495] 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I- e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (n-h)), or Formula (Aa)), 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 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I- c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II- d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (n-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I- ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (II- f), (H-g), or (n-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0496] 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.

[0497] 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 a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II- h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I- h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I- c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (II- d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (H-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0498] 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 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 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.

[0499] 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (Il-e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (II) (e.g., (II-c), (II-cc), (Il-d), (Il-dd), (II- e), (Il-ee), (Il-f), (Il-g), or (II-h)), or Formula (Aa)), 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 (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-aa), (I-b), (I-bb), (I-c), (I-cc), (I-d), (I-dd), (I-e), (I-ee), (I-f), (I-g), or (I-h)), Formula (...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (A):Formula (A) or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, or 2; each X1is independently selected from the group consisting of CH2, CHRa, C(Ra)2, O, N(Rd), C(=O), and S(0)o-2, provided that -(X4)m- does not include any O-O, O-N, N-S(0)o, or 0-S(0)o-2 bonds;Ring C is selected from the group consisting of: C3-15 cycloalkylene, 4-15 membered heterocyclylene, 6-15 membered arylene, and 5-15 membered heteroarylene, each of which is optionally substituted with 1-4 R7, wherein: each R7is independently selected from the group consisting of Raand Rb; p is an integer from 3 to 10; each LAis independently selected from the group consisting of: LA1, LA2, LA3, and LA4, provided that 0-2 occurrences of LAare LA4, and 0-3 occurrences of LAare selected from the group consisting of LA2and LA3; each LA1is independently selected from the group consisting of: -CH2-, -CHRL-, and - C(RL)2-, wherein each RLis independently selected from the group consisting of: halo, cyano, -OH, -Ci-6 alkoxy, -Ci-6 haloalkoxy, -NRdRe, C(=0)N(Rf)2, and Ci-6 alkyl optionally substituted with 1-6 Rc;Aj^RL2 each LA2is independently selected from the group consisting of:rL2wherein each RL2is independently selected from the group consisting of: H, halo, CN, and Ci-6 alkyl optionally substituted with 1-6 Rc; each LA3is independently selected from the group consisting of: -N(Rd)-, -O-, -S(0)o- 2-, and C(=O); each LA4is independently selected from the group consisting of: C3-10 cycloalkylene, 4-10 membered heterocyclylene, Ce-io arylene, and 5-10 membered heteroarylene, each of which is optionally substituted with 1-3 Rg;Ring B is selected from the group consisting of: Ce-io arylene and 5-10 membered heteroarylene, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb;Y1is selected from the group consisting of: a bond, -N(H)-, -N(CI-3 alkyl)-, -N(C3-6 cycloalkyl)-, -O-, and -S(0)o-2-; n is 0 or 1;Y2is a straight-chain Ci-6 alkylene optionally substituted with 1-6 RY; each RYis independently selected from the group consisting of: halo, cyano, -OH, oxo, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 alkyl, and Ci-6 haloalkyl, or a pair of RYon the same or different carbon atom(s) taken together with the atom(s) connecting them form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring, each of which is optionally substituted with 1-3 independently selected C1.3 alkyl;R3is selected from the group consisting of:(a) -H;(b) -halo;(c) -NRdRe;(d) C3-10 cycloalkyl or 3-15 membered heterocyclyl, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb; and(e) Ce-io aryl or 5-10 membered heteroaryl, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb;E1is N, CH, or CR6;R4, R5, and R6are independently selected from the group consisting of:(a) -H;(b) halo;(c) cyano;(d) Ci-6 alkyl;(e) Ci-6 haloalkyl;(f) Ci-6 alkoxy;(g) Ci-6 haloalkoxy;(h) -(Co-3 alkylene)-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl portion is optionally substituted with 1-3 Rg; and(i) -0-(Co-3 alkylene)-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl portion is optionally substituted with 1-3 Rg; each Rais independently selected from the group consisting of:(a) halo;(b) cyano;(c) -OH;(d) oxo;(e) -Ci-6 alkoxy;(f) -Ci-6 haloalkoxy;(g) -NRdRe;(h) C(=O)Ci-6alkyl;(i) C(=O)Ci-6haloalkyl; a) C(=O)OH;(k) C(=O)OCi-6alkyl;(l) C(=O)OCi-6haloalkyl;(m) C(=O)N(Rf)2;(n) S(0)o-2(Ci-6 alkyl);(o) S(0)o-2(Ci-6 haloalkyl);(p) S(O)i-2N(Rf)2; and(q) Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rbland -Rbl, wherein: b is 1, 2, or 3; 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 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; each Rcis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NRdRe, C(=O)Ci-6 alkyl, C(=O)Ci-6 haloalkyl, C(=O)OCi-6 alkyl, C(=O)OCi-6 haloalkyl, C(=O)OH, C(=O)N(Rf)2, S(O)0.2(Ci.6alkyl), S(O)0.2(Ci.6haloalkyl), and S(O)i-2N(Rf)2; 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)i-2(Ci-6 alkyl), S(O)i-2(Ci-6 haloalkyl), S(O)i-2N(Rf)2, and Ci-6 alkyl optionally substituted with 1-3 Rb; each Rfis independently selected from the group consisting of: H and Ci-6 alkyl optionally substituted with 1-3 Rb; each Rgis independently selected from the group consisting of: Rb, C1.3 alkyl, and Ci- 3 haloalkyl; and each Rbis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NH2, -N(H)(CI-3 alkyl), and -N(CI-3 alkyl)2.

2. The compound of claim 1, wherein the compound of Formula (A) is a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound of Formula (A) is a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof, wherein E1is CH or CR6.

4. The compound of any one of claims 1-3, wherein m is 0.

5. The compound of any one of claims 1-4, wherein Ring C is a 4-15 membered heterocyclylene optionally substituted with 1-4 R7; or wherein Ring C is a 4-6 membered heterocyclylene optionally substituted with 1-3 R7; wherein Ring C is a piperidinylene optionally substituted with 1-3 R7.

6. The compound of any one of claims 1-5, wherein Ring C is:wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; and cc represents the point of attachment to -(LA)P-.

7. The compound of claim 6, wherein cl is 0.

8. The compound of claims 6 or 7, wherein Ringwherein Ringoptionally substituted with1-3 F; or wherein Ring9. The compound of any one of claims 1-5, wherein Ring C is a 7-10 membered heterocyclylene optionally substituted with 1-3 R7.

10. The compound of claim 9, wherein Ring C has one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms.

11. The compound of any one of claims 1-5 or 9-10, wherein Ring C is, wherein cl is 0, 1, or 2; and cc represents the point of attachment to -(LA)p-12. The compound of any one of claims 1-11, wherein p is 4, 5, or 6; or wherein p is 6, 7, or 8.

13. The compound of any one of claims 1-12, wherein each LAis independently selected from the group consisting of: LA1, LA3, and LA4.

14. The compound of any one of claims 1-13, wherein 0-1 occurrence of LAis LA4; and each remaining LAis independently selected from the group consisting of LA1and LA3.

15. The compound of any one of claims 1-14, wherein one occurrence of LAis LA4; and each remaining LAis independently LA1.

16. The compound of any one of claims 1-14, wherein each LAis independently LA117. The compound of any one of claims 1-14, wherein 1-2 occurrence of LAis independently LA3; and each remaining LAis independently LA1.

18. The compound of any one of claims 1-11, wherein p is 4, 5, or 6; one occurrence of LAis LA4; and each remaining LAis independently LA1.

19. The compound of any one of claims 1-11, wherein p is 6, 7, or 8; and each LAis independently LA1.

20. The compound of claim 19, wherein each LAis -CH2-.

21. The compound of any one of claims 1-11, wherein p is 6, 7, or 8; one occurrence of LAis C(=O); a second occurrence of LAis N(Rd) (e.g., NH); and each remaining LAis independently LA1.

22. The compound of any one of claims 1-11 or 21, wherein -(LA)P- is: -(LAla)aia- C(=O)NH-(LAlb)aib-M, wherein: ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1; and bb represents the point of attachment to Ring C.

23. The compound of claim 22, wherein alb is 2; and ala is 2, 3, or 4; or wherein alb is 1; and ala is 3, 4, or 5.

24. The compound of any one of claims 22-23, wherein each of LAlaand LAlbis CH2.

25. The compound of any one of claims 1-3, wherein: m is 0;Ring C is:wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; and cc represents the point of attachment to -(LA)P-;-(LA)P- is: -(LAla)aia-C(=O)NH-(LAlb)aib-M, wherein: ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or each LAlaand LAlbis independently selected LA1; and bb represents the point of attachment to Ring C.

26. The compound of claim 25, wherein alb is 2; and ala is 2, 3, or 4; orwherein alb is 1; and ala is 3, 4, or 5.

27. The compound of claims 25 or 26, wherein each of LAlaand LAlbis CH2.

28. The compound of any one of claims 23-27, wherein Ring C is29. The compound of any one of claims 23-28, wherein cl is 0.

30. The compound of any one of claims 1-3, wherein: m is 0;Ring C is:, wherein: cl is 0, 1, or 2; cc represents the point of attachment to -(LA)P-; and-(LA)p- is: -(LAla)aia-C(=O)NH-(LAlb)aib-ii, wherein: ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or each LAlaand LAlbis independently selected LA1; and bb represents the point of attachment to Ring C.

31. The compound of claim 30, wherein alb is 2; and ala is 2, 3, or 4; or wherein alb is 1; and ala is 3, 4, or 5.

32. The compound of claims 30 or 31, wherein each of LAlaand LAlbis CH2; and cl is 0.

33. The compound of any one of claims 1-32, wherein Ring B is a Ce-io arylene optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb.

34. The compound of any one of claims 1-33, wherein Ring B is naphthylene optionally substituted with 1-4 Ra.

35. The compound of any one of claims 1-34, wherein Ringwherein R2aand R2care independently H or Ra; and aa represents the point of attachment to -(LAp'36. The compound of claim 35, wherein R2ais -OH; or wherein R2ais H or -NH2.

37. The compound of any one of claims 34-36, wherein R2cis halo or H.

38. The compound of any one of claims 1-34, wherein Ring, wherein aa represents the point of attachment to -(LA)P-.

39. The compound of any one of claims 1-34, wherein Ring, wherein aa represents the point of attachment to -(LA)P-.

40. The compound of any one of claims 1-33, wherein Ring B is phenylene optionally substituted with 1-4 Ra.

41. The compound of any one of claims 1-33 or 40, wherein Ring B is, wherein R2a, R2b, and R2care independently H or Ra; and aa represents the point of attachment to -(LA)P-; or wherein Ring, wherein R2aand R2care independently H or Ra; and aa represents the point of attachment to -(LA)P-.

42. The compound of claim 41, wherein R2ais -OH; or wherein R2ais -NH2.

43. The compound of claims 41 or 42, wherein R2cis halo (e.g., -Cl).

44. The compound of any one of claims 1-33, wherein Ring B is a 5-10 membered heteroarylene, which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb.

45. The compound of any one of claims 1-33 or 44, wherein Ring B is a 9-10 membered bicyclic heteroarylene, which is optionally substituted with 1-3 Ra.

46. The compound of any one of claims 1-33 or 44-45, wherein Ring B is, wherein R2cis H or Ra; and aa represents the point of attachment to -(LA)P-.

47. The compound of claim 46, wherein R2cis halo.

48. The compound of any one of claims 1-33 or 44-47, wherein Ring B is, wherein aa represents the point of attachment to -(LA)P-.

49. The compound of any one of claims 1-48, wherein Y1is -O-.

50. The compound of any one of claims 1-49, wherein n is 1.

51. The compound of any one of claims 1-50, wherein Y2is a straight-chain C1.3 alkylene optionally substituted with 1-3 RY.

52. The compound of any one of claims 1-51, wherein Y2is -CH2-.

53. The compound of any one of claims 1-51, wherein Y2is54. The compound of any one of claims 1-53, wherein R3is a 4-10 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb; or wherein R3is a monocyclic 4-6 membered heterocyclyl optionally substituted with 1- 3 Ra, wherein the heterocyclyl includes at least one ring nitrogen atom.

55. The compound of any one of claims 1-54, wherein R3ioptionally substituted with 1-3 Raon one or more ring carbon atoms; or wherein R3isoptionally substituted with 1-3 Ra; or wherein R3is a bicyclic 7-10 membered heterocyclyl optionally substituted with 1-6Ra; or whereinoptionally substituted with 1-3 Ra; or wherein R3is selected from the group consisting of:; or whereinwherein R3is selected from the group consisting of:, , each of which is optionally substituted with 1-3 Ra.

56. The compound of any one of claims 1-55, wherein Y1is -O-; n is 1; Y2is -CH2-optionally substituted with 1-3 Ra.

57. The compound of claim 56, wherein R3is selected from the group consisting58. The compound of claims 56 or 57 wherein59. The compound of any one of claims 1-48, wherein Y1is -O-; n is 1; Y2is; and R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra.

60. The compound of claim 59, wherein R3is selected from the group consistingeach of which is optionally substituted with 1-3 Ra.

61. The compound of any one of claims 1-60, wherein R4is H.

62. The compound of any one of claims 1-61, wherein R5is -F.

63. The compound of any one of claims 1-60, wherein R4is H; and R5is -F.

64. The compound of any one of claims 1 or 3-63, wherein E1is CH or CR6, wherein R6is halo (e.g., -F, or -Cl).

65. The compound of claim 1, wherein the compound is a compound of Formula (Aa):Formula (Aa) or a pharmaceutically acceptable salt thereof, wherein:Ring C is a 4-10 membered heterocyclylene optionally substituted with 1-4 R7, wherein Ring C has one ring nitrogen atom, 0-1 ring oxygen atom, and no additional ring heteroatoms;Ring B is selected from the group consisting of: Ce-io arylene and 5-10 membered heteroarylene, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: Raand Rb; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; andR5is H or halo.

66. The compound of claim 65, wherein:E1is N, CH, or C-halo;Ring C is selected from the group consisting of:wherein: cl is 0, 1, or 2; cc represents the point of attachment to -(LAlb)aib-; each R7aand R7bis an independently selected R7; andRing B is selected from the group consisting of:wherein R2ais -OH or -NH2; R2band R2care independently H or halo (e.g., -Cl); and aa represents the point of attachment to -(LAla)aia-.

67. The compound of claims 1 or 2, wherein the compound is a compound ofFormula (I-c) or (I-cc):Formula (I-c)Formula (I-cc) or a pharmaceutically acceptable salt thereof, wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1; R2aand R2care independently H or Ra;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; andR5is H or halo.

68. The compound of claims 1 or 3, wherein the compound is a compound ofFormula (II-c) or (II-cc):Formula (II-c)Formula (II-cc) or a pharmaceutically acceptable salt thereof, wherein: E1is CH or CR6; cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;R2aand R2care independently H or Ra;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; andR5is H or halo.

69. The compound of claims 1 or 2, wherein the compound is a compound of Formula (I-d) or (I-dd):Formula (I-dd) or a pharmaceutically acceptable salt thereof, wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;R2aand R2care independently Ra;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; and R5is H or halo.

70. The compound of claims 1 or 3, wherein the compound is a compound of Formula (Il-d) or (Il-dd):Formula (Il-dd) or a pharmaceutically acceptable salt thereof, wherein:E1is CH or CR6; cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or6; each LAlaand LAlbis an independently selected LA1;R2aand R2care independently Ra;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; andR5is H or halo.

71. The compound of claims 1 or 2, wherein the compound is a compound of Formula (I-e) or (I-ee):or a pharmaceutically acceptable salt thereof, wherein: cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;R2cis H or Ra;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; andR5is H or halo.

72. The compound of claims 1 or 3, wherein the compound is a compound ofFormula (Il-e) or (Il-ee):or a pharmaceutically acceptable salt thereof, wherein:E1is CH or CR6; cl is 0, 1, or 2; each R7aand R7bis an independently selected R7; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1; R2cis H or Ra;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; andR5is H or halo.

73. The compound of claims 1 or 2, wherein the compound is a compound of Formula (I-f):Formula (I-f) or a pharmaceutically acceptable salt thereof, wherein: cl is 0, 1, or 2; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or each LAlaand LAlbis an independently selected LA1;R2aand R2care independently Ra;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; andR5is H or halo.

74. The compound of claims 1 or 3, wherein the compound is a compound of Formula (Il-f):Formula (Il-f) or a pharmaceutically acceptable salt thereof, wherein: cl is 0, 1, or 2; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or each LAlaand LAlbis an independently selected LA1;R2aand R2care independently Ra;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; and R5is H or halo.

75. The compound of claims 1 or 2, wherein the compound is a compound ofFormula (I-g):Formula (I-g) or a pharmaceutically acceptable salt thereof, wherein: cl is 0, 1, or 2; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or each LAlaand LAlbis an independently selected LA1;R2aand R2care independently H or Ra;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; andR5is H or halo.

76. The compound of claims 1 or 3, wherein the compound is a compound of Formula (Il-g) :or a pharmaceutically acceptable salt thereof, wherein:E1is CH or CR6; cl is 0, 1, or 2; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or each LAlaand LAlbis an independently selected LA1;R2aand R2care independently H or Ra;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; andR5is H or halo.

77. The compound of claims 1 or 2, wherein the compound is a compound of Formula (I-h):Formula (I-h) or a pharmaceutically acceptable salt thereof, wherein: cl is 0, 1, or 2; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or each LAlaand LAlbis an independently selected LA1;R2cis H or Ra;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; andR5is H or halo.

78. The compound of claims 1 or 3, wherein the compound is a compound ofFormula (Il-h):or a pharmaceutically acceptable salt thereof, wherein:E1is CH or CR6;cl is 0, 1, or 2; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1;R2cis H or Ra;R3is a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra; andR5is H or halo.

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

80. A pharmaceutical composition comprising a compound of any one of claims 1-79, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

81. 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 1-79, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 80.

82. 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 1-79, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 80.

83. A method of treating a KRas-associated cancer in a subject, the method 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 1-79 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim80.

84. 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 1-79 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 80.

85. The method of any one of claims 81-84, wherein the KRas-associated cancer is a mutant KRas-associated cancer.

86. The method of claim 85, wherein the mutant KRas-associated cancer is a KRas G12A-associated cancer, a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, a KRas G12 S -associated cancer, or a KRas G12V-associated cancer; or wherein the mutant KRas-associated cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer; or wherein the mutant KRas-associated cancer is a KRas G12D-associated cancer; or wherein the mutant KRas-associated cancer is a KRas G12R-associated cancer; or wherein the mutant KRas-associated cancer is a KRas G12V-associated cancer.

87. The method of any one of claims 82 or 84, 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.

88. The method of claim 87, 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.

89. The method of claim 88, wherein the substitution of glycine 12 is a substitution to alanine, cysteine, aspartic acid, arginine, serine, or valine; orwherein the substitution of glycine 12 is a substitution to aspartic acid; or wherein the substitution of glycine 12 is a substitution to arginine; or wherein the substitution of glycine 12 is a substitution to valine.

90. The method of any one of claims 81-89, 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, testicular cancer, thymus cancer, thyroid cancer, urothelial cancer, uterine cancer, and a combination thereof; or wherein the KRas-associated cancer is pancreatic cancer.

91. A compound of Formula (SI-Aa):Formula (SI-Aa) or salts thereof, wherein:Ring C is a 4-10 membered heterocyclylene optionally substituted with 1-4 R7, wherein Ring C has one ring nitrogen atom, 0-1 ring oxygen atom, and no additional ring heteroatoms, wherein: each R7is independently selected from the group consisting of Raand Rb;Ring B is selected from the group consisting of: Ce-io arylene and 5-10 membered heteroarylene, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: Raand Rb; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1; each LA1is independently selected from the group consisting of: -CH2-, -CHRL-, and - C(RL)2-, wherein each RLis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NRdRe, C(=O)N(Rf)2, and Ci-6 alkyl optionally substituted with 1- 6 Rc;R3is: a 5-8 membered heterocyclyl optionally substituted with 1-3 Ra, or-NRdRe(e.g., -NMe2); andY1is selected from the group consisting of: a bond, -N(H)-, -N(CI-3 alkyl)-, -N(C3-6 cycloalkyl)-, -O-, and -S(0)o-2-;Y2is a straight-chain Ci-6 alkylene optionally substituted with 1-6 RY; each RYis independently selected from the group consisting of: halo, cyano, -OH, oxo, Ci-6 alkoxy, Ci-6 haloalkoxy, Ci-6 alkyl, and Ci-6 haloalkyl, or a pair of RYon the same or different carbon atom(s) taken together with the atom(s) connecting them form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring, each of which is optionally substituted with 1-3 independently selected C1.3 alkyl;E1is N, CH, or CR6;R5is H or halo;R6are independently selected from the group consisting of:(a) -H;(b) halo;(c) cyano;(d) Ci-6 alkyl;(e) Ci-6 haloalkyl;(f) Ci-6 alkoxy;(g) Ci-6 haloalkoxy;(h) -(Co-3 alkylene)-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl portion is optionally substituted with 1-3 Rg; and(i) -0-(Co-3 alkylene)-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl portion is optionally substituted with 1-3 Rg; each Rais independently selected from the group consisting of:(a) halo;(b) cyano;(c) -OH;(d) oxo;(e) -Ci-6 alkoxy;(f) -Ci-6 haloalkoxy;(g) -NRdRe;(h) C(=O)Ci-6alkyl;(i) C(=O)Ci-6haloalkyl; a) C(=O)OH;(k) C(=O)OCi-6alkyl;(l) C(=O)OCi-6haloalkyl;(m) C(=O)N(Rf)2;(n) S(0)o-2(Ci-6 alkyl);(0) S(0)o-2(Ci-6 haloalkyl);(p) S(O)i-2N(Rf)2; and(q) Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rbland -Rbl, wherein: b is 1, 2, or 3;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 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; each Rcis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NRdRe, C(=O)Ci-6 alkyl, C(=O)Ci-6 haloalkyl, C(=O)OCi-6 alkyl, C(=O)OCi-6 haloalkyl, C(=O)OH, C(=O)N(Rf)2, S(0)o-2(Ci-6 alkyl), S(0)o-2(Ci-6 haloalkyl), and S(O)i-2N(Rf)2; 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)i-2(Ci-6 alkyl), S(O)i-2(Ci-6 haloalkyl), S(O)i-2N(Rf)2, and Ci-6 alkyl optionally substituted with 1-3 Rb; each Rfis independently selected from the group consisting of: H and Ci-6 alkyl optionally substituted with 1-3 Rb; each Rgis independently selected from the group consisting of: Rb, C1.3 alkyl, and Ci- 3 haloalkyl; and each Rbis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NH2, -N(H)(CI-3 alkyl), and -N(CI-3 alkyl)2; or a compound of Formula (SII-Aa):Formula (SII-Aa) or salts thereof, wherein:Rsis Ci-6 alkyl optionally substituted with 1-3 Rc;Ring C is a 4-10 membered heterocyclylene optionally substituted with 1-4 R7, wherein Ring C has one ring nitrogen atom, 0-1 ring oxygen atom, and no additional ring heteroatoms, wherein:each R7is independently selected from the group consisting of Raand Rb;Ring B is selected from the group consisting of: Ce-io arylene and 5-10 membered heteroarylene, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: Raand Rb; ala and alb are independently integers from 0 to 5, provided that ala + alb is 4, 5, or 6; each LAlaand LAlbis an independently selected LA1; each LA1is independently selected from the group consisting of: -CH2-, -CHRL-, and - C(RL)2-, wherein each RLis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NRdRe, C(=O)N(Rf)2, and Ci-6 alkyl optionally substituted with 1- 6 Rc;E1is N, CH, or CR6;R5is H or halo;R6is selected from the group consisting of:(a) -H;(b) halo;(c) cyano;(d) Ci-6 alkyl;(e) Ci-6 haloalkyl;(1) Ci-6 alkoxy;(g) Ci-6 haloalkoxy;(h) -(C0-3 alkylene)-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl portion is optionally substituted with 1-3 Rg; and(i) -0-(Co-3 alkylene)-C3-6 cycloalkyl, wherein the C3-6 cycloalkyl portion is optionally substituted with 1-3 Rg; each Rais independently selected from the group consisting of:(a) halo;(b) cyano;(c) -OH;(d) oxo;(e) -Ci-6 alkoxy;(f) -Ci-6 haloalkoxy;(g) -NRdRe;(h) C(=O)Ci-6alkyl;(i) C(=O)Ci-6haloalkyl; a) C(=O)OH;(k) C(=O)OCi-6alkyl;(l) C(=O)OCi-6haloalkyl;(m) C(=O)N(Rf)2;(n) S(0)o-2(Ci-6 alkyl);(o) S(0)o-2(Ci-6 haloalkyl);(p) S(O)i-2N(Rf)2; and(q) Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rbland -Rbl, wherein: b is 1, 2, or 3; 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 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; each Rcis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NRdRe, C(=O)Ci-6 alkyl, C(=O)Ci-6 haloalkyl, C(=O)OCi-6 alkyl, C(=O)OCi-6 haloalkyl, C(=O)OH, C(=O)N(Rf)2, S(0)o.2(Ci-6 alkyl), S(0)o-2(Ci-6 haloalkyl), and S(O)i-2N(Rf)2; 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)i-2(Ci-6 alkyl), S(O)i-2(Ci-6 haloalkyl), S(O)i-2N(Rf)2, and Ci-6 alkyl optionally substituted with 1-3 Rh; each Rfis independently selected from the group consisting of: H and Ci-6 alkyl optionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, C1.3 alkyl, and Ci-3 haloalkyl; and each Rhis independently selected from the group consisting of: halo, cyano, -OH, -Ci- 6 alkoxy, -Ci-6 haloalkoxy, -NH2, -N(H)(CI-3 alkyl), and -N(CI-3 alkyl)2.

92. Any of the compounds, compositions, combinations, pharmaceutical compositions, methods, uses, and processes as substantially provided herein.

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