Pyridopyrimidine KRas inhibitors

Abstract

The present disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, that inhibit a KRas protein. In some embodiments, the KRas protein is dysregulated (e.g., the KRas protein is mutated or amplified). These compounds are useful for treating diseases, disorders, or conditions in which increased and / or persistent (e.g., enhanced) KRas activation, such as KRas activation associated with mutant KRas proteins, 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). The present 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

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Nos. 63 / 398,737, filed August 17, 2022, 63 / 426,885, filed November 21, 2022, 63 / 456,316, filed March 31, 2023, and 63 / 526,503, filed July 13, 2023, each of which is incorporated by reference in its entirety.

[0002] Description of electronically submitted text files This application contains a Sequence Listing that has been submitted electronically in XML format. The Sequence Listing XML is incorporated herein by reference. The XML file, created on August 14, 2023, is named TRLN-008-004WO1_ST26_SL.xml and is 2,059 bytes in size.

[0003] Technical Field The present disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, that inhibit KRas GTPase (e.g., a dysregulated KRas GTPase (referred to herein as a dysregulated KRas protein)). In some embodiments, the KRas protein is a dysregulated KRas protein having a mutation (referred to herein as a mutated KRas protein). These compounds are useful for treating diseases, disorders, or conditions in which increased and / or sustained (e.g., enhanced) KRas activation, such as KRas activation associated with mutant KRas proteins, 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). The present disclosure also provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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, and methods of using and making same. [Background technology]

[0004] background 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 amino acid positions 12, 13, and 61. In some cases, mutations can lead to sustained KRas activation (GTP-bound state) due, for example, to a lack of intrinsic GTPase activity and / or insensitivity to GTPase-activating proteins (GAPs), resulting in increased KRas signaling. Specifically, some of the most common protein mutations include mutations at position 12 (hereinafter referred to as G12X), such as G12A, G12C, G12D, G12R, G12S, and G12V, at position 13 (hereinafter referred to as G13X), such as G13C, G13D, and G13V, and at position Q61 (hereinafter referred to as Q61X), such as Q61E, Q61H, Q61K, Q61L, Q61P, and Q61R.

[0005] Although KRas is widely recognized as a target for the design and development of therapies that can specifically bind to and inhibit KRas signaling in cancer cells, it has long been considered undruggable, and currently there are few approved KRas-targeted therapies.

[0006] In some embodiments, the KRas protein is a dysregulated KRas protein having a mutation (referred to herein as a mutant KRas protein). These compounds are useful for treating diseases, disorders, or conditions in which increased and / or sustained (e.g., enhanced) 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). The disclosure also provides compositions containing the same, as well as methods of using and making the same. Summary of the Invention

[0007] overview The present disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, that inhibit KRas proteins (e.g., dysregulated KRas proteins such as mutant KRas proteins). These compounds are useful for treating diseases, disorders, or conditions in which increased KRas activation, such as KRas activation associated with mutant KRas proteins 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). The present disclosure also provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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, and methods of using and making same.

[0008] Provided herein are compounds of formula (A): TIFF2025528836000001.tif54128 or a pharmaceutically acceptable salt thereof, During the ceremony, m is 0, 1, or 2; each X 1 CH2, CHR a , C(R a )2, O, N(R d ), C(=O), and S(O) 0~2 independently selected from the group consisting of -(X 1 ) m- is OO, ON, NS(O)0, OS(O) 0~2 Does not include bonds, Ring C is C 3~15 cycloalkyl, 4- to 15-membered heterocyclylene, 6- to 15-membered arylene, and 5- to 15-membered heteroarylene, each of which is independently selected from the group consisting of 1 to 4 R 7 may be substituted with R 7 Each of R a and R b are independently selected from the group consisting of p is an integer from 3 to 10, Each L A L A1 , L A2 , L A3 , and L A4 independently selected from the group consisting of: A 0 to 2 occurrences of L A4 and L A 0 to 3 occurrences of L A2 and L A3 is selected from the group consisting of Each L A1 -CH2-, -CHR L - and -C(R L )2-, wherein each R L are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)N(R f )2 and 1 to 6 R c C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each L A2 is, independently, TIFF2025528836000002.tif19128, and each R L2 are independently H, halo, CN, and 1 to 6 R c C optionally substituted with 1~6 independently selected from the group consisting of alkyl, LA3 Each of the groups independently represents -N(R d )-, -O-, -S(O) 0~2 -, and C(=O), Each L A4 is C 3~10 Cycloalkylene, 4-10 membered heterocyclylene, C 6~10 arylene, and 5- to 10-membered heteroarylene, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Ring B is C 6~10 R is selected from the group consisting of arylene and 5- to 10-membered heteroarylene; a and R b each optionally substituted with 1 to 6 substituents independently selected from the group consisting of Y 1 is a bond, -N(H)-, -N(C 1~3 alkyl)-, -N(C 3~6 cycloalkyl)-, -O-, and -S(O) 0~2 - selected from the group consisting of n is 0 or 1, Y 2 is 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are independently halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y are, together with the atoms connecting them, one to three independently selected C 1~3 C, each of which may be substituted with alkyl 3~6 forming a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, R 3 teeth, (a)-H, (b)-Halo, (c)-NRd R e , (d)R a and R b each optionally substituted with 1 to 6 substituents independently selected from the group consisting of 3~10 cycloalkyl or 3- to 15-membered heterocyclyl, and (e)R a and R b each optionally substituted with 1 to 6 substituents independently selected from the group consisting of 6~10 Aryl or 5-10 membered heteroaryl is selected from the group consisting of E 1 is N, CH, or CR 6 and R 4 , R 5 , and R 6 teeth, (a)-H, (b) halo, (c) Cyano, (d)C 1~6 Alkyl, (e)C 1~6 haloalkyl, (f)C 1~6 Alkoxy, (g)C 1~6 haloalkoxy, (h)C 3~6 Cycloalkyl moiety is 1 to 3 R g -(C 0~3 Alkylene)-C 3~6 cycloalkyl, and (I C 3~6 Cycloalkyl moiety is 1 to 3 R g -O-(C 0~3 Alkylene)-C 3~6 cycloalkyl are independently selected from the group consisting of R a Each of the (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each optionally substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 Alkynyl are independently selected from the group consisting of R b Each of the b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b are independently -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; R b1 Each of the 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2 and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R g But independently, R h , C 1~3 Alkyl, and C 1~3haloalkyl; Each R h are independently halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 alkyl)2.

[0009] In some embodiments, the compound of Formula (A) has the formula (I): TIFF2025528836000003.tif51128 or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the compound of Formula (A) has the formula (II): TIFF2025528836000004.tif51128 or a pharmaceutically acceptable salt thereof, wherein E 1 is CH or CR 6 is.

[0011] Also provided herein are pharmaceutical compositions comprising a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] Provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0013] Also provided herein are methods for treating cancer in a subject in need thereof, comprising: (a) administering to a subject a therapeutically effective amount of KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation) to the patient; and (b) administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0014] As used herein, a subject is diagnosed with 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), the method comprising administering to a subject identified or diagnosed with a KRas-associated disease or disorder a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0015] The present disclosure also provides a method of treating a KRas-associated disease or disorder in a subject (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)), wherein 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 cancer, or a KRas G12V-associated cancer)). 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0016] 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)) in a subject, comprising administering to a subject 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) Further provided herein are methods, comprising administering to a subject identified or diagnosed with a G12V-associated cancer a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0017] The present disclosure also provides 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)) in a subject, wherein the cancer in the subject is KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V-associated cancer)). G12V mutation) and administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0018] To facilitate understanding of the present disclosure described herein, several terms are provided. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. Unless otherwise defined, 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 mentioned throughout this specification and the attached appendices is incorporated herein by reference in its entirety. In the event of a conflict between this disclosure and any content incorporated by reference, the present disclosure shall control.

[0019] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed Description The present disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, that inhibit KRas proteins (e.g., dysregulated KRas proteins such as mutant KRas proteins). These compounds are useful for treating diseases, disorders, or conditions associated with KRas dysregulation (e.g., KRas mutation or amplification), for example, where increased and / or sustained (e.g., enhanced) 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 may also be useful for treating diseases, disorders, or conditions, for example, where a mutant KRas protein (e.g., a resistance mutation) confers intrinsic resistance to one or more KRas inhibitors (e.g., KRas inhibitors selective for KRas G12C mutant proteins) or non-KRas-targeted therapeutic agents. 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. The present disclosure also provides compositions containing, and methods of using and making, a compound of Formula (A) provided herein (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof.

[0021] 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, for example, Hunter et al. Mol Cancer Res. 2015, 13(9):1325-35. Ras family members are guanine nucleotide-binding proteins typically found in the inner leaflet of the cell membrane. Wild-type Ras proteins are activated when bound to GTP but inactive when bound to GDP. Typically, growth factors bind to extracellular receptors and induce nucleotide exchange with the help of guanine nucleotide exchange factors (GEFs) (e.g., Son of sevenless homolog 1 (SOS1)). These GEFs dissociate GDP from the Ras protein, allowing GTP to bind. When bound to GTP, Ras proteins can interact with effector proteins such as cRAF. Hydrolysis of GTP to form GDP can inactivate Ras proteins, and hydrolysis can be achieved through intrinsic GTPase activity that can be enhanced by binding to GTPase-activating proteins (GAPs). There are three major RAS proteins in humans: KRas, HRas, and NRas.

[0022] Some oncogenic KRas missense mutations prevent or delay GTP hydrolysis, which can lead to the accumulation of active KRas. KRas-associated signaling pathways are persistently activated in many cancers and are involved in cell growth and proliferation, differentiation, protein synthesis, glucose metabolism, cell survival, and inflammation.

[0023] Mutant KRas proteins often have altered Raf affinity and / or altered intrinsic GTPase activity. See, e.g., Table 1, reprinted from Hunter et al. Mol Cancer Res. 2015, 13(9):1325-35. These changes and other factors may contribute to increased KRas signaling in mutant KRas proteins.

[0024] [Table 1]

[0025] Compound Embodiments As used herein, the term "compound of formula (A): TIFF2025528836000006.tif54128 or a pharmaceutically acceptable salt thereof, During the ceremony, m is 0, 1, or 2; each X 1 CH2, CHR a , C(R a )2, O, N(R d ), C(=O), and S(O) 0~2 independently selected from the group consisting of -(X 1 ) m - is OO, ON, NS(O)0, OS(O) 0~2 Does not include bonds, Ring C is C 3~15 cycloalkyl, 4- to 15-membered heterocyclylene, 6- to 15-membered arylene, and 5- to 15-membered heteroarylene, each of which is independently selected from the group consisting of 1 to 4 R 7 may be substituted with R 7 Each of R a and R b are independently selected from the group consisting of p is an integer from 3 to 10, Each L A L A1 , L A2 , L A3 , and L A4 independently selected from the group consisting of: A 0 to 2 occurrences of L A4 and L A 0 to 3 occurrences of L A2 and L A3 is selected from the group consisting of Each L A1 -CH2-, -CHR L - and -C(RL )2-, wherein each R L are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)N(R f )2 and 1 to 6 R c C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each L A2 is, independently, TIFF2025528836000007.tif19128, and each R L2 are independently H, halo, CN, and 1 to 6 R c C optionally substituted with 1~6 independently selected from the group consisting of alkyl, L A3 Each of the groups independently represents -N(R d )-, -O-, -S(O) 0~2 -, and C(=O), Each L A4 is C 3~10 Cycloalkylene, 4-10 membered heterocyclylene, C 6~10 arylene, and 5- to 10-membered heteroarylene, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Ring B is R a and R b C, each of which may be substituted with 1 to 6 substituents independently selected from the group consisting of 6~10 selected from the group consisting of arylene and 5- to 10-membered heteroarylene; Y 1 is a bond, -N(H)-, -N(C 1~3 alkyl)-, -N(C 3~6 cycloalkyl)-, -O-, and -S(O) 0~2 - selected from the group consisting of n is 0 or 1, Y 2 is 1 to 6 R YOptionally substituted linear C 1~6 is alkylene, Each R Y are independently halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y are, together with the atoms connecting them, one to three independently selected C 1~3 C, each of which may be substituted with alkyl 3~6 forming a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, R 3 teeth, (a)-H, (b)-Halo, (c)-NR d R e , (d)R a and R b each optionally substituted with 1 to 6 substituents independently selected from the group consisting of 3~10 cycloalkyl or 3- to 15-membered heterocyclyl, and (e)R a and R b each optionally substituted with 1 to 6 substituents independently selected from the group consisting of 6~10 Aryl or 5-10 membered heteroaryl is selected from the group consisting of E 1 is N, CH, or CR 6 and R 4 , R 5 , and R 6 teeth, (a)-H, (b) halo, (c) Cyano, (d)C 1~6 Alkyl, (e)C 1~6 haloalkyl, (f)C 1~6Alkoxy, (g)C 1~6 haloalkoxy, (h)C 3~6 Cycloalkyl moiety is 1 to 3 R g -(C 0~3 Alkylene)-C 3~6 cycloalkyl, and (I C 3~6 Cycloalkyl moiety is 1 to 3 R g -O-(C 0~3 Alkylene)-C 3~6 cycloalkyl are independently selected from the group consisting of R a Each of the (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each optionally substituted with C 1~6Alkyl, C 2~6 Alkenyl, or C 2~6 Alkynyl are independently selected from the group consisting of R b Each of the b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b are independently -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; R b1 Each of the 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2 and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R g But independently, R h , C 1~3 Alkyl, and C 1~3 haloalkyl; Each R h are independently halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 alkyl)2.

[0026] In some embodiments, the compound of Formula (A) has the formula (I): TIFF2025528836000008.tif51128 or a pharmaceutically acceptable salt thereof, During the ceremony, m is 0, 1, or 2; each X 1 CH2, CHR a , C(R a )2, O, N(R d ), C(=O), and S(O) 0~2 independently selected from the group consisting of -(X 1 ) m - is OO, ON, NS(O)0, OS(O) 0~2 Does not include bonds, Ring C is C 3~15 cycloalkyl, 4- to 15-membered heterocyclylene, 6- to 15-membered arylene, and 5- to 15-membered heteroarylene, each of which is independently selected from the group consisting of 1 to 4 R 7 may be substituted with R 7 Each of R a and R b are independently selected from the group consisting of p is an integer from 3 to 10, Each L A L A1 , L A2 , L A3 , and L A4 independently selected from the group consisting of: A 0 to 2 occurrences of L A4 and L A 0 to 3 occurrences of L A2 and L A3 is selected from the group consisting of Each L A1 -CH2-, -CHR L - and -C(R L )2-, wherein each R L are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)N(R f )2 and 1 to 6 R c C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each L A2 is, independently, TIFF2025528836000009.tif19128, and each R L2 are independently H, halo, CN, and 1 to 6 R c C optionally substituted with 1~6 independently selected from the group consisting of alkyl, L A3 Each of the groups independently represents -N(R d )-, -O-, -S(O) 0~2-, and C(=O), Each L A4 is C 3~10 Cycloalkylene, 4-10 membered heterocyclylene, C 6~10 arylene, and 5- to 10-membered heteroarylene, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Ring B is R a and R b C, each of which may be substituted with 1 to 6 substituents independently selected from the group consisting of 6~10 selected from the group consisting of arylene and 5- to 10-membered heteroarylene; Y 1 is a bond, -N(H)-, -N(C 1~3 alkyl)-, -N(C 3~6 cycloalkyl)-, -O-, and -S(O) 0~2 - selected from the group consisting of n is 0 or 1, Y 2 is 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are independently halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y are, together with the atoms connecting them, one to three independently selected C 1~3 C, each of which may be substituted with alkyl 3~6 forming a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, R 3 teeth, (a)-H, (b)-Halo, (c)-NR d R e , (d)R a and Rb each optionally substituted with 1 to 6 substituents independently selected from the group consisting of 3~10 cycloalkyl or 3- to 15-membered heterocyclyl, and (e)R a and R b each optionally substituted with 1 to 6 substituents independently selected from the group consisting of 6~10 Aryl or 5-10 membered heteroaryl is selected from the group consisting of R 4 and R 5 Each of the (a)-H, (b) halo, (c) Cyano, (d)C 1~6 Alkyl, (e)C 1~6 haloalkyl, (f)C 1~6 Alkoxy, (g)C 1~6 haloalkoxy, (h)C 3~6 Cycloalkyl moiety is 1 to 3 R g -(C 0~3 Alkylene)-C 3~6 cycloalkyl, and (I C 3~6 Cycloalkyl moiety is 1 to 3 R g -O-(C 0~3 Alkylene)-C 3~6 cycloalkyl are independently selected from the group consisting of R a Each of the (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each optionally substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 Alkynyl are independently selected from the group consisting of R b Each of the b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b are independently -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; R b1 Each of the 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2 and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R g But independently, R h , C 1~3 Alkyl, and C 1~3 haloalkyl; Each R h are independently halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3alkyl), and -N(C 1~3 alkyl)2.

[0027] In some embodiments, the compound of Formula (A) has the formula (II): TIFF2025528836000010.tif51128 or a pharmaceutically acceptable salt thereof, wherein E 1 is CH or CR 6 is.

[0028] In some embodiments of Formula (A), Formula (I), or Formula (II), m is 0.

[0029] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring C contains 1 to 4 R 7 In some embodiments, ring C is a 4- to 15-membered heterocyclylene optionally substituted with 1 to 4 R 7 and Ring C has 1 ring nitrogen atom, 0 to 1 ring oxygen atoms, and no additional ring heteroatoms.

[0030] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring C contains 1 to 3 R 7 In some embodiments, ring C is a 4- to 6-membered heterocyclylene optionally substituted with 1 to 3 R 7 and piperidinylene optionally substituted by:

[0031] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring C is TIFF2025528836000011.tif22128, c1 is 0, 1 or 2, and each R 7a and R 7b are independently selected R 7 and cc is -(L A ) p In some embodiments, c1 is 0. In some embodiments, ring C is TIFF2025528836000012.tif21128. In some embodiments, ring C is TIFF2025528836000013.tif21128, R 7a is C optionally substituted with 1 to 3 F 1~3 In some embodiments, Ring C is: TIFF2025528836000014.tif21128, R 7a is -OH.

[0032] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring C contains 1 to 3 R 7 In some embodiments, ring C has one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms.

[0033] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring C is TIFF2025528836000015.tif20128, where c1 is 0, 1, or 2, and cc is -(L A ) p represents the point of attachment to -. In some embodiments, c1 is 0.

[0034] In some embodiments of Formula (A), Formula (I), or Formula (II), p is 4, 5, or 6.

[0035] In some embodiments of Formula (A), Formula (I), or Formula (II), p is 6, 7, or 8.

[0036] In some embodiments of Formula (A), Formula (I), or Formula (II), each L A L A1 , L A3 , and L A4 are independently selected from the group consisting of:

[0037] In some embodiments of Formula (A), Formula (I), or Formula (II), LA 0 to 1 occurrences of L A4 and each of the remaining L A are each independently L A1 and L A3 is selected from the group consisting of:

[0038] In some embodiments of Formula (A), Formula (I), or Formula (II), L A One occurrence of L A4 and each of the remaining L A are each independently L A1 is.

[0039] In some embodiments of Formula (A), Formula (I), or Formula (II), each L A is independently L A1 is.

[0040] In some embodiments of Formula (A), Formula (I), or Formula (II), L A One or two occurrences of independently L A3 and each of the remaining L A are each independently L A1 is.

[0041] In some embodiments of Formula (A), Formula (I), or Formula (II), p is 4, 5, or 6. A One occurrence of L A4 and each of the remaining L A is independently L A1 In some embodiments, -(L A ) p - is -(L A1 ) 0~5 -L A4 -(L A1 ) 0~5 and p is 4, 5, or 6. In some embodiments, L A4 are phenylene or 5- to 6-membered heteroarylene, each of which is selected from 1 to 3 R g In some embodiments, L A4 is 1 to 2 R g For example, LA4 can be a triazolylene or an oxadiazolylene (e.g., 1,2,4-oxadiazolylene). In some embodiments, L A1 is CH2.

[0042] In some embodiments of Formula (A), Formula (I), or Formula (II), -(L A ) p - is -(L A1a ) a1a -L A4 -(L A1b ) a1b - bb wherein a1a and a1b are independently an integer of 0 to 5, a1a+a1b is 3, 4, or 5, and each L A1a and L A1b are independently selected L A1 and L A4 are phenylene or 5- to 6-membered heteroarylene, each of which is selected from 1 to 3 R g and bb represents the point of attachment to ring C. In some embodiments, L A4 is 1 to 2 R g In some embodiments, L is a 5-membered heteroarylene optionally substituted with A4 teeth, TIFF2025528836000016.tif17128, wherein dd is selected from the group consisting of -(L A1b ) a1b - represents the point of attachment to the -. For example, L A4 teeth, TIFF2025528836000017.tif16128, where dd is -(L A1b ) a1b In some embodiments, a1b is 1 and a1a is 2, 3, or 4. In some embodiments, L A1a and L A1b In some embodiments, p is 6, 7, or 8, and each L A is independently L A1 In some embodiments, L A Each of is -CH2-.

[0043] In some embodiments of Formula (A), Formula (I), or Formula (II), p is 6, 7, or 8. A One occurrence of is C(=O) and L A The second occurrence of N(R d ) and each of the remaining L A are each independently L A1 is.

[0044] In some embodiments of Formula (A), Formula (I), or Formula (II), -(L A ) p -ha-(L A1a ) a1a -C(=O)NH-(L A1b ) a1b - bb where a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6, and each L A1a and L A1b are independently selected L A1 and bb represents the point of attachment to ring C. In some embodiments, a1b is 2 and a1a is 2, 3, or 4. In some embodiments, a1b is 1 and a1a is 3, 4, or 5. In some embodiments, L A1a and L A1b Each of these is CH2.

[0045] In some embodiments of Formula (A), Formula (I), or Formula (II), m is 0. Ring C is TIFF2025528836000018.tif22128, where c1 is 0, 1, or 2, and each R 7a and R 7b are independently selected R 7 and cc is -(L A ) p represents the point of attachment to -(L A ) p - is -(L A1a ) a1a -L A4 -(L A1b ) a1b -bb wherein a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 3, 4, or 5; and each L A1a and L A1b are independently selected L A1 and L A4 are phenylene or 5- to 6-membered heteroarylene, each of which is selected from 1 to 3 R g and bb represents the point of attachment to ring C. In some embodiments, L A4 is 1 to 2 R g In some embodiments, L is a 5-membered heteroarylene optionally substituted with A4 teeth, TIFF2025528836000019.tif16128, where dd is -(L A1b ) a1b In some embodiments, a1b is 1 and a1a is 2, 3, or 4. In some embodiments, L A1a and L A1b Each of is CH. In some embodiments, ring C is TIFF2025528836000020.tif21128. In some embodiments, ring C is TIFF2025528836000021.tif21128, R 7a In some embodiments, c1 is 0.

[0046] In some embodiments of Formula (A), Formula (I), or Formula (II), m is 0. Ring C is TIFF2025528836000022.tif22128, where c1 is 0, 1, or 2, and each R 7a and R 7b are independently selected R 7 and cc is -(L A ) p represents the point of attachment to -, p is 6, 7, or 8, and each L A are independently selected L A1 In some embodiments, L AEach of is -CH-. In some embodiments, ring C is TIFF2025528836000023.tif21128. In some embodiments, ring C is TIFF2025528836000024.tif21128, R 7a is —OH. In some embodiments, c1 is 0. In some embodiments, c1 is 0.

[0047] In some embodiments of Formula (A), Formula (I), or Formula (II), m is 0. Ring C is TIFF2025528836000025.tif23128, where c1 is 0, 1, or 2, and each R 7a and R 7b are independently selected R 7 and cc is -(L A ) p represents the point of attachment to -(L A ) p - is -(L A1a ) a1a -C(=O)NH-(L A1b ) a1b - bb wherein a1a and a1b are independently an integer of 0 to 5, a1a+a1b is 4, 5, or 6, and each L A1a and L A1b are independently selected L A1 and bb represents the point of attachment to ring C. In some embodiments, a1b is 2 and a1a is 2, 3, or 4. In some embodiments, a1b is 1 and a1a is 3, 4, or 5. In some embodiments, L A1a and L A1b Each of is CH. In some embodiments, ring C is TIFF2025528836000026.tif22128. In some embodiments, ring C is TIFF2025528836000027.tif22128, R 7ais —OH. In some embodiments, c1 is 0. In some embodiments, c1 is 0.

[0048] In some embodiments of Formula (A), Formula (I), or Formula (II), m is 0. Ring C is TIFF2025528836000028.tif20128, where c1 is 0, 1 or 2, and cc is -(L A ) p represents the point of attachment of - and -(L A ) p - is -(L A1a ) a1a -C(=O)NH-(L A1b ) a1b - bb wherein a1a and a1b are independently an integer of 0 to 5, a1a+a1b is 4, 5, or 6, and each L A1a and L A1b are independently selected L A1 and bb represents the point of attachment to ring C. In some embodiments, a1b is 2 and a1a is 2, 3, or 4. In some embodiments, a1b is 1 and a1a is 3, 4, or 5. In some embodiments, L A1a and L A1b Each of is CH. In some embodiments, c is 0.

[0049] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is R a and R b C optionally substituted with 1 to 6 substituents independently selected from the group consisting of 6~10 It is an arylene.

[0050] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B contains 1 to 4 R a and naphthylene which may be substituted by.

[0051] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is TIFF2025528836000029.tif34128, where R 2a and R 2c are independently H or R a and aa is -(L A ) p In some embodiments, R 2a is —OH. In some embodiments, R 2a is -NH. In some embodiments, R 2a is —H. In some embodiments, R 2c is halo (e.g., F) or H.

[0052] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is TIFF2025528836000030.tif35128, where aa is -(L A ) p - represents the point of attachment to

[0053] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is TIFF2025528836000031.tif34128, where aa is -(L A ) p - represents the point of attachment to

[0054] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B contains 1 to 4 R a and phenylene which may be substituted by.

[0055] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is TIFF2025528836000032.tif29128, where R 2a , R 2b , and R 2c are independently H or R a and aa is -(L A ) p In some embodiments, R 2ais —OH. In some embodiments, R 2a is -NH. In some embodiments, R 2c is halo (e.g., —Cl).

[0056] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is TIFF2025528836000033.tif29128, where R 2a and R 2c are independently H or R a and aa is -(L A ) p In some embodiments, R 2a is —OH. In some embodiments, R 2a is -NH. In some embodiments, R 2c is halo (e.g., —Cl).

[0057] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is R a and R b In some embodiments, ring B is a 9- to 10-membered heteroarylene having 1 to 2 ring nitrogen atoms and 0 to 1 additional ring heteroatom selected from the group consisting of O and S, and the heteroarylene is optionally substituted with 1 to 3 R a may be substituted with.

[0058] In some embodiments of Formula (A), Formula (I), or Formula (II), Ring B is TIFF2025528836000034.tif27128, where R 2c is H or R a and aa is -(L A ) p In some embodiments, R 2c is a halo. For example, R 2c For example, ring B can be -Cl. TIFF2025528836000035.tif27128, where aa is -(L A ) p - represents the point of attachment to

[0059] In some embodiments of Formula (A), Formula (I), or Formula (II), Y 1 is -O-.

[0060] In some embodiments of Formula (A), Formula (I), or Formula (II), n is 1.

[0061] In some embodiments of Formula (A), Formula (I), or Formula (II), Y 2 is 1 to 3 R Y Optionally substituted linear C 1~3 It is alkylene.

[0062] In some embodiments of Formula (A), Formula (I), or Formula (II), Y 2 is -CH2-.

[0063] In some embodiments of Formula (A), Formula (I), or Formula (II), Y 2 teeth, TIFF2025528836000036.tif14128.

[0064] In some embodiments of Formula (A), Formula (I), or Formula (II), R 3 is R a and R b and a 4- to 10-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of:

[0065] In some embodiments of Formula (A), Formula (I), or Formula (II), R 3 is 1 to 3 R a and the heterocyclyl contains at least one ring nitrogen atom.

[0066] In some embodiments of Formula (A), Formula (I), or Formula (II), R 3 teeth, TIFF2025528836000037.tif16128, and one to three R on one or more ring carbon atoms. a may be substituted with.

[0067] In some embodiments of Formula (A), Formula (I), or Formula (II), R 3 teeth, TIFF2025528836000038.tif11128, and one to three R on one or more ring carbon atoms. a may be substituted with.

[0068] In some embodiments of Formula (A), Formula (I), or Formula (II), R 3 is 1 to 6 R a and optionally substituted 7-10 membered bicyclic heterocyclyl.

[0069] In some embodiments of Formula (A), Formula (I), or Formula (II), R 3 teeth, TIFF2025528836000039.tif19128, 1 to 3 R a may be substituted with.

[0070] In some embodiments of Formula (A), Formula (I), or Formula (II), R 3 teeth, TIFF2025528836000040.tif25128. For example, R 3 teeth, It can be TIFF2025528836000041.tif23128.

[0071] In some embodiments of Formula (A), Formula (I), or Formula (II), R 3 teeth, TIFF2025528836000042.tif17128, each of which is selected from the group consisting of 1 to 3 R a may be substituted with.

[0072] In some embodiments of Formula (A), Formula (I), or Formula (II), Y 1 is -O-, n is 1, and Y 2 is -CH2- and R 3 teeth, TIFF2025528836000043.tif19128, 1 to 3 R a In some embodiments, R 3 teeth, TIFF2025528836000044.tif25128, for example, R 3 teeth, It can be TIFF2025528836000045.tif23128.

[0073] In some embodiments of Formula (A), Formula (I), or Formula (II), Y 1 is -O-. n is 1 and Y 2 teeth TIFF2025528836000046.tif14128, R 3 is 1 to 3 R a In some embodiments, R 3 teeth, TIFF2025528836000047.tif17128, each of which is selected from the group consisting of 1 to 3 R a may be substituted with.

[0074] In some embodiments of Formula (A), Formula (I), or Formula (II), Y 1 is -O-. n is 1 and Y 2 teeth TIFF2025528836000048.tif14128, R 3 is -NR d R e For example, R 3 can be -NMe2.

[0075] In some embodiments of Formula (A), Formula (I), or Formula (II), R 4 is H.

[0076] In some embodiments of Formula (A), Formula (I), or Formula (II), R 5 is -F.

[0077] In some embodiments of Formula (A), Formula (I), or Formula (II), R 4 is H and R 5 is -F.

[0078] In some embodiments of Formula (A), Formula (I), or Formula (II), E 1 is CR 6 In some embodiments, R 6 is halo (e.g., —F or —Cl).

[0079] In some embodiments of Formula (A), Formula (I), or Formula (II), E 1 is CH.

[0080] In some embodiments of Formula (A), the compound has the formula (Aa): TIFF2025528836000049.tif49128 or a pharmaceutically acceptable salt thereof, During the ceremony, Ring C is 1 to 4 R 7 wherein ring C has 1 ring nitrogen atom, 0 to 1 ring oxygen atoms, and no additional ring heteroatoms; Ring B is R a and R b C, each of which may be substituted with 1 to 3 substituents independently selected from the group consisting of 6~10 selected from the group consisting of arylene and 5- to 10-membered heteroarylene; a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected LA1 and R 3 is 1 to 3 R a or -NR d R e and R 5 is H or halo.

[0081] In some embodiments of Formula (Aa), E 1 is N, CH, or C-halo; Ring C is TIFF2025528836000050.tif22128 and TIFF2025528836000051.tif20128; where: c1 is 0, 1, or 2; cc is -(L A1b ) a1b - represents the point of attachment to Each R 7a and R 7b are independently selected R 7 and Ring B is TIFF2025528836000052.tif34128, R 2a is -OH or -NH2, and R 2b and R 2c are independently H or halo (e.g., —Cl), and aa is —(L A1a ) a1a In some embodiments, c1 is 0. In some embodiments, R 7a is, if present, OH.

[0082] In some embodiments of Formula (Aa), a1b is 2 and a1a is 2, 3, or 4. In some embodiments of Formula (Aa), a1b is 1 and a1a is 3, 4, or 5.

[0083] In some embodiments of Formula (Aa), L A1a and LA1b Each of these is CH2.

[0084] In some embodiments of Formula (Aa), Y 2 is CH2 and R 3 teeth TIFF2025528836000053.tif23128 (e.g. TIFF2025528836000054.tif24128) and R 5 is F.

[0085] In some embodiments of Formula (Aa), Y 2 teeth, TIFF2025528836000055.tif14128, R 3 Ha-NR d R e and R 5 is F. For example, R 3 can be -NMe2.

[0086] In some embodiments of Formula (Aa), R 6 is -F or -Cl, and R 5 is -F.

[0087] In some embodiments of Formula (I), the compound has the formula (Ia) or (I-aa): TIFF2025528836000056.tif129128 or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; Each R 7a and R 7b are independently selected R 7 and a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 3, 4, or 5; Each L A1a and L A1b are independently selected L A1 and L A4 is 1 to 3 R gphenylene or 5- to 6-membered heteroarylene, each of which may be substituted by R 2a and R 2c are independently H or R a and Y 2 is -CH2- or TIFF2025528836000057.tif14128, R 3 is 1 to 3 R a is a 5- to 8-membered heterocyclyl optionally substituted by R 5 is H or halo.

[0088] In some embodiments of Formula (Ia) or (I-aa), L A4 is 1 to 2 R g In some embodiments of Formula (Ia) or (I-aa), L is a 5-membered heteroarylene optionally substituted with A4 teeth, TIFF2025528836000058.tif16128, where dd is -(L A1b ) a1b - represents the point of attachment to

[0089] In some embodiments of Formula (Ia) or (I-aa), a1b is 1 and a1a is 2, 3, or 4. In some embodiments of Formula (Ia), L A1a and L A1b Each of these is CH2.

[0090] In some embodiments of Formula (I), the compound has the formula (Ib) or (I-bb): TIFF2025528836000059.tif127128 or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; Each R 7a and R 7b are independently selected R 7 and p is 6, 7, or 8; R 2a and R 2c are independently H or R a and Y 2 is -CH2- or TIFF2025528836000060.tif14128, R 3 is 1 to 3 R a is a 5- to 8-membered heterocyclyl optionally substituted by R 5 is H or halo.

[0091] In some embodiments of Formula (Ib) or (I-bb), each L A1 is CH2.

[0092] In some embodiments of Formula (I), the compound has the formula (Ic) or (I-cc): TIFF2025528836000061.tif129128 or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; Each R 7a and R 7b are independently selected R 7 and a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected L A1 and R 2a and R 2c are independently H or R a and Y 2 is -CH2- or TIFF2025528836000062.tif14128, R 3 is 1 to 3 R a is a 5- to 8-membered heterocyclyl optionally substituted by R5 is H or halo.

[0093] In some embodiments of Formula (Ic) or (I-cc), a1b is 2 and a1a is 2, 3, or 4.

[0094] In some embodiments of Formula (Ic) or (I-cc), L A1a and L A1b Each of these is CH2.

[0095] In some embodiments of Formula (II), the compound has the formula (II-c) or (II-cc): TIFF2025528836000063.tif122128 or a pharmaceutically acceptable salt thereof, During the ceremony, E 1 is CH or CR 6 and c1 is 0, 1, or 2; Each R 7a and R 7b are independently selected R 7 and a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected L A1 and R 2a and R 2c are independently H or R a and Y 2 is -CH2- or TIFF2025528836000064.tif14128, R 3 is 1 to 3 R a is a 5- to 8-membered heterocyclyl optionally substituted by R 5 is H or halo.

[0096] In some embodiments of Formula (I), the compound has the formula (Id) or (I-dd): TIFF2025528836000065.tif129128 or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; Each R 7a and R 7b are independently selected R 7 and a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected L A1 and R 2a and R 2c is independently R a and Y 2 is -CH2- or TIFF2025528836000066.tif14128, R 3 is 1 to 3 R a is a 5- to 8-membered heterocyclyl optionally substituted by R 5 is H or halo.

[0097] In some embodiments of Formula (II), the compound has the formula (II-d) or (II-dd): TIFF2025528836000067.tif122128 or a pharmaceutically acceptable salt thereof, During the ceremony, E 1 is CH or CR 6 and c1 is 0, 1, or 2; Each R 7a and R 7b are independently selected R 7 and a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected L A1 and R 2a and R 2c is independently R a and Y 2 is -CH2- or TIFF2025528836000068.tif14128, R 3 is 1 to 3 R a is a 5- to 8-membered heterocyclyl optionally substituted by R 5 is H or halo.

[0098] In some embodiments of Formula (I), the compound has the formula (Ie) or (I-ee): TIFF2025528836000069.tif125128 or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; Each R 7a and R 7b are independently selected R 7 and a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected L A1 and R 2c is H or R a and Y 2 is -CH2- or TIFF2025528836000070.tif14128, R 3 is 1 to 3 R a or -NR d R e (e.g., -NMe2), R 5is H or halo.

[0099] In some embodiments of Formula (II), the compound has the formula (II-e) or (II-ee): TIFF2025528836000071.tif125128 or a pharmaceutically acceptable salt thereof, During the ceremony, E 1 is CH or CR 6 and c1 is 0, 1, or 2; Each R 7a and R 7b are independently selected R 7 and a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected L A1 and R 2c is H or R a and Y 2 is -CH2- or TIFF2025528836000072.tif14128, R 3 is 1 to 3 R a or -NR d R e (e.g., -NMe2), R 5 is H or halo.

[0100] In some embodiments of Formula (I), the compound has the formula (If): TIFF2025528836000073.tif59128 or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected L A1 and R 2a and R 2c is independently R a and Y 2 is -CH2- or TIFF2025528836000074.tif14128, R 3 is 1 to 3 R a is a 5- to 8-membered heterocyclyl optionally substituted by R 5 is H or halo.

[0101] In some embodiments of Formula (II), the compound has the formula (II-f): TIFF2025528836000075.tif59128 or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected L A1 and R 2a and R 2c is independently R a and Y 2 is -CH2- or TIFF2025528836000076.tif14128, R 3 is 1 to 3 R a is a 5- to 8-membered heterocyclyl optionally substituted by R 5 is H or halo.

[0102] In some embodiments of Formula (I), the compound has the formula (Ig): TIFF2025528836000077.tif62128 or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected L A1 and R 2a and R 2c are independently H or R a and Y 2 is -CH2- or TIFF2025528836000078.tif14128, R 3 is 1 to 3 R a is a 5- to 8-membered heterocyclyl optionally substituted by R 5 is H or halo.

[0103] In some embodiments of Formula (II), the compound has the formula (II-g): TIFF2025528836000079.tif62128 or a pharmaceutically acceptable salt thereof, During the ceremony, E 1 is CH or CR 6 and c1 is 0, 1, or 2; a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected L A1 and R 2a and R 2c are independently H or R a and Y 2 is -CH2- or TIFF2025528836000080.tif14128, R 3 is 1 to 3 R a is a 5- to 8-membered heterocyclyl optionally substituted by R 5 is H or halo.

[0104] In some embodiments of Formula (I), the compound has the formula (Ih): TIFF2025528836000081.tif59128 or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected L A1 and R 2c is H or R a and Y 2 is -CH2- or TIFF2025528836000082.tif14128, R 3 is 1 to 3 R a or -NR d R e (e.g., -NMe2), R 5 is H or halo.

[0105] In some embodiments, the compound of Formula (II) has the formula (II-h): TIFF2025528836000083.tif59128 or a pharmaceutically acceptable salt thereof, During the ceremony, E 1 is CH or CR 6 and c1 is 0, 1, or 2; a1a and a1b are independently an integer of 0 to 5, provided that a1a+a1b is 4, 5, or 6; Each L A1a and L A1b are independently selected L A1 and R 2c is H or R a and Y 2 is -CH2- or TIFF2025528836000084.tif14128, R 3 is 1 to 3 R a or -NR d R e (e.g., -NMe2), R 5 is H or halo.

[0106] In some embodiments of Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (II-c), (II-cc), (Id), (I-dd), (II-d), (II-dd), (Ie), (I-ee), (II-e), (II-ee), (If), (II-f), (Ig), (II-g), (Ih), or (II-h), a1b is 2 and a1a is 2, 3, or 4.

[0107] In some embodiments of Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (II-c), (II-cc), (Id), (I-dd), (II-d), (II-dd), (Ie), (I-ee), (II-e), (II-ee), (If), (II-f), (Ig), (II-g), (Ih), or (II-h), a1b is 1 and a1a is 3, 4, or 5.

[0108] In some embodiments of formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (II-c), (II-cc), (Id), (I-dd), (II-d), (II-dd), (Ie), (I-ee), (II-e), (II-ee), (If), (II-f), (Ig), (II-g), (Ih), or (II-h), L A1a and L A1b Each of these is CH2.

[0109] In some embodiments of Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (II-c), (II-cc), (Id), (I-dd), (II-d), (II-dd), (If), (II-f), (Ig), or (II-g), R 2a is -NH2.

[0110] In some embodiments of Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (II-c), (II-cc), (Id), (I-dd), (II-d), (II-dd), (Ie), (I-ee), (II-e), (II-ee), (If), (II-f), (Ig), (II-g), (Ih), or (II-h), R 2c is -F. In some embodiments of Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (II-c), (II-cc), (Id), (I-dd), (II-d), (II-dd), (Ie), (I-ee), (II-e), (II-ee), (If), (II-f), (Ig), (II-g), (Ih), or (II-h), R 2c is -Cl.

[0111] In some embodiments of Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (II-c), (II-cc), (Id), (I-dd), (II-d), (II-dd), (Ie), (I-ee), (II-e), (II-ee), (If), (II-f), (Ig), (II-g), (Ih), or (II-h), c1 is 0.

[0112] In some embodiments of Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (II-c), (II-cc), (Id), (I-dd), (II-d), (II-dd), (Ie), (I-ee), (II-e), or (II-ee), R 7a is, if present, OH.

[0113] In some embodiments of Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (II-c), (II-cc), (Id), (I-dd), (II-d), (II-dd), (Ie), (I-ee), (II-e), or (II-ee), Y 2 is CH2 and R 3 teeth TIFF2025528836000085.tif23128 (e.g. TIFF2025528836000086.tif23128) and R 5 is F.

[0114] In some embodiments of formula (Ie), (I-ee), (II-e), (II-ee), (Ih), or (II-h), Y 2 teeth, TIFF2025528836000087.tif14128, R 3 is -NR d R e and R 5 is F. For example, R 3 can be -NMe2.

[0115] In some embodiments of Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (II-c), (II-cc), (Id), (I-dd), (II-d), (II-dd), (Ie), (I-ee), (II-e), or (II-ee), R 6 -F or -Cl, and R 5 is -F.

[0116] In some embodiments, the compound is selected from the group consisting of the compounds in Table C1 or a pharmaceutically acceptable salt thereof.

[0117] [Table C1] TIFF2025528836000089.tif225128TIFF2025528836000090.tif220128TIFF2025528836000091.tif215128TIFF2025528836000092.tif214128TIFF2025528836000093.tif219128TIFF2025528836000094.tif228128TIFF2025528836000095.tif229128TIFF2025528836000096.tif220128TIFF2025528836000097.tif214128TIFF2025528836000098.tif225128TIFF2025528836000099.tif217128TIFF2025528836000100.tif211128TIFF2025528836000101.tif211128TIFF2025528836000102.tif218128TIFF2025528836000103.tif230128TIFF2025528836000104.tif215128TIFF2025528836000105.tif231128TIFF2025528836000106.tif224128TIFF2025528836000107.tif242128TIFF2025528836000108.tif239128TIFF2025528836000109.tif242128TIFF2025528836000110.tif239128TIFF2025528836000111.tif241128TIFF2025528836000112.tif232128TIFF2025528836000113.tif231128TIFF2025528836000114.tif233128TIFF2025528836000115.tif233128TIFF2025528836000116.tif238128TIFF2025528836000117.tif238128TIFF2025528836000118.tif238128TIFF2025528836000119.tif242128TIFF2025528836000120.tif242128TIFF2025528836000121.tif220128TIFF2025528836000122.tif225128TIFF2025528836000123.tif240128TIFF2025528 836000124.tif231128TIFF2025528836000125.tif236128TIFF2025528836000126.tif146128. Note : A stereocenter (e.g., a chiral center or an axially asymmetric center) is * ", this stereocenter has been resolved but its absolute configuration has not been assigned.

[0118] Exemplary compounds of Formula (A) (e.g., compounds of Formula (I) (e.g., compounds of Formula (A) (e.g., compounds of Formula (I) (e.g., compounds of Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih))), compounds of Formula (II) (e.g., compounds of Formula (II-c), (II-cc), (II-d), (II-dd), (II-e), (II-ee), (II-f), (II-g), or (II-h), or compounds of Formula (Aa)) The compounds include those set forth in Table C1 of U.S. Provisional Application No. 63 / 398,737, filed August 17, 2022, Table C1 of U.S. Provisional Application No. 63 / 426,885, filed November 21, 2022, Table C1 of U.S. Provisional Application No. 63 / 456,316, filed March 31, 2023, and Table C1 of U.S. Provisional Application No. 63 / 526,503, filed July 13, 2023, or a pharmaceutically acceptable salt thereof, each Table C1 of which is incorporated herein by reference in its entirety.

[0119] Exemplary compounds of formula (A) are 101, 101a, 102, 102a, 103, 103a, 104, 104a, 105, 105a, 106, 106a, 107, 107a, 108, 108a, 109, 109a, 110, 110a, 111, 111a, 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, 124a, 125a, 126a, 127a, 128a, 129a, 130a, 131a, 132a, 133a, 134a, 135a, 136a, 137a, 138a, 139a, 140a, 141a, 142a, 143a, 144a, 145a, 146a, 147a, 148a, 149a, 150a, 151a, 152a, 153a, 154a, 155a, 156a, 157a, 158a, 159a, 160a, 161a, 162a, 163a, 3, 123a, 124, 124a, 125, 125a, 126, 126a, 127, 127a, 128, 128a, 129, 129a, 130, 130a, 131, 131a, 132, 132a, 133, 133a, 134, 134a, 135, 13 5a, 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, 16 6, 166a, 167, 167a, 170, 170a, 171, 171a, 172, 172a, 173, 173a, 174, 174a, 175, 175a, 176, 176a, 177, 178, 179, 179a, 180, 180a, 181, 181 a, 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.

[0120] Exemplary compounds of formula (Aa) include 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, 168a, 169, 170a, 171a, 172a, 173a, 174a, 175a, 176a, 177a, 178a, 179a, 180a, 181a, 182a, 183a, 184a, 185a, 186a, 187a, 188a, 189a, 190a, 191a, 192a, 193a, 194a, 195a, 196a, 197a, 198a, 199a, 200a, 201a, 202a, 203a, 204a, 205a, 206a, 207a, 208a, 209a, 210a, 211 7a, 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.

[0121] Exemplary compounds of formula (I) are 101, 101a, 102, 102a, 103, 103a, 104, 104a, 105, 105a, 106, 106a, 107, 107a, 108, 108a, 109, 109a, 110, 110a, 111, 111a, 112, 112a, 113, 113a, 114, 114a, 115, 115a, 115b, 115c, 116, 116a, 117, 117b, 117c, 117d, 117e, 117f, 117g, 117h, 117i, 117j ... a, 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, 13 7, 137a, 138, 138a, 139, 139a, 140, 140a, 140b, 140c, 141, 141a, 143, 143a, 151, 151a, 152, 152a, 153, 153 a, 154, 154a, 156, 156a, 157, 157a, 159, 159a, 159b, 159c, 160, 160a, 161, 161a, 162, 162a, 164, 164a, 167, These include compounds 167a, 170, 170a, 171, 171a, 172, 172a, 173, 173a, 176, 176a, 177, 178, 179, 179a, 181, 181a, 182c, 182a, 185, 185a, 186, 186a, 189, 189a, 192, 192a, 193, 193a, 194, 194a, 196, 196a, 201, 201a, 203, and 203a.

[0122] Exemplary compounds of Formula (Ia) include compounds 126, 126a, 127, 127a, 128, and 128a.

[0123] Exemplary compounds of formula (I-aa) include compounds 101, 101a, 102, 102a, 103, 103a, 119, 119a, 120, and 120a.

[0124] Exemplary compounds of formula (Ib) include compounds 130, 130a, 131, and 131a.

[0125] Exemplary compounds of formula (I-bb) include compounds 111, 111a, 112, and 112a.

[0126] Exemplary compounds of formula (Ic) include compounds 136 and 136a.

[0127] Exemplary compounds of formula (I-cc) include compounds 117, 117a, 118, 118a, 135, 135a, 170, 170a, 189, and 189a.

[0128] Exemplary compounds of formula (Id) include compounds 138, 138a, 140, 140a, 140b, 140c, 156, and 156a.

[0129] Exemplary compounds of formula (I-dd) include compounds of formula 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.

[0130] Exemplary compounds of formula (I-ee) include compounds 167, 167a, 196, and 196a.

[0131] Exemplary compounds of formula (If) include compounds 162 and 162a.

[0132] Exemplary compounds of formula (Ig) include compounds 173, 173a, 192, 192a, 193, 193a, 194, and 194a.

[0133] Exemplary compounds of formula (Ih) include compounds 203 and 203a.

[0134] Exemplary compounds of formula (II) include compounds of 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.

[0135] Exemplary compounds of formula (II-c) include compounds 175, 175a, 190, 190a, 191, and 191a.

[0136] Exemplary compounds of formula (II-d) include compounds 158 and 158a.

[0137] Exemplary compounds of formula (II-dd) include compounds 155, 155a, 165, and 165a.

[0138] Exemplary compounds of formula (II-e) include compounds 199 and 199a.

[0139] Exemplary compounds of formula (II-ee) include compounds 166, 166a, 197a, 197b, 202, 202a, and 202b.

[0140] Exemplary compounds of formula (II-g) include compounds 195 and 195a.

[0141] Exemplary compounds of formula (II-h) include compounds 198, 198a, 200, and 200a.

[0142] Certain examples of compounds of Formula (A) (e.g., Formula (I) or (II)) were synthesized using methods involving resolution of stereoisomeric mixtures (e.g., SFC separation of stereoisomers). In Table C1, resolved stereocenters in these compounds are marked with an asterisk (i.e., "* "). In some cases, stereoisomeric resolution is performed during the final step of the synthesis, thereby providing individual stereoisomers of a compound of Formula (A) (e.g., Formula (I) or (II)). Alternatively, in some other cases, resolution is performed on an intermediate or starting material, where each of the constituent stereoisomers of the intermediate or starting material can be subjected separately to a subsequent step of the synthesis to provide the respective compound of Formula (A) (e.g., Formula (I) or (II)) as a separate stereoisomer. 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., Examples 65, 66, 68, 69, 76, 77, 78, 79, 84, and 85). One of skill in the art will understand that under either approach for stereoisomeric resolution, stereoisomers having both the (R) and (S) configurations at the resolved stereocenter are provided. See Table C2, where compounds listed in Table C1 containing a stereochemical designation where the stereoisomer is presented with an asterisk are provided in non-stereoisomeric form followed by the respective stereoisomers having the (R) and (S) configurations.

[0143] [Table C2] TIFF2025528836000128.tif241128TIFF2025528836000129.tif241128

[0144] Also provided herein is a KRas protein (e.g., a dysregulated KRas protein (e.g., a mutant KRas protein)) non-covalently bound to a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof. In some embodiments, Gly10 of the KRas protein interacts non-covalently with ring C of a compound of Formula (A) (e.g., Formula (I)) or a pharmaceutically acceptable salt thereof (e.g., via a hydrogen bond between the carbonyl of Gly10 and the OH present on ring C, and / or via a water-mediated interaction between the NH group of Gly10 and the OH present on ring C). Without wishing to be bound by theory, in some embodiments, the interaction between Gly10 of the KRas protein and ring C of a compound of Formula (A) (e.g., Formula (I)) or a pharmaceutically acceptable salt thereof promotes inhibition of the interaction between the KRas protein and Raf-RBD. In some embodiments, Arg68 of the KRas protein interacts non-covalently with ring C of a 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 the 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 ring C of a compound of Formula (A) (e.g., Formula (I)) or a pharmaceutically acceptable salt thereof promotes inhibition of the interaction between the KRas protein and Raf-RBD.

[0145] chemical definition The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0146] The term "oxo" refers to a divalent double-bonded oxygen atom (i.e., "=O"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl.

[0147] The term "alkyl" refers to a saturated acyclic hydrocarbon radical, which may be straight or branched, containing the indicated number of carbon atoms. For example, C 1~10 indicates that the group may have 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can be either unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, and n-hexyl. The term "saturated," as used in this context, means that only single bonds exist between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0148] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with an independently selected halo (e.g., -CF3, -CHF2, or -CH2F).

[0149] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0150] 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 the avoidance of doubt, in "cycloalkylene" and "heterocyclylene," the two radicals may be on the same ring carbon atom (e.g., TIFF2025528836000130.tif20128) or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring carbon and / or nitrogen atoms)) (e.g., TIFF2025528836000131.tif20128).

[0151] The term "alkenyl" refers to an acyclic hydrocarbon chain that may be straight or branched and has one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2~6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups may be either unsubstituted or substituted with one or more substituents.

[0152] The term "alkynyl" refers to an acyclic hydrocarbon chain that may be straight or branched and has one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2~6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups may be either unsubstituted or substituted with one or more substituents.

[0153] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbons in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system), and in which 0, 1, 2, 3, or 4 atoms of each ring can be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0154] The term "cycloalkyl" as used herein refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated hydrocarbon group, e.g., having 3 to 20 ring carbons, preferably 3 to 15 ring carbons, and more preferably 3 to 12 ring carbons or 3 to 10 ring carbons or 3 to 6 ring carbons, where the cycloalkyl group may be substituted. The term "saturated" as used in this context means that only single bonds exist between the constituent carbon atoms. Examples of saturated cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Partially unsaturated cycloalkyls can have any degree of unsaturation, provided that one or more double bonds are present in the cycloalkyl, none of the rings in the ring system are aromatic, and the partially unsaturated cycloalkyl group as a whole is not fully saturated. Examples of partially unsaturated cycloalkyls include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkyl may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which two rings are connected through exactly 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.

[0155] The term "heteroaryl," as used herein, means a monocyclic, bicyclic, tricyclic, 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 is independently selected from N, O, S( TIFF2025528836000132.tif15128), and P( TIFF2025528836000133.tif13128), and at least one ring in the system is aromatic (but it is not required to be a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can be either 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, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, and pyrido[2,3-d]pyrimidinyl. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazolyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolinyl, and others. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For clarity, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, where each ring nitrogen adjacent to the carbonyl is a pyridonyl (e.g., TIFF2025528836000134.tif22128), pyrimidonyl (e.g., TIFF2025528836000135.tif22128), pyridazinonyl (e.g., TIFF2025528836000136.tif20128), pyrazinonyl (e.g., TIFF2025528836000137.tif20128), and imidazolonyl (e.g., TIFF2025528836000138.tif16128), and each ring nitrogen adjacent to the carbonyl is tertiary (i.e., an oxo group (i.e., "=O") herein is a component of a heteroaryl ring).

[0156] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated ring system having 3 to 15 ring atoms (e.g., a 5- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 15-membered tricyclic ring system) having 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic, wherein the heteroatoms are O, N, S ( TIFF2025528836000139.tif15128), and P( TIFF2025528836000140.tif13128) (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 N, O, S, or P heteroatoms, respectively, in the case of monocyclic, bicyclic, or tricyclic rings), where 0, 1, 2, or 3 atoms in each ring can be replaced by a substituent. The term "saturated," as used in this context, means that only single bonds exist 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 can have any degree of unsaturation, provided that one or more double bonds are present in the heterocyclyl, none of the rings in the ring system are aromatic, and the partially unsaturated heterocyclyl group is not fully saturated overall. Examples of partially unsaturated heterocyclyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl.

[0157] Heterocyclyl may contain multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyl include 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2-azabicyclo[1.1.1]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, 2-azabicyclo[2.2.2]octyl, Heterocyclyl includes 3-azabicyclo[3.2.1]octyl, 2-oxabicyclo[1.1.0]butyl, 2-oxabicyclo[2.1.0]pentyl, 2-oxabicyclo[1.1.1]pentyl, 3-oxabicyclo[3.1.0]hexyl, 5-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 7-oxabicyclo[2.2.1]heptyl, 6-oxabicyclo[3.1.1]heptyl, 7-oxabicyclo[4.2.0]octyl, 2-oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2.1]octyl, etc. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are connected through only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentyl, 4-azaspiro[2.5]octyl, 1-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2-azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, 1,7-diazaspiro[4.5]decyl, 7-azaspiro[4.5]decyl, 2,5-diazaspiro[3.6]decyl, 3-azaspiro[5.5]undecyl, 2-oxaspiro[2 .2]pentyl, 4-oxaspiro[2.5]octyl, 1-oxaspiro[3.5]nonyl, 2-oxaspiro[3.5]nonyl, 7-oxaspiro[3.5]nonyl, 2-oxaspiro[4.4]nonyl, 6-oxaspiro[2.6]nonyl, 1,7-dioxaspiro[4.5]decyl, 2,5-dioxaspiro[3.6]decyl, 1-oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl, and the like.

[0158] As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (e.g., one or more double or triple bonds between constituent ring atoms in addition to the degree of unsaturation due to the ring itself), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0159] For the avoidance of doubt, unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form bicyclic or higher ring systems (e.g., tricyclic, polycyclic ring systems), such rings and cyclic groups are defined as those in which the points of fusion are (i) adjacent ring atoms (e.g., 0 to 0 atom bridges (e.g., TIFF2025528836000141.tif13128) on a [xx0] ring system), (ii) a single ring atom (spiro-fused ring system) (e.g., TIFF2025528836000142.tif20128), or (iii) an arrangement of consecutive ring atoms (bridged ring systems with all bridge lengths > 0) (e.g., It is understood that this encompasses those having fused rings, including those located on the TIFF2025528836000143.tif15128.

[0160] Additionally, atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. As used herein, isotopes include 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 13 C and 14 Contains C.

[0161] Additionally, compounds disclosed generically or specifically herein are intended to include all tautomeric forms. Thus, by way of example, the moiety: The compound containing TIFF2025528836000144.tif16128 is the moiety: TIFF2025528836000145.tif18128 are encompassed. Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxyl encompass pyridone or pyrimidone tautomeric forms.

[0162] The compounds provided herein can include various stereochemical forms.Compounds also include diastereomers and optical isomers, for example, mixtures of enantiomers, including racemic mixtures, and individual enantiomers and diastereomers resulting from structural asymmetry in a particular compound.Unless otherwise indicated, the disclosed compounds are named or depicted by structure without specifying stereochemistry, and if they have one or more chiral centers, it is understood that they represent all possible stereoisomers of the compound.

[0163] Treatment method Indications Provided herein is a method for inhibiting KRas protein. Provided herein is an inhibitor of 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)) that is useful for treating or preventing a disease or disorder associated with KRas dysregulation (i.e., a KRas-related disease or disorder), such as, for example, cardiovascular disease, inflammatory disease and / or autoimmune disease, or cancer (e.g., a KRas-related cancer).

[0164] As used herein, the term "KRas-associated disease or disorder" refers to a disease or disorder associated with or involving dysregulation of the expression, activity, or levels of the KRAS gene, KRas protein, or any of them (e.g., one or more) (e.g., any of the types of dysregulation of the expression, activity, or levels of the KRAS gene, KRas protein, or any of them described herein). Non-limiting examples of KRas-associated diseases or disorders include, for example, cancer, cardiovascular disease (e.g., arteriovenous malformation), endometritis, and inflammatory and / or autoimmune diseases (e.g., autoimmunity and non-malignant syndromes of abnormal leukocyte homeostasis). See, for example, 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.

[0165] As used herein, the term "mutated KRas-associated disease or disorder" refers to a disease or disorder associated with or involving a KRas mutation (e.g., a KRAS gene and / or a KRas protein having a mutation corresponding to a mutation in the KRas protein). Non-limiting examples of mutant KRas-associated diseases or disorders include, for example, cancer, cardiovascular disease (e.g., arteriovenous malformation), endometritis, and inflammatory and / or autoimmune diseases (e.g., autoimmunity and non-malignant syndromes of abnormal leukocyte homeostasis). See, for example, 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.

[0166] The phrase "dysregulated expression or activity or levels of the KRAS gene, KRas protein, or any of them" refers to a genetic mutation (e.g., a mutation in the KRAS gene that results in the expression of a KRas protein that comprises at least one amino acid deletion compared to the wild-type KRas protein, a mutation in the KRAS gene that results in the expression of a KRas protein that has one or more point mutations compared to the wild-type KRas protein, a mutation in the KRAS gene that results in the expression of a KRas protein that has at least one inserted amino acid compared to the wild-type KRas protein, a gene duplication that results in an increased level of the 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 the KRas protein in a cell), an alternatively spliced ​​version of KRas mRNA that results in a KRas protein that has at least one amino acid deletion in the KRas protein compared to the wild-type KRas protein, or an increased expression (e.g., increased levels) of wild-type KRas protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As one example, the dysregulation of the expression, activity, or level of the KRAS gene, KRas protein, or any of them can be a mutation in the KRAS gene that encodes a KRas protein with reduced GTPase activity and / or increased signaling activity compared to a protein encoded by a KRAS gene that does not contain the mutation. As another example, the dysregulation of the expression, activity, or level of the KRAS gene, KRas protein, or any of them can be KRas amplification. In some embodiments, the KRas amplification is amplification of wild-type KRas. In some embodiments, the KRas amplification is amplification of mutant KRas.

[0167] As used herein, a "dysregulated KRas protein" refers to (i) a KRas protein having a mutation (e.g., a deletion of at least one amino acid compared to the wild-type KRas protein, one or more point mutations compared to the wild-type KRas protein, an insertion of at least one amino acid compared to the wild-type KRas protein), (ii) a KRas protein that results, for example, from a gene duplication event of a gene encoding a KRas protein (e.g., a wild-type KRas protein), thus resulting in an increased level and / or activity of the KRas protein (e.g., a wild-type KRas protein) in a cell, (iii) a KRas protein that results from a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that may also result in an increased level and / or activity of the KRas protein (e.g., a wild-type KRas protein) in a cell, (iv) a KRas protein that results in a KRas protein having a deletion of at least one amino acid in the KRas protein compared to the wild-type KRas protein, (v) refers to a KRas protein resulting from an alternatively spliced ​​version of mRNA, or (v) a KRas protein resulting from increased expression (e.g., increased levels) of wild-type KRas protein in mammalian cells due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). In some embodiments, the dysregulated KRas protein is a dysregulated human KRas protein.

[0168] As used herein, a "mutant KRas protein" refers to a KRas protein that contains substitutions, insertions, deletions, truncations, and / or fusions relative to the wild-type human KRas sequence shown in SEQ ID NO: 1. For example, a mutant human KRas protein contains a substitution at any amino acid position (relative to SEQ ID NO: 1).

[0169] As used herein, "KRas G12X mutant protein" refers to a KRas protein that includes a substitution of glycine at the 12th amino acid position (relative to SEQ ID NO: 1) with any other amino acid.

[0170] As used herein, "KRas G12A mutant protein" refers to a KRas protein containing a glycine to alanine substitution at amino acid position 12 (relative to SEQ ID NO: 1).

[0171] As used herein, a "KRas G12C mutant protein" refers to a KRas protein that contains a glycine to cysteine ​​substitution at the 12th amino acid position (relative to SEQ ID NO: 1).

[0172] As used herein, "KRas G12D mutant protein" refers to a KRas protein that contains a glycine to aspartic acid substitution at the 12th amino acid position (relative to SEQ ID NO: 1).

[0173] As used herein, "KRas G12R mutant protein" refers to a KRas protein containing a glycine to arginine substitution at amino acid position 12 (relative to SEQ ID NO: 1).

[0174] As used herein, "KRas G12S mutant protein" refers to a KRas protein that contains a glycine to serine substitution at the 12th amino acid position (relative to SEQ ID NO: 1).

[0175] As used herein, a "KRas G12V mutant protein" refers to a KRas protein that contains a glycine to valine substitution at the 12th amino acid position (relative to SEQ ID NO: 1).

[0176] As used herein, "KRas G13X mutant protein" refers to a KRas protein that includes a substitution of glycine at the 13th amino acid position (relative to SEQ ID NO: 1) with any other amino acid.

[0177] As used herein, a "KRas G13C mutant protein" refers to a KRas protein containing a glycine to cysteine ​​substitution at the 13th amino acid position (relative to SEQ ID NO: 1).

[0178] As used herein, "KRas G13D mutant protein" refers to a KRas protein that contains a glycine to aspartic acid substitution at the 13th amino acid position (relative to SEQ ID NO: 1).

[0179] As used herein, a "KRas G13V mutant protein" refers to a KRas protein that contains a glycine to valine substitution at the 13th amino acid position (relative to SEQ ID NO: 1).

[0180] As used herein, "KRas Q61X mutant protein" refers to a KRas protein that contains a substitution of glutamine at amino acid position 61 (relative to SEQ ID NO: 1) with any other amino acid.

[0181] As used herein, "KRas Q61E mutant protein" refers to a KRas protein containing a glutamine to glutamic acid substitution at amino acid position 61 (relative to SEQ ID NO: 1).

[0182] As used herein, "KRas Q61H mutant protein" refers to a KRas protein containing a glutamine to histidine substitution at amino acid position 61 (relative to SEQ ID NO: 1).

[0183] As used herein, "KRas Q61K mutant protein" refers to a KRas protein containing a glutamine to lysine substitution at amino acid position 61 (relative to SEQ ID NO: 1).

[0184] As used herein, "KRas Q61L mutant protein" refers to a KRas protein containing a glutamine to leucine substitution at amino acid position 61 (relative to SEQ ID NO: 1).

[0185] As used herein, "KRas Q61P mutant protein" refers to a KRas protein containing a glutamine to proline substitution at amino acid position 61 (relative to SEQ ID NO: 1).

[0186] As used herein, "KRas Q61R mutant protein" refers to a KRas protein containing a glutamine to arginine substitution at amino acid position 61 (relative to SEQ ID NO: 1).

[0187] As used herein, a "KRas inhibitor" includes any compound that exhibits KRas protein inactivation activity (e.g., inhibits or reduces KRas signaling activity). KRas inhibitors described herein have an IC of 1 μM or less in the nucleotide exchange assay described herein. 50 value, IC of 1 μM or less in the Raf kinase interaction assay described herein 50In some embodiments, the KRas inhibitor inhibits the signaling activity of a wild-type KRas protein. In some embodiments, the KRas inhibitor inhibits the signaling activity of a dysregulated KRas protein, resulting in a decrease in other downstream effectors, such as activated Raf or ERK. In some embodiments, the KRas inhibitor inhibits the signaling activity of a mutant KRas protein. In some embodiments, the 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 may be referred to as a "pan-KRas inhibitor." In some embodiments, the KRas inhibitor inhibits one or more mutant KRas proteins, and such a KRas inhibitor may be referred to as a "mutant KRas inhibitor" or by the mutant it inhibits. For example, a KRas inhibitor that inhibits a KRas G12R mutant protein may be referred to as a "KRas G12R inhibitor." As another example, a KRas inhibitor that inhibits both KRas G12C and KRas G12D mutant proteins may be referred to as a "KRas G12C inhibitor" and / or a "KRas G12D inhibitor." In some embodiments, a "mutant KRas inhibitor" inhibits more than one mutant KRas protein and may be referred to as a "pan-mutant KRas inhibitor." In some embodiments, the pan-mutated 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" may 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 may be referred to as a "KRas G13D inhibitor." In some embodiments, a KRas inhibitor may inhibit a KRas protein having one or more mutations, and such a KRas inhibitor may be referred to as a "mutant KRas inhibitor," regardless of whether the mutant KRas inhibitor also inhibits a wild-type KRas protein. In some embodiments, the KRas inhibitor is a mutant KRas inhibitor. In some embodiments, the KRas inhibitor is an allosteric inhibitor.

[0188] A compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is a KRas inhibitor. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is a mutant KRas inhibitor.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is 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 G13E mutant protein, a KRas G13F mutant protein, a KRas G13G mutant protein, a KRas G13H ... The present invention inhibits two or more mutant KRas proteins selected from the group consisting of KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, KRas Q61P mutant protein and KRas Q61R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G12D mutant protein, KRas G12R mutant protein, KRas G12V mutant protein, or a combination thereof.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G12D mutant protein, KRas G12V mutant protein, or both. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G12R mutant protein, KRas G12V mutant protein, or both. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G12D mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G12R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G12V mutant protein.

[0189] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is an inhibitor of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. The present invention inhibits two or more mutant KRas proteins selected from the group consisting of G12V mutant proteins.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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. The present invention inhibits four or more mutant KRas proteins selected from the group consisting of G12V mutant proteins.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof inhibits five or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. Inhibits G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas The present invention inhibits two or more mutant KRas proteins selected from the group consisting of G12V mutant proteins.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. The present invention inhibits four or more mutant KRas proteins selected from the group consisting of G12V mutant proteins.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof inhibits KRas. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G12C mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (II-dd), (II-e), (II-ee), (II-f), (II-g), or (II-h)), or a pharmaceutically acceptable salt thereof, inhibits KRas. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof inhibits KRas G12D mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa)). , (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), a compound of formula (II) (e.g., (II-c), (II-cc), (II-d), (II-dd), (II-e), (II-ee), (II-f), (II-g), or (II-h) or a pharmaceutically acceptable salt thereof, inhibits KRas In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof does not inhibit KRas. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof inhibits KRas. Inhibits G12S mutant proteins. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G12V mutant proteins.

[0190] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is a compound of Formula (A) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is an inhibitor of KRas G13C mutant protein, KRas G13D mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of KRas G13C mutant protein, KRas G13D mutant protein, and KRas G13V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is effective against KRas G13C mutant proteins, KRas G13D mutant proteins, and KRas In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas. Inhibits G13C mutant proteins. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G13D mutant proteins.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G13V mutant protein.

[0191] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is a compound of Formula (A) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is an inhibitor of KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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 Q61R ... The compound inhibits two or more mutant KRas proteins selected from the group consisting of Q61P mutant protein and KRas mutant protein.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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. The present invention inhibits four or more mutant KRas proteins selected from the group consisting of Q61R mutant proteins.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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. Inhibits Q61R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas Q61E mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas. Inhibits Q61L mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas Q61P mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas Q61R mutant protein.

[0192] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12X mutant proteins, KRas G13X mutant proteins, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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 In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits three or more mutant human KRas proteins selected from the group consisting of a KRas G12X mutant protein, a KRas G13X mutant protein, and a KRas Q61X mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is used to treat KRas G12X mutant proteins, KRas G13X mutant proteins, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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 The present invention inhibits one or more mutant KRas proteins selected from the group consisting of KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas The compound inhibits two or more mutant KRas proteins selected from the group consisting of KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas The present invention inhibits three or more mutant KRas proteins selected from the group consisting of KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas The compound inhibits four or more mutant KRas proteins selected from the group consisting of KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, 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 Five or more mutant KRas proteins selected from the group consisting of 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, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is 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 G13E mutant protein, a KRas G13F mutant protein, a KRas G13G mutant protein, a KRas G13H ... G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, KRas Q61P mutant protein and KRas In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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 It inhibits KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.

[0193] In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12V mutant protein, KRas G13D mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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 G13D mutant protein. The present invention inhibits two or more mutant KRas proteins selected from the group consisting of Q61H mutant proteins.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12V mutant protein, KRas G13D mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is used to inhibit KRas G12D mutant protein, KRas G12R mutant protein, and KRas In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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 In some such embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is useful for treating bladder cancer.

[0194] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12V mutant protein, and KRas G13D mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12V mutant protein, and KRas G13D mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12V mutant protein, and KRas G13D mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is used to treat KRas G12C mutant proteins, KRas G12D mutant proteins, and KRas In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G12D mutant protein, KRas G12V mutant protein, or both. In some such embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is useful for treating cervical cancer.

[0195] In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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 G12R mutant protein. The present invention inhibits one or more mutant KRas proteins selected from the group consisting of G12V mutant proteins.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some such embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is useful for treating colorectal cancer.

[0196] In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is 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 The present invention inhibits one or more mutant KRas proteins selected from the group consisting of G13V mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein. In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is 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 The present invention inhibits two or more mutant KRas proteins selected from the group consisting of a G13V mutant protein, a KRas Q61H mutant protein, and a KRas Q61L mutant protein.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is 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 The present invention inhibits three or more mutant KRas proteins selected from the group consisting of G13V mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein.In some such embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is useful for treating endometrial cancer.

[0197] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, and KRas The present invention inhibits one or more mutant KRas proteins selected from the group consisting of Q61H mutant proteins. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, and KRas The present invention inhibits two or more mutant KRas proteins selected from the group consisting of Q61H mutant proteins.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G12D mutant protein, KRas G12V mutant protein, or both.In some such embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is useful for treating esophageal or gastric cancer.

[0198] In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas The present invention inhibits one or more mutant KRas proteins selected from the group consisting of KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas The compound inhibits two or more mutant KRas proteins selected from the group consisting of KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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 G12R mutant protein. The present invention inhibits one or more mutant KRas proteins selected from the group consisting of G12V mutant proteins.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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. The present invention inhibits three or more mutant KRas proteins selected from the group consisting of G12V mutant proteins.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is used to treat KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some such embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is useful for treating leukemia.

[0199] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, and KRas The present invention inhibits one or more mutant KRas proteins selected from the group consisting of Q61R mutant proteins. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, and KRas The present invention inhibits two or more mutant KRas proteins selected from the group consisting of Q61R mutant proteins.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, and KRas G12R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, and KRas G12R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is used to treat KRas G12C mutant proteins, KRas G12D mutant proteins, and KRas In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G12D mutant protein, KRas G12R mutant protein, or both.In some such embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is useful for treating melanoma.

[0200] In some embodiments, the compound of Formula (A) (e.g., a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of a KRas G13D mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas Q61H mutant protein, and a KRas Q61L mutant protein. The compound inhibits two or more mutant KRas proteins selected from the group consisting of 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, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is 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 The present invention inhibits three or more mutant KRas proteins selected from the group consisting of KRas Q61H mutant protein, and KRas Q61L mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits KRas G12A mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein.In some such embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is useful for treating lung cancer (e.g., non-small cell lung cancer).

[0201] In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is 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 G13E mutant protein, a KRas G13F mutant protein, a KRas G13G mutant protein, a KRas G13H ... The present invention inhibits one or more mutant KRas proteins selected from the group consisting of a Q61H mutant protein and a KRas Q61R mutant protein. In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is 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 G13E mutant protein, a KRas G13F mutant protein, a KRas G13G mutant protein, a KRas G13H ... The compound inhibits two or more mutant KRas proteins selected from the group consisting of a Q61H mutant protein and a KRas Q61R mutant protein.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is 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 G13E mutant protein, a KRas G13F mutant protein, a KRas G13G mutant protein, a KRas G13H ... The present invention inhibits three or more mutant KRas proteins selected from the group consisting of KRas Q61H mutant protein, and KRas Q61R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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. The present invention inhibits three or more mutant KRas proteins selected from the group consisting of G12V mutant proteins.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is used to treat KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some such embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is useful for treating pancreatic cancer.

[0202] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas The present invention inhibits one or more mutant KRas proteins selected from the group consisting of Q61R mutant proteins. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas The present invention inhibits two or more mutant KRas proteins selected from the group consisting of Q61R mutant proteins.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting of KRas G12A mutant protein, KRas G12R mutant protein, and KRas In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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 such embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia)), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is useful for treating testicular cancer (e.g., seminoma).

[0203] In some embodiments, a compound of Formula (A) (e.g., a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof binds to a GTP-bound KRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof can selectively bind to KRas protein in the GTP-bound state.

[0204] In some embodiments, a compound of Formula (A) (e.g., a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof binds to GDP-bound KRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof can selectively bind to a GDP-bound KRas protein.

[0205] An exemplary sequence of the mature human KRas protein is shown below (UniProtKB entry P01116) (SEQ ID NO: 1). MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ RVEDAFYTLV REIRQYRLKK ISKEEKTPGC VKIKKCIIM

[0206] As used herein, "selective" or "selectively," when referring to a compound being assayed, exhibits at least 5-fold (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) superior performance (e.g., binding affinity and / or potency) in an assay for a particular condition relative to a comparison protein variant in the assay. For example, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, exhibits a greater potency of KRas than wild-type KRas protein, as determined by surface plasmon resonance (SPR) assay. and then "selectively" binds to the G12X mutant protein, and then binds to a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), a compound of Formula (II) (e.g., Formula (II-c), (II-cc), (II-d), (II-dd), (II-e), (II-ee), (II-f), (II-g), or (II-h)). The compound of formula (II-g), (II-h)), or formula (Aa) or a pharmaceutically acceptable salt thereof has a KD value for any one or more KRas mutant proteins selected from the group consisting of KRasG12X mutant proteins that is at least 5-fold (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) smaller than the KD value for wild-type KRas protein, as measured by SPR assay.As a further example, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof has an EC 50 Values ​​are EC 50In another example, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, exhibits a greater ability to interact with KRas than wild-type KRas protein, as determined by a Raf kinase interaction assay. The compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof "selectively" inhibits the G13X mutant protein, and exhibits an IC50 value for the KRasG13X protein that is at least 5-fold (e.g., at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) less than the IC50 value for the wild-type KRas protein when measured in a Raf kinase interaction assay.As a further example, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, may be used to enhance the activity of KRas protein over wild-type KRas protein as determined by a nucleotide exchange assay. and "selectively" inhibits KRasG12R mutant protein, and then a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, has an IC50 of KRasG12R mutant protein as measured in a nucleotide exchange assay. 50 Values ​​are IC of wild-type KRas protein 50 at least 5-fold (eg, at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) smaller than the value.

[0207] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is a pan-mutated KRas inhibitor (i.e., capable of inhibiting two or more mutant KRas proteins (e.g., two or more of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein)). For example, such a compound inhibits each mutant KRas protein (e.g., two or more mutant KRas proteins) with an IC of less than 1 μM. 50 In another example, such a compound can inhibit the activity of the compound with an independent IC50 of less than 1 μM in at least one of two cell lines (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). 50 For example, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, can inhibit ERK phosphorylation in a cell line expressing a KRas G12R mutant protein at IC 50at less than 1 μM, and a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a cell line expressing a KRasG12V mutant protein at an IC of less than 1 μM. 50 In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof does not inhibit a particular KRas protein (e.g., wild-type KRas or one or more dysregulated KRas proteins). For example, such a compound inhibits an interaction between a KRas protein that it does not inhibit (e.g., a dysregulated KRas protein) and one or more Raf proteins with an IC of 1 μM or greater (e.g., greater than 2 μM, greater than 5 μM, greater than 10 μM, or greater than 30 μM).50 As another example, such a compound can inhibit ERK phosphorylation in a cell line expressing a KRas protein that it does not inhibit (e.g., a dysregulated KRas protein) with an IC of 1 μM or greater (e.g., greater than 2 μM, greater than 5 μM, greater than 10 μM, or greater than 30 μM). 50 can be inhibited by

[0208] The potency of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia)), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof can be measured, for example, by direct measurement methods (e.g., surface plasmon resonance or isothermal titration calorimetry) by radiolabeling the compound prior to binding, isolating the compound / protein complex, and determining the amount of bound radiolabel. or by performing a competition experiment in which the new compound is incubated with a protein bound to a known radioligand. As another example, the occupancy of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof can be determined using proximity-based techniques such as time-resolved fluorescence resonance energy transfer (FRET). For example, a labeled probe that binds mutually exclusively to the inhibitor is used, and an antibody (e.g., an antibody that binds to an N-terminal tag) is used that binds to a location on the protein that is distinct from the location to which a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is attached. It will be understood that the antibody and probe can be tagged with any suitable FRET pair.See, for example, International Publication Nos. 2021 / 041671, 2021 / 120890, and U.S. Publication No. 2021 / 0179633.

[0209] In some cases, the binding affinity (e.g., dissociation constant K) of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, to a KRas protein (e.g., a wild-type KRas protein or a mutant KRas protein) in a GDP-bound state and / or a GTP-bound state may be determined. D The binding affinity of a KRas protein in its GDP-bound state can be measured by loading the KRas protein with GDP (e.g., at the concentration described in Example B1). The binding affinity of a KRas protein in its GTP-bound state can be measured by loading the KRas protein with GMPPNP (e.g., at the concentration described in Example B1).

[0210] Another exemplary assay for determining the potency of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is , measuring the effect of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof on cell proliferation. Cell proliferation assays can be performed in several formats, including 2D and 3D. Similarly, cell proliferation assays can be performed using any suitable 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 involves growing cells in a 3D medium, catalyzing the cells with a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), a compound of Formula (II) (e.g., Formula (II-c), (II-cc), (II-d), (II-dd), (II-e), (I (II-ee), (II-f), (II-g), or (II-h)), or a compound of Formula (Aa)) or a pharmaceutically acceptable salt thereof, measuring cell proliferation using an appropriate reagent (e.g., CELLTITERGLO® 3D), and then measuring cell proliferation using a compound of Formula (A) (e.g., a compound of Formula (I) (e.g., Formulas (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd) ), (Ie), (I-ee), (If), (Ig), or (Ih)), a compound of 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 a pharmaceutically acceptable salt thereof) is compared with a signal from a control experiment (e.g., a compound of Formula (A) (e.g., a compound of Formula (I) (e.g., Formula (Ia), (I (II-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), a compound of Formula (II) (e.g., (II-c), (II-cc), (II-d), (II-dd), (II-e), (II-ee), (II-f), (II-g), or (II-h)), or lacking a compound of Formula (Aa)).As another illustrative example, a 2D cell proliferation assay can involve plating cells onto a growth surface, optionally allowing the cells to grow for a period of time, and detecting a signal of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), Formula (II) (e.g., Formula (II-c), (II-cc), (II-d), (II (II-dd), (II-e), (II-ee), (II-f), (II-g), or (II-h)), or Formula (Aa)) or a pharmaceutically acceptable salt thereof, measuring cell proliferation using an appropriate reagent (e.g., CELLTITERGLO®), and then measuring cell proliferation using a compound of Formula (A) (e.g., Formula (I) (e.g., Formulas (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-d)

[0033] The signal from an experiment comprising a compound of Formula (I) (e.g., Formula (Ia), (Iaa), (Ib) or (Ic)), or Formula (II) (e.g., (II-d), (II-dd), (II-e), (II-ee), (II-f), (II-g), or (II-h)), or Formula (Aa)), or a pharmaceutically acceptable salt thereof, is compared with a signal from a control experiment (e.g., a compound of Formula (I) (e.g., Formula (Ia), (Iaa), (Ib) , (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof). In some embodiments, cell 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. Patent Application Publication Nos. 2021 / 0179633, 2021 / 0230142, and 2019 / 0284144.

[0211] As another example, the potency and / or efficacy of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof can be evaluated, for example, in 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, for example, U.S. Patent Application Publication No. 2021 / 0179633.

[0212] Further assays may include, for example, assays based on hydrogen exchange (HX) mass spectrometry. Such assays may be used to determine, for example, whether a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits or blocks the 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 In such assays, the rate of hydrogen exchange of backbone amide hydrogens can be used to assess whether a non-hydrolyzable GTP mimetic (GMPPNP), GDP, or a nucleotide of Formula (A) (e.g., Formula (I) (e.g., Formulas (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), Formula (II) (e.g., Formulas (II-c), (II-cc), (II-d), (II-i), or (II-j)) stabilizes the GTP- or GDP-bound state of a nucleotide of Formula (II). (II-dd), (II-e), (II-ee), (II-f), (II-g), or (II-h)), or a compound of formula (Aa)) or a pharmaceutically acceptable salt thereof, can be measured for KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein (e.g., a KRasG12D mutant protein, a KRasG12R mutant protein, or a KRasG12V mutant protein)). See, e.g., Lim et al. Angew Chem Int Ed Engl. 2014, 53(1):199-204.

[0213] In some embodiments, the efficacy of a compound of Formula (A) provided herein (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is, for example, in a range of EC 50 A lower EC value when determined under substantially similar conditions can be determined by the 50 Compounds with higher EC 50 In some embodiments, the EC 50 The value can be determined in cells (e.g., 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, e.g., a dysregulated KRas protein (e.g., a mutated or amplified KRas protein), or a fragment thereof.

[0214] In some embodiments, the potency of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, as provided herein, is measured by IC 50A lower IC value can be determined when determined under substantially similar conditions. 50 Compounds with higher IC 50 In some embodiments, IC50 values ​​can be determined in cells expressing a KRas protein, e.g., a dysregulated KRas protein (e.g., a mutated KRas protein or an amplified KRas protein), e.g., 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).

[0215] In some embodiments, measuring the efficacy of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof comprises measuring phosphorylation of a downstream kinase, such as ERK (e.g., ERK1 and / or ERK2) or MEK. Such assays can be used, for example, to measure inhibition of KRas signaling activity in cell lines (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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof for a period of time, followed by lysis or permeabilization, and the content of total ERK or MEK and phosphorylated ERK or phosphorylated MEK can be measured (e.g., using antibodies or Invitrogen InstantOne using kits such as the ERK1 / ERK2(Phospho)[pT202 / pY204] / [pT185 / pY187] ELISA, MesoScale Discovery p / t ERK1 / 2, AlphaScreen SureFire® p-ERK1 / 2(Thr202 / Tyr204), or HTRF® Phospho-ERK(Thr202 / Tyr204) Cell Kit (CisBio). In some embodiments, multiple concentrations of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof can be used to construct a dose-response curve. See, for example, International Publication No. 2021 / 041671, U.S. Publication Nos. 2021 / 0122764, 2018 / 0334454, 2021 / 0179633, 2018 / 0334454, and 2019 / 0144444.

[0216] An exemplary ERK phosphorylation protocol is as follows: In some embodiments, the ERK phosphorylation assay can be performed using the AlphaLisa SUREFIRE® Ultra Multiplex Phospho / Total ERK1 / 2 (Thr202 / Tyr204) Assay Kit. Cells were seeded into plates (e.g., white opaque-bottom Perkin Elmer CulturPlate-384 (product number 6007680)) at the desired concentration one day before treatment with a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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)) overnight at standard 37°C, 5% CO2 incubation. The cells are MIAPACA2 (KRas G12C), H358 (KRas G12C), AGS (KRas G12D), ASPC1 (KRas G12D), GP2D (KRas G12D), LS180 (KRas G12D), Panc04.03 (KRas G12D), HPAFII (KRas G12D), Panc02.03(KRas G12D), A427(KRas G12D), HPAC(KRas G12D), TCCPAN2(KRas G12R), PSN1(KRas G12R), KP2(KRas G12R), LS123(KRas G12S), SW620(KRas G12V), H727(KRas The cell line may be any cell of interest, such as KRas G12V, CFPAC1 (KRas G12V), CAPAN1 (KRas G12S), 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, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is dispensed into the treatment plate (e.g., in a 9-point DRC format (1:3 dilution), 10-μM top concentration, in triplicate, using a Tecan D300e compound printer). The treatment plates are then returned to a standard 37°C, 5% CO2 humidified incubator for the designated treatment time. After compound treatment, all media is removed from the treatment plates, followed by cell lysis (e.g., using 1x lysis buffer according to the manufacturer's protocol). Next, acceptor mix (prepared according to the manufacturer's protocol) is added to each well of the assay plate and incubated for 2 hours at room temperature on an orbital shaker. After incubation with the acceptor mix, donor mix (prepared according to the manufacturer's protocol) is added to each well of the assay plate, covered to protect from light, and incubated overnight at room temperature on an orbital shaker. The assay plate is read the next day (e.g., on a BMG Labtech PHERAstar FSX microplate reader). Data are then analyzed by calculating the ratio of ERK1 / 2 phosphorylation to total ERK1 / 2 for each individual well. TIFF2025528836000146.tif13128

[0217] Replicate ratios for each concentration are averaged and normalized to the DMSO control or other corresponding co-treatments, followed by variable slope (four parameter) non-linear regression curve fitting for each compound of interest. Data are expressed as IC 50 The value can be reported as:

[0218] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits 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)) at an IC 50 In some embodiments, the compound inhibits 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 IC of less than 200 nM. 50 (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 compound may have 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. 50 and can inhibit ERK phosphorylation in cell lines 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))).

[0219] 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 a GTP-bound state (e.g., by abrogating the GTPase activity of the protein). Such assays can be useful, for example, to determine the affinity of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, for the GTP-bound state, potentially independent of GTP cycling of the KRas protein, and / or to determine the effect of the compound on downstream signaling (e.g., interaction with the RBD and / or phosphorylation of downstream kinases such as ERK). See 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:10.1101 / 2021.09.11.459913).

[0220] In some embodiments, the efficacy of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof as a KRas inhibitor can be assessed by its effect on nucleotide exchange from GDP to GTP. For example, nucleotide exchange can be measured via the increase in fluorescence of protein-bound N-methylanthraniloyl (MANT)-GDP upon addition of an excess of a non-hydrolyzable GTP analog, such as guanosine-5'-[(β,γ)-imido]triphosphate (GppNHp, sometimes called 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 a decrease in fluorescence of an incubation mixture of KRas protein-bound fluorophore-tagged GDP (e.g., Bodipy-GDP (e.g., EDA-GTP-DY-647P1)) with a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, followed by treatment with unlabeled GTP. In such assays, exchanging fluorophore-tagged GDP (e.g., Bodipy-GDP) for unlabeled GTP reduces the TR-FRET signal.As another example, nucleotide exchange can be measured via an 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, followed by treatment with labeled GTP. In such an assay, exchange of GDP for labeled GTP results in an increase in the FRET signal. See, e.g., 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., SOS1) can be added to accelerate nucleotide exchange.

[0221] Inhibition of SOS1-catalyzed exchange of GDP to GTP on KRas protein by a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, can be measured using methods known in the art, such as one or more of the methods described herein (e.g., the method described in Example B2 herein). Further examples of in vitro assays include assays that determine inhibition of GTPase activity of KRas protein. In some embodiments, the efficacy of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof can be assessed by its effect on GTPase activity (or lack thereof, as decreased GTPase activity is generally believed to be associated with aberrant signal transduction). For example, the GTPase activity of a KRas protein can be measured using a phosphate assay system that continuously measures phosphate release. In some embodiments, the GTPase activity of KRas protein can be measured using a purine nucleoside phosphorylase-based (PNP) assay. See, for example, Hunter et al. Mol Cancer Res. 2015, 13(9):1325-35.Some embodiments use an enzyme-linked immunosorbent assay (ELISA) to detect changes in the amount of GST-Ras-RBD bound to 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 The effect of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof on the GTPase activity of a G12V mutant protein) can be measured. See, e.g., U.S. Patent 2021 / 0179633.

[0222] An exemplary SOS1-catalyzed nucleotide exchange assay protocol is as follows: GDP-nucleotide-loaded GST-KRas G12R(1-169) is mixed with anti-GST (Cisbio) antibody in assay buffer (20 mM HEPES pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.005% NP40, 1% DMSO) to create a 1.5x solution. 10 μL of the 1.5x KRas-Ab solution is added to a well of a black, low-volume 384-well assay plate. A compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is added to the wells using acoustic transfer technique. A 10-point dose response of each compound is performed with a top dose of 30 μM. The KRas / Ab-compound mixture is incubated at room temperature for 1 hour. A 3x solution of SOS1(564-1049) and EDA-GTP-DY-647P1 (Jena Bioscience) is prepared in assay buffer. Five microliters of SOS1-labeled GTP solution is added to the wells to initiate the nucleotide exchange reaction. The final concentrations of KRas G12R and SOS1 are 10 nM and 200 nM, respectively. Time-resolved fluorescence is read on a PHERAstar plate reader equipped with filter modules for 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]. IC 50 Values ​​are calculated using a four parameter variable response sigmoidal dose-response curve fit in Graphpad Prism software.

[0223] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits SOS1-catalyzed GDP for GTP exchange on KRas protein with an IC50 of less than 1 μM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compound has an IC of less than 200 nM. 50 The compounds inhibit the SOS1-catalyzed exchange of GDP for GTP on the KRas protein at an IC 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 (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 SOS1-catalyzed exchange of GDP for GTP on the KRas protein at an IC 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. 50 can be inhibited by

[0224] Further assays for assessing the efficacy of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 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 nucleotide complexes (e.g., as affected by a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof) for the Ras binding domain (RBD) of KRas, a RAF protein kinase. For example, a FLAG-tagged KRas protein can be preloaded with the GTP analog GppNHp and then incubated with biotinylated Raf-RBD to form a complex. A competition assay can then be performed by adding untagged KRas protein preloaded with GppNHp over a range of concentrations, which are preloaded with various test molecules. The affinity of KRas protein for Raf kinase can be determined by measuring the proximity-dependent signal after addition of streptavidin donor and anti-flag acceptor beads (e.g., ALPHASCREEN® beads).See, for example, 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 a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, that can selectively bind to the GTP state, the His-tagged KRas protein can selectively bind to the GTP state. The antibody may be preloaded with an analog GppNHP and then incubated with a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia)), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof to form a complex. A competition assay can then be performed by adding Raf-RBD. The IC is determined using the proximity-dependent signal after addition of the alpha detection reagent compared to the signal from the same experiment using GDP instead of GppNHP. 50Value can be determined.For example, see International Publication No. 2021 / 085653.It is understood that in many cases, tagging technology (for example, FLAG tag, His tag, biotinylation) can be changed by those skilled in the art in assay.In some embodiments, RAF kinase interaction assay can be combined with nucleotide exchange assay. For example, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof can be used to inhibit 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 The KRas mixture may be incubated with a KRas (e.g., G12V mutant protein) and GDP, followed by the introduction of GTP (and, optionally, a GEF such as SOS1). RAF (e.g., cRAF) acceptor beads (e.g., GST-tagged acceptor beads) are then incubated with the KRas mixture, followed by the introduction of donor beads (e.g., glutathione donor beads) and measurement using ALPHASCREEN® technology. As an alternative to ALPHASCREEN® technology, any suitable FRET pair can be used to perform homogeneous time-resolved fluorescence. See also, e.g., U.S. Patent Application Publication Nos. 2018 / 0334454 and 2021 / 0230142.Another exemplary assay for measuring the affinity of KRas:nucleotide complexes to the RBD involves incubating cells with a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, followed by pulling down non-RBD-bound KRas using immobilized RBD. See, e.g., U.S. Patent Application Publication No. 2019 / 0233440. As another example, a compound of formula (A) (e.g., formula (I) (e.g., formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a drug thereof The effect of a biologically acceptable salt on the interaction between Ras and Raf-RBD can be assessed using HiBiT and / or NANOBIT™ technology, in which two portions of an enzyme are fused or inserted into two proteins of interest (e.g., KRas and Raf-RBD). When the two proteins of interest are in close proximity, the two portions of the enzyme complement each other, resulting in an enzyme with signaling activity (e.g., luminescence generation). In some such assays, the affinity of the two portions of the enzyme can be adjusted to reduce or eliminate signal, for example, based on the proximity driven by the two portions of the enzyme. See, e.g., Schwinn, et al., ACS Chemical Biology 13.2 (2018): 467-474.Similarly, a compound of formula (A) (e.g., formula (I) (e.g., formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof. The effect of acceptable salts on the interaction between KRas and Raf-RBD can be assessed using NANOBRET™ technology, in which two parts of a signaling system (e.g., a protein and a ligand) are fused or inserted into two proteins of interest (e.g., KRas and Raf-RBD). When the two proteins of interest are in close proximity, the two parts of the signaling system have signaling activity (e.g., produce fluorescence). See Durrant, et al. Molecular Cancer Therapeutics 20.9(2021):1743-1754. In some embodiments, a RAF kinase interaction assay is used to determine that a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof is selective for a GDP-bound or GTP-bound 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)).

[0225] Inhibition of the interaction between KRas protein and Raf-RBD by a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof can be measured using methods known in the art (e.g., using one or more methods described herein (e.g., Example B3)).

[0226] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, modulates the interaction between a KRas protein and one or more Raf proteins. In some embodiments, the compound has an IC of less than 1 μM. 50 In some embodiments, the compounds inhibit the interaction between the KRas protein and the Raf-RBD at an IC of less than 200 nM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). 50 The compound inhibits the interaction between the KRas protein and Raf-RBD 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 (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM, less than 0.1 nM, or less than 0.01 nM). For example, the compound inhibits the interaction between the KRas protein and Raf-RBD with an IC50 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. 50 and inhibits.

[0227] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits the interaction between KRas protein and Raf-RBD in the absence of cyclophilin A with an IC of less than 1 μM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). 50 In some embodiments, the compounds inhibit cyclophilin A at an IC of less than 200 nM in the absence of cyclophilin A. 50 The compound inhibits the interaction between KRas protein and Raf-RBD 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 in the absence of cyclophilin A (e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM, less than 0.1 nM, or less than 0.01 nM). For example, the compound inhibits the interaction between KRas protein and Raf-RBD 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 in the absence of cyclophilin A. 50 and inhibits.

[0228] Another exemplary assay for evaluating the efficacy of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof includes measuring phosphorylation of a downstream kinase such as ERK (e.g., ERK1 and / or ERK2) or MEK. Such assays can be used, for example, to measure inhibition of KRas signaling activity in cell lines (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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof for a period of time, and then lysed or permeabilized, and the content of total ERK or MEK and phosphorylated ERK or phosphorylated MEK can be measured (e.g., using antibodies, or Invitrogen InstantOne Use kits such as 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, can be used to construct a dose-response curve. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in a cell line expressing a KRas protein (e.g., a mutant KRas protein (e.g., a KRasG12D mutant protein, a KRasG12R mutant protein, or a KRasG12V mutant protein)). 50 In some embodiments, the compounds inhibit ERK phosphorylation in cell lines 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 IC 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). 50 For example, the compound may have 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. 50and can inhibit ERK phosphorylation in cell lines 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)).

[0229] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof may selectively inhibit one or more mutant KRas proteins over, for example, wild-type KRas proteins. The selectivity between wild-type and mutant KRas proteins described herein can be measured using a cell proliferation assay in which cell proliferation is dependent on signaling activity. For example, HEK293 cells transfected with an appropriate version of wild-type KRas or with KRas containing one or more mutations described herein (e.g., G12D, G12R, or G12V mutations) can be used. Proliferation assays are performed over a range of inhibitor concentrations (e.g., 10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM), and the EC 50 Calculate.

[0230] See also the assays described in International Publication Nos. 2021 / 120890, 2021 / 041671, and U.S. Patent Application Publication Nos. 2021 / 0130369, 2021 / 0179633, 2018 / 0334454, and 2021 / 0122764.

[0231] The pharmacokinetic parameters of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, e.g., a mouse model, a rat model, a dog model, or a non-human primate (e.g., a cynomolgus monkey) model. d ), maximum plasma concentration (C max ), maximum plasma concentration time (t max ), half-life (t 1 / 2 Pharmacokinetic parameters, including the area under the curve (AUC), and oral bioavailability (%F), can be calculated, for example, using a non-compartmental model. In some embodiments, a reference compound (e.g., a first KRas inhibitor (e.g., MRTX1133)) can be used as a comparator. See, for example, Example 3 of WO 2023 / 098425 ("Pharmacokinetics Experiment in Mice").

[0232] Certain pharmacokinetic parameters of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, can be evaluated in hepatocytes, such as mice, rats, dogs, non-human primates (e.g., cynomolgus monkeys), or human hepatocytes. Clearance (CL) and half-life (t 1 / 2Pharmacokinetic parameters, including (i) and (ii) can be calculated. In some embodiments, a reference compound (e.g., a first KRas inhibitor (e.g., MRTX1133)) can be used as a comparator. See, for example, Example VI of WO 2023 / 284881 ("Liver Microsome Metabolic Stability").

[0233] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is used to 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 In some embodiments, a compound of Formula (A) (e.g., a compound of Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 or a pharmaceutically acceptable salt thereof may selectively inhibit a KRas protein (e.g., a wild-type KRas protein and / or a mutant KRas protein (e.g., a KRasG12D mutant protein, a KRasG12R mutant protein, and / or a KRasG12V mutant protein (e.g., a KRasG12D mutant protein and / or a KRasG12V mutant protein)) over another GTPase or non-GTPase target.In some embodiments, the compounds provided herein can exhibit nanomolar potency against KRas proteins (e.g., wild-type KRas proteins and / or mutant KRas proteins (e.g., KRas G12D mutant proteins, KRas G12R mutant proteins, and / or KRas G12V mutant proteins (e.g., KRas G12D mutant proteins and / or KRas G12V mutant proteins))) and have minimal activity against related GTPases (e.g., wild-type NRas proteins and / or wild-type HRas proteins).

[0234] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, exhibits reduced 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 G12R mutant protein) compared to the inhibition of a related GTPase (e.g., a wild-type NRas protein and / or a wild-type HRas protein). In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, may exhibit greater inhibition of KRas proteins (e.g., wild-type KRas proteins and / or mutant KRas proteins (e.g., KRas Inhibition of KRas G12D mutant protein, KRas G12R mutant protein and / or KRas G12V mutant protein (e.g., KRas G12D mutant protein and / or KRas G12V mutant protein) may be at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater than inhibition of the related GTPase (e.g., wild-type NRas protein and / or wild-type HRas protein).In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting 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 The inhibition of the G12V mutant protein))) can be shown to be up to 10,000-fold greater than the inhibition of related GTPases (eg, wild-type NRas protein and / or wild-type HRas protein).

[0235] In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting 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 The inhibition of the G12V mutant protein))) can be shown to be about 2- to about 10-fold greater than the inhibition of a related GTPase (eg, wild-type NRas protein and / or wild-type HRas protein). In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting 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 The inhibition of the G12V mutant protein))) can be shown to be about 10- to about 100-fold greater than the inhibition of the related GTPase (eg, wild-type NRas protein and / or wild-type HRas protein).In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting 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 The inhibition of the G12V mutant protein))) can be shown to be about 100- to about 1000-fold greater than the inhibition of the related GTPase (eg, wild-type NRas protein and / or wild-type HRas protein). In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting 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 The inhibition of the G12V mutant protein))) can be shown to be about 1,000 to about 10,000 times greater than the inhibition of the related GTPase (eg, wild-type NRas protein and / or wild-type HRas protein).

[0236] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is used to treat 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 It is possible to demonstrate potent and selective inhibition of the G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is capable of inhibiting 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 G12V mutant protein)) rather than another GTPase or non-GTPase target. The present invention can selectively inhibit the KRas G12D mutant protein and / or the KRas G12V mutant protein).In some embodiments, the compounds provided herein can exhibit nanomolar potency against mutant KRas proteins (e.g., KRas G12D mutant proteins, KRas G12R mutant proteins, and / or KRas G12V mutant proteins (e.g., KRas G12D mutant proteins and / or KRas G12V mutant proteins)) and have minimal activity against related GTPases (e.g., wild-type KRas proteins, wild-type NRas proteins, and / or wild-type HRas proteins).

[0237] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, exhibits increased inhibition of mutant KRas proteins (e.g., KRas G12D mutant protein, KRas G12R mutant protein, and / or KRas G12V mutant protein (e.g., KRas G12D mutant protein and / or KRas G12V mutant protein) compared to inhibition of wild-type KRas protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, may exhibit greater inhibition of KRas mutant proteins (e.g., KRas G12D mutant protein, KRas G12R mutant protein, and / or KRas G12V mutant protein (e.g., KRas G12D mutant protein and / or KRas The inhibition of the G12V mutant protein)) may be at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than the inhibition of the wild-type KRas protein.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting 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 It can be shown that the inhibition of the G12V mutant protein)) is up to 10,000-fold greater than that of the wild-type KRas protein.

[0238] In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting 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 It can be shown that the inhibition of the G12V mutant protein) is about 2- to about 10-fold greater than the inhibition of the wild-type KRas protein. In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting 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 It can be shown that inhibition of the G12V mutant protein) is about 10 to about 100 times greater than inhibition of the wild-type KRas protein.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting 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 The inhibition of the G12V mutant protein) can be shown to be about 100 to about 1000 times greater than the inhibition of the wild-type KRas protein. In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is selected from the group consisting 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 The G12V mutant protein)) can exhibit approximately 1,000 to 10,000 times greater inhibition than the wild-type KRas protein.

[0239] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is a compound of Formula (A) or a pharmaceutically acceptable salt thereof, that has minimal activity against a wild-type NRas protein and / or a wild-type HRas protein, 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 It may exhibit nanomolar potency against KRas G12D mutant protein and / or KRas G12V mutant protein). In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is capable of inhibiting 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 G12V mutant protein)) compared to the inhibition of wild-type NRas protein and / or wild-type HRas protein. It may show greater inhibition of KRas G12D mutant protein and / or KRas G12V mutant protein).In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is capable of inhibiting at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater inhibition of dysregulated KRas protein (e.g., mutant KRas protein (e.g., KRas G12D mutant protein ... KRas G12R mutant protein and / or KRas G12V mutant protein (e.g., KRas G12D mutant protein and / or KRas In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, may exhibit 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) compared to inhibition of a wild-type NRas protein and / or a wild-type HRas protein). Up to 1000-fold greater inhibition of KRas G12D mutant protein and / or KRas G12V mutant protein (e.g., KRas G12D mutant protein and / or KRas G12V mutant protein))) may be observed.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is capable of inhibiting 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 G12V mutant protein)) compared to the inhibition of wild-type NRas protein and / or wild-type HRas protein. It may show up to 10,000-fold greater inhibition of KRas G12D mutant protein and / or KRas G12V mutant protein).

[0240] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is capable of inhibiting 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 G12V mutant protein)) compared to the 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, may exhibit 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 and / or a KRas G12V mutant protein) compared to the inhibition of a wild-type HRas protein and / or a wild-type NRas protein). The inhibitors may exhibit about 10- to about 100-fold greater inhibition of KRas G12D mutant protein, KRas G12R mutant protein, and / or KRas G12V mutant protein (for example, KRas G12D mutant protein and / or KRas G12V mutant protein).In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is capable of inhibiting 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 G12V mutant protein)) compared to the inhibition of wild-type NRas protein and / or wild-type HRas protein. The inhibitor can exhibit approximately 100 to 1000 times greater inhibition than that of KRas G12D mutant protein and / or KRas G12V mutant protein). In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is capable of inhibiting 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 G12V mutant protein)) compared to the inhibition of wild-type NRas protein and / or wild-type HRas protein. The inhibitor can exhibit approximately 1,000 to 10,000 times greater inhibition than that of KRas G12D mutant protein and / or KRas G12V mutant protein).

[0241] Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (II-dd), (II-e), (II-ee), (II-f), (II-g), or (II- The compounds of formula (h)), or formula (Aa)), or a pharmaceutically acceptable salt thereof, are useful for treating diseases and disorders including cardiovascular diseases (e.g., arteriovenous malformations or Moonan syndrome), endometritis, inflammatory diseases and / or abnormal leukocyte disorders (e.g., autoimmune and non-malignant syndromes of abnormal leukocyte homeostasis), and proliferative disorders such as cancer, 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)).

[0242] In certain embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, is useful for preventing diseases and disorders defined herein (e.g., cardiovascular disease, endometriosis, and inflammatory and / or autoimmune diseases, or cancer).

[0243] In some embodiments of any of the methods or uses described herein, the inflammatory and / or autoimmune disease is a RAS-associated autoimmune leukoproliferative disorder. See, e.g., Niemela et al. Blood. 2011, 117(10):2883-6.

[0244] In some embodiments, the subject has been identified or diagnosed with a cancer with KRas dysregulation (e.g., 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., tumor sample) with KRas dysregulation (e.g., KRas mutation or amplification) (e.g., as determined using a regulatory agency-approved assay or kit). The subject may have a cancer (e.g., one or more tumor samples) that is positive for KRas dysregulation (e.g., KRas mutation or amplification) (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a cancer (e.g., tumor sample) with KRas dysregulation (e.g., KRas mutation or amplification) (e.g., when 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 clinical records indicating that the subject has a cancer (e.g., a tumor sample) with KRas dysregulation (e.g., KRas mutation or amplification) (optionally, the clinical records indicate that the subject should be treated with any of the compounds and / or compositions provided herein).

[0245] In some such embodiments, the cancer (e.g., 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, the 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, the 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., 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.

[0246] In some embodiments, the cancer (e.g., tumor sample) has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation (e.g., a KRas G12D mutation or a KRas G12V mutation). In some embodiments, the cancer (e.g., tumor sample) has a KRas G12D mutation or a KRas G12V mutation. In some embodiments, the cancer (e.g., tumor sample) has a KRas G12D mutation. In some embodiments, the cancer (e.g., tumor sample) has a KRas G12R mutation. In some embodiments, the cancer (e.g., tumor sample) has a KRas G12V mutation.

[0247] As used herein, the term "KRas-associated cancer" refers to a cancer associated with or having dysregulation of the expression, activity, or levels of the KRAS gene, KRas protein, or any of them (e.g., one or more) (e.g., any of the types of dysregulation of the expression, activity, or levels of the KRAS gene, KRas protein, or any of them described herein). Non-limiting examples of KRas-associated cancers are described herein.

[0248] As used herein, the term "mutated KRas-associated cancer" refers to a cancer associated with or harboring a KRas mutation (e.g., a KRAS gene and / or a KRas protein having a mutation corresponding to a mutation in the KRas protein). Non-limiting examples of mutant KRas-associated cancers are described herein.

[0249] As used herein, the term "KRas G12X-associated cancer" refers to a cancer associated with or harboring a KRas G12X mutation (e.g., a KRAS gene having a mutation corresponding to a G12X mutation in a KRas protein and / or a KRas protein having a G12X mutation). Non-limiting examples of KRas G12X-associated cancers are described herein.

[0250] As used herein, the term "KRas G12A-associated cancer" refers to a cancer associated with or harboring 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 KRas G12A-associated cancers are described herein.

[0251] As used herein, the term "KRas G12C-associated cancer" refers to a cancer associated with or harboring a KRas G12C mutation (e.g., a KRAS gene having a mutation corresponding to a G12C mutation in a KRas protein and / or a KRas protein having a G12C mutation). Non-limiting examples of KRas G12C-associated cancers are described herein.

[0252] As used herein, the term "KRas G12D-associated cancer" refers to a cancer associated with or harboring a KRas G12D mutation (e.g., a KRAS gene having a mutation corresponding to a G12D mutation in a KRas protein and / or a KRas protein having a G12D mutation). Non-limiting examples of KRas G12D-associated cancers are described herein.

[0253] As used herein, the term "KRas G12R-associated cancer" refers to a cancer associated with or harboring a KRas G12R mutation (e.g., a KRAS gene having a mutation corresponding to a G12R mutation in a KRas protein and / or a KRas protein having a G12R mutation). Non-limiting examples of KRas G12R-associated cancers are described herein.

[0254] As used herein, the term "KRas G12S-associated cancer" refers to a cancer associated with or harboring a KRas G12S mutation (e.g., a KRAS gene having a mutation corresponding to a G12S mutation in a KRas protein and / or a KRas protein having a G12S mutation). Non-limiting examples of KRas G12S-associated cancers are described herein.

[0255] As used herein, the term "KRas G12V-associated cancer" refers to a cancer associated with or harboring a KRas G12V mutation (e.g., a KRAS gene having a mutation corresponding to a G12V mutation in a KRas protein and / or a KRas protein having a G12V mutation). Non-limiting examples of KRas G12V-associated cancers are described herein.

[0256] As used herein, the term "KRas G13X-associated cancer" refers to a cancer associated with or harboring a KRas G13X mutation (e.g., a KRAS gene having a mutation corresponding to a G13X mutation in a KRas protein and / or a KRas protein having a G13X mutation). Non-limiting examples of KRas G13X-associated cancers are described herein.

[0257] As used herein, the term "KRas G13C-associated cancer" refers to a cancer associated with or harboring a KRas G13C mutation (e.g., a KRAS gene having a mutation corresponding to a G13C mutation in a KRas protein and / or a KRas protein having a G13C mutation). Non-limiting examples of KRas G13C-associated cancers are described herein.

[0258] As used herein, the term "KRas G13D-associated cancer" refers to a cancer associated with or harboring a KRas G13D mutation (e.g., a KRAS gene having a mutation corresponding to a G13D mutation in a KRas protein and / or a KRas protein having a G13D mutation). Non-limiting examples of KRas G13D-associated cancers are described herein.

[0259] As used herein, the term "KRas G13V-associated cancer" refers to a cancer associated with or harboring a KRas G13V mutation (e.g., a KRAS gene having a mutation corresponding to a G13V mutation in a KRas protein and / or a KRas protein having a G13V mutation). Non-limiting examples of KRas G13V-associated cancers are described herein.

[0260] As used herein, the term "KRas Q61X-associated cancer" refers to a cancer associated with or harboring a KRas Q61X mutation (e.g., a KRAS gene having a mutation corresponding to a Q61X mutation in a KRas protein and / or a KRas protein having a Q61X mutation). Non-limiting examples of KRas Q61X-associated cancers are described herein.

[0261] As used herein, the term "KRas Q61E-associated cancer" refers to a cancer associated with or harboring a KRas Q61E mutation (e.g., a KRAS gene having a mutation corresponding to the Q61E mutation in the KRas protein and / or a KRas protein having the Q61E mutation). Non-limiting examples of KRas Q61E-associated cancers are described herein.

[0262] As used herein, the term "KRas Q61H-associated cancer" refers to a cancer associated with or harboring a KRas Q61H mutation (e.g., a KRAS gene having a mutation corresponding to the Q61H mutation in the KRas protein and / or a KRas protein having the Q61H mutation). Non-limiting examples of KRas Q61H-associated cancers are described herein.

[0263] As used herein, the term "KRas Q61K-associated cancer" refers to a cancer associated with or harboring a KRas Q61K mutation (e.g., a KRAS gene having a mutation corresponding to the Q61K mutation in the KRas protein and / or a KRas protein having the Q61K mutation). Non-limiting examples of KRas Q61K-associated cancers are described herein.

[0264] As used herein, the term "KRas Q61L-associated cancer" refers to a cancer associated with or harboring a KRas Q61L mutation (e.g., a KRAS gene having a mutation corresponding to a Q61L mutation in a KRas protein and / or a KRas protein having a Q61L mutation). Non-limiting examples of KRas Q61L-associated cancers are described herein.

[0265] As used herein, the term "KRas Q61P-associated cancer" refers to a cancer associated with or harboring a KRas Q61P mutation (e.g., a KRAS gene having a mutation corresponding to the Q61P mutation in the KRas protein and / or a KRas protein having the Q61P mutation). Non-limiting examples of KRas Q61P-associated cancers are described herein.

[0266] As used herein, the term "KRas Q61R-associated cancer" refers to a cancer associated with or harboring a KRas Q61R mutation (e.g., a KRAS gene having a mutation corresponding to a Q61R mutation in a KRas protein and / or a KRas protein having a Q61R mutation). Non-limiting examples of KRas Q61R-associated cancers are described herein.

[0267] Such mutations may be associated with the development of various cancers. See, for example, Hunter et al. Mol Cancer Res. 2015, 13(9):1325-35.

[0268] Provided herein are methods of treating cancer in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is treatment-naive for cancer. In some embodiments, the subject has received one or more lines of prior therapy for cancer.

[0269] Also provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject as monotherapy a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is treatment-naive for cancer. In some embodiments, the subject has received one or more lines of prior therapy for cancer.

[0270] Provided herein is the use of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of, e.g., any of the cancers provided herein.

[0271] Provided herein is the use of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for the treatment of cancer, e.g., any of the cancers provided herein.

[0272] Provided herein is the use of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, e.g., any of the cancers provided herein.

[0273] Provided herein is a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a pharmaceutical. Also provided herein is a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the treatment of cancer, e.g., any of the cancers provided herein.

[0274] Provided herein is a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating cancer, e.g., any of the cancers provided herein.

[0275] As used herein, "monotherapy" when referring to Formula (A) (e.g., Formula (I) (e.g., Formula (Ia)), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, includes a monotherapy of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb) , (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), Formula (II) (e.g., (II-c), (II-cc), (II-d), (II-dd), (II-e), (II-ee), (II-f), (II-g), or (II-h)), or a compound of Formula (Aa)), or a pharmaceutically acceptable salt thereof, is the only therapeutic agent or therapy (e.g., anti-cancer agent or therapy) administered to the subject during a treatment cycle (e.g., no additional targeted therapeutic agents, anti-cancer agents, chemotherapeutic agents, or checkpoint inhibitors are administered to the subject during a treatment cycle). As one of ordinary skill in the art would understand, monotherapy does not exclude the co-administration of pharmaceutical agents for the treatment of side effects or general symptoms associated with cancer or treatment, such as pain, rash, edema, photosensitivity, itching, skin discoloration, hair brittleness, hair loss, brittle, cracked, discolored nails, swollen calluses, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms including nausea, diarrhea, and loss of appetite.

[0276] As used herein, "the subject has previously received one or more therapeutic agents or therapies for cancer" means that the subject has previously received one or more therapeutic agents or therapies for cancer (e.g., anti-cancer agents or therapies) during a previous treatment cycle, such as a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof. In some embodiments, the subject is unable to tolerate one or more of the previously administered therapeutic agents or therapies for cancer. In some embodiments, the subject has failed to respond to one or more previously administered therapeutic agents or therapies for cancer. In some embodiments, the subject has failed to adequately respond to one or more previously administered therapeutic agents or therapies for cancer. In some embodiments, the subject has stopped responding to one or more previously administered therapeutic agents or therapies for cancer. In some embodiments, the lack of response, inadequate response, or aborted response can be determined by objective criteria (e.g., by criteria such as tumor volume or RECIST 1.1). In some embodiments, the lack of response, inadequate response, or aborted response can be determined by the subject's physician.

[0277] As used herein, "a subject is treatment-naive with respect to cancer" means that the subject has not previously been administered one or more therapeutic agents or therapies for cancer.

[0278] For any of the solid tumors described herein, the solid tumor can be a primary tumor or a metastatic (or secondary) tumor. As used herein, a "primary" tumor is a tumor located at the site where the tumor began to grow (i.e., where it originated). As used herein, a "metastatic" (or "secondary") tumor is a tumor that has spread from the original tumor site to other parts of the body. In some embodiments, the metastatic or secondary tumor is the same type of cancer as the primary tumor. In some embodiments, the metastatic or secondary tumor is not genetically identical to the primary tumor.

[0279] Provided herein are methods of treating cancer in a subject in need of such treatment, the methods comprising: a) detecting 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 the KRas protein, and / or detecting a mutation, KRAS gene copy number gain, and / or KRas detecting KRas protein having increased mRNA or protein expression); and b) administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof. 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 G12R-associated cancer) in a subject in need of such treatment; Also provided herein is a method of treating a G12V-associated cancer, comprising administering to a subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.For example, a method 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, comprising: a) detecting 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 the KRas protein, and / or detecting a mutation, KRAS gene copy number gain, and / or KRas and b) detecting KRas protein having increased mRNA or protein expression; and c) administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof.

[0280] In some embodiments of any of the methods or uses described herein, the cancer (e.g., 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))) is selected from the group consisting of breast cancer (e.g., invasive breast cancer, 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 gland cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), multiple neuroendocrine tumors type I and type II, parathyroid cancer, pituitary tumor, thyroid cancer (e.g., papillary thyroid carcinoma)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer, bile duct cancer, 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 (GIST), liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic islet cell carcinoma), small intestine cancer, or stomach cancer (e.g., gastric adenocarcinoma, signet ring cell gastric carcinoma)), genitourinary cancer (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., clear cell renal cell carcinoma, papillary renal cell carcinoma, kidney pigmented macules) chromophobe), prostate cancer (e.g., prostatic adenocarcinoma), testicular cancer (e.g., testicular germ cell tumor, seminoma), or ureteral cancer), gynecological cancer (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, endocervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., ovarian serous carcinoma, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinosarcoma, endometrioid adenocarcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, uterine corpus endometrial carcinoma,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, pharyngeal cancer (e.g., hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), blood 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)), or non-Hodgkin lymphoma (e.g., Burkitt lymphoma, BL, diffuse large B-cell lymphoma) Diffuse histiocytic lymphoma (DHL), follicular lymphoma (FL), intravascular large B cell lymphoma (IVLBCL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SMLL), and idiopathic leukemia (ILM) are also included. lymphoma, SLL), or myeloma (e.g., multiple myeloma), Li-Fraumeni tumor, mesenteric cancer (e.g., omental carcinoma, peritoneal carcinoma), pleural cancer, respiratory cancer (e.g., laryngeal 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's sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), skin cancer (e.g., melanoma), thymic carcinoma (e.g., thymoma), or a combination thereof.

[0281] In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., a mutant KRas-associated cancer)) is blood cancer, 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 cancer, rectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thymic 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 blood cancer, bile duct cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous cancer, pancreatic cancer, prostate cancer, rectal cancer, testicular cancer (e.g., seminoma), skin cancer, gastric cancer, thymic cancer, thyroid cancer, urothelial cancer, or uterine cancer.

[0282] In some embodiments, the cancer is a blood cancer, brain cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, gastric cancer, thymic cancer, urothelial cancer, or uterine cancer. In some embodiments, the cancer is a KRas G12D-associated cancer.

[0283] 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.

[0284] In some embodiments, the cancer is a blood 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 cancer, ovarian cancer, pancreatic cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer (e.g., seminoma), thymic cancer, or uterine cancer. In some embodiments, the cancer is a G12V-associated cancer.

[0285] 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 blood cancer, soft tissue cancer, cervical cancer, colon cancer, endometrial cancer, liver cancer, lung cancer, pancreatic cancer, rectal cancer, skin cancer, gastric 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 a 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 a colorectal cancer, gastric cancer, gastroesophageal cancer, head and neck squamous cell carcinoma, or lung cancer (e.g., NSCLC). See, e.g., the public database cBioPortal.

[0286] In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., a mutant KRas-associated cancer)) is pancreatic cancer or metastatic pancreatic cancer. In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., a mutant KRas-associated cancer)) is pancreatic ductal adenocarcinoma (PDAC). In some such embodiments, the pancreatic cancer is a KRas G12R-associated cancer.

[0287] In some embodiments, the cancer (e.g., a KRas-associated cancer (e.g., a mutant KRas-associated cancer)) is advanced stage lung adenocarcinoma.

[0288] In some embodiments, the cancer has a solid tumor. In some embodiments, the solid tumor has KRas dysregulation (e.g., 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.

[0289] Also provided herein are methods of treating a solid tumor in a subject in need thereof, the methods comprising: (a) detecting KRas dysregulation (e.g., 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Also provided are methods of treating a solid tumor in a subject in need thereof, comprising: (a) detecting a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, or a KRas 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.Further provided herein are methods of treating a solid tumor in a subject in need thereof, the methods comprising: (a) detecting a KRas G12D or 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Further 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.Further 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Further 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0290] In some embodiments, the cancer is bladder cancer. In some embodiments, the bladder cancer has KRas dysregulation (e.g., 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.

[0291] Also provided herein are methods of treating bladder cancer in a subject in need thereof, comprising: (a) detecting KRas dysregulation (e.g., 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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)), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Also provided are methods of treating bladder cancer in a subject in need thereof, 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 G13D mutation in a sample from the subject; Provided herein are methods comprising (b) detecting the Q61H mutation, and (c) administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.Further provided herein are methods of treating bladder cancer in a subject in need thereof, comprising: (a) detecting a KRas G12D or 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Further provided herein is a method of treating bladder cancer in a subject in need thereof, 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.Further provided herein is a method of treating bladder cancer in a subject in need thereof, 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Further provided herein is a method of treating bladder cancer in a subject in need thereof, 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0292] In some embodiments, the cancer is cervical cancer. In some embodiments, the cervical cancer has KRas dysregulation (e.g., 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.

[0293] Also provided herein are methods of treating cervical cancer in a subject in need thereof, the methods comprising: (a) detecting KRas dysregulation (e.g., 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. 1. A method of treating cervical cancer in a subject in need thereof, comprising: (a) detecting a KRas G12C mutation, a KRas G12D mutation, a KRas G12V mutation, or a KRas G12C mutation in a sample from the subject; Provided herein are methods comprising (a) detecting a G13D mutation; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.Further provided herein are methods of treating cervical cancer in a subject in need thereof, 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Further provided herein is a method of treating cervical cancer in a subject in need thereof, 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.Further provided herein is a method of treating cervical cancer in a subject in need thereof, 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0294] In some embodiments, the cancer is colorectal cancer. In some embodiments, the colorectal cancer has KRas dysregulation (e.g., KRas mutation or amplification). For example, the colorectal cancer has a KRas mutation selected from the group consisting of: KRas G12A mutation, KRas G12C mutation, KRas G12D mutation, KRas G12R mutation, KRas G12S mutation, KRas G12V mutation, KRas G13C mutation, KRas G13D mutation, KRas G13V mutation, KRas Q61E mutation, KRas Q61H mutation, KRas Q61K mutation, KRas Q61L mutation, KRas Q61P mutation, and 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.

[0295] Also provided herein are methods of treating colorectal cancer in a subject in need thereof, the methods comprising: (a) detecting KRas dysregulation (e.g., 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Also provided are methods of treating colorectal cancer in a subject in need thereof, 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 Q61E mutation in a sample from the subject; Provided herein are methods comprising (a) detecting the Q61R mutation; and (b) administering to a subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.Further provided herein are methods of treating colorectal cancer in a subject in need thereof, 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Further provided herein is a method of treating 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.Further provided herein is a method of treating 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. Further provided herein is a method of treating colorectal cancer in a subject in need thereof, 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0296] In some embodiments, the cancer is endometrial cancer. In some embodiments, the endometrial cancer has KRas dysregulation (e.g., KRas mutation or amplification). For example, the endometrial cancer has a KRas mutation selected from the group consisting of: KRas G12A mutation, KRas G12C mutation, KRas G12D mutation, KRas G12S mutation, KRas G12V mutation, KRas G13C mutation, KRas G13D mutation, KRas G13V mutation, KRas Q61H mutation, and 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.

[0297] Also provided herein are methods of treating endometrial cancer in a subject in need thereof, the methods comprising: (a) detecting KRas dysregulation (e.g., 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 (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (I-dd), (Ie), (I-ee), (If), (Ig), or (Ih)), 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. 1. A method of treating endometrial cancer in a subject in need thereof, 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 Provided herein are methods comprising (b) detecting the Q61L mutation, and (b) administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (Ia), (I-aa), (Ib), (I-bb), (Ic), (I-cc), (Id), (...

Claims

1. Formula (A): or a pharmaceutically acceptable salt thereof, During the ceremony, m is 0, 1, or 2; Each X １ is CH ２ , CHR ａ , C(R ａ ) ２ , O, N(R ｄ ), C(═O), and S(O) ０～２ Independently selected from the group consisting of -(X １ ) ｍ - is O-O, O-N, N-S(O) ０ Also, O-S(O) ０～２ Does not include bonds, Ring C is C ３～１５ cycloalkyl, 4- to 15-membered heterocyclylene, 6- to 15-membered arylene, and 5- to 15-membered heteroarylene, each of which is independently selected from the group consisting of 1 to 4 R ７ may be substituted with R ７ Each of ａ and R ｂ are independently selected from the group consisting of p is an integer from 3 to 10, Each L Ａは , L Ａ１ , L Ａ２ , L Ａ３ , and L Ａ４ independently selected from the group consisting of: Ａ 0 to 2 occurrences of L Ａ４ and L Ａ 0 to 3 occurrences of L Ａ２ and L Ａ３ is selected from the group consisting of Each L Ａ１ is -CH ２ --, --CHR Ｌ -, and -C(R Ｌ ) ２ -, where each R Ｌ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NR ｄ R ｅ , C(=O)N(R ｆ ) ２ , and 1 to 6 R ｃ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Each L Ａ２ is, independently, and each R Ｌ２ are independently H, halo, CN, and 1 to 6 R ｃ C optionally substituted with １～６ is selected from the group consisting of alkyl, L Ａ３ Each of the groups independently represents —N(R ｄ )-, -O-, -S(O) ０～２ -, and C(=O); L Ａ４ Each of the ３～１０ Cycloalkylene, 4- to 10-membered heterocyclylene, C ６～１０ arylene, and 5- to 10-membered heteroarylene, each of which is independently selected from the group consisting of 1 to 3 R ｇ may be substituted with Ring B is R ａ and R ｂ C, each of which is optionally substituted with 1 to 6 substituents independently selected from the group consisting of ６～１０ selected from the group consisting of arylene and 5- to 10-membered heteroarylene; Y １ represents a bond, -N(H)-, -N(C １～３ alkyl)-, -N(C ３～６ cycloalkyl)-, —O—, and —S(O) ０～２ - selected from the group consisting of n is 0 or 1; Y ２ is 1 to 6 R Ｙ A linear C optionally substituted with １～６ is alkylene, Each R Ｙ are independently halo, cyano, —OH, oxo, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkyl, and C １～６ haloalkyl; A pair of R on the same or different carbon atoms Ｙ together with the atoms connecting them, represent 1 to 3 independently selected C １～３ C, each of which may be substituted with alkyl ３～６ forming a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, R ３ teeth, (a)-H, (b)-halo, (c)-NR ｄ R ｅ 、 (d) R ａ and R ｂ each optionally substituted with 1 to 6 substituents independently selected from the group consisting of ３～１０ cycloalkyl or 3- to 15-membered heterocyclyl, and (e) R ａ and R ｂ each optionally substituted with 1 to 6 substituents independently selected from the group consisting of ６～１０ Aryl or 5- to 10-membered heteroaryl are independently selected from the group consisting of E １ is N, CH, or CR ６ and R ４ , R ５ , and R ６ teeth, (a)-H, (b) halo, (c) cyano, (d) C １～６ Alkyl, (e) C １～６ haloalkyl, (f) C １～６ Alkoxy, (g) C １～６ haloalkoxy, (h) C ３～６ The cycloalkyl moiety is 1 to 3 R ｇ -(C ０～３ alkylene)-C ３～６ cycloalkyl, and (i) C ３～６ The cycloalkyl moiety may be substituted with 1 to 3 Rg groups, ０～３ alkylene)-C ３～６ cycloalkyl are independently selected from the group consisting of R ａ Each of the (a) halo, (b) cyano, (c) —OH, (d) oxo, (e)-C １～６ Alkoxy, (f)-C １～６ haloalkoxy, (g)-NR ｄ R ｅ 、 (h) C(=O)C １～６ Alkyl, (i) C(=O)C １～６ haloalkyl, (j)C(=O)OH, (k)C(=O)OC １～６ Alkyl, (l)C(=O)OC １～６ haloalkyl, (m)C(=O)N(R ｆ ) ２ 、 (n) S(O) ０～２ (C １～６ alkyl), (o)S(O) ０～２ (C １～６ haloalkyl), (p)S(O) １～２ N (R ｆ ) ２ , and (q) 1 to 6 R ｃ each of which is optionally substituted with １～６ Alkyl, C ２～６ Alkenyl, or C ２～６ Alkynyl are independently selected from the group consisting of R ｂ Each of -(L ｂ ) ｂ -R ｂ１ and -R ｂ１ are independently selected from the group consisting of b is 1, 2, or 3; Each -L ｂ are independently —O—, —N(H)—, —N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ alkylene; R ｂ１ Each of the ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R ｇ may be substituted with Each R ｃ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NR ｄ R ｅ , C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)OH, C(=O)N(R ｆ ) ２ , S(O) ０～２ (C １～６ alkyl), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N (R ｆ ) ２ are independently selected from the group consisting of Each R ｄ and R ｅ is H, C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)N(R ｆ ) ２ , S(O) １～２ (C １～６ alkyl), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N (R ｆ ) ２ , and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, R ｆ Each of the groups is H and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Each R ｇ But independently, R ｈ , C １～３ Alkyl, and C １～３ haloalkyl; Each R ｈ are independently halo, cyano, —OH, —C １～６ Alkoxy, -C １～６ Haloalkoxy, —NH ２ , -N(H)(C １～３ alkyl), and —N(C １～３ alkyl) ２ selected from the group consisting of The compound or a pharmaceutically acceptable salt thereof.

2. The compound of formula (A) is a compound of formula (I): or a pharmaceutically acceptable salt thereof.

3. The compound of formula (A) may be a compound of formula (II): or a pharmaceutically acceptable salt thereof, １ but CH or CR ６ 2. The compound of claim 1, wherein:

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

5. Ring C is a ring having 1 to 4 R ７ or a 4- to 15-membered heterocyclylene optionally substituted by Ring C is a ring having 1 to 3 R ７ or a 4- to 6-membered heterocyclylene optionally substituted by Ring C is a ring having 1 to 3 R ７ piperidinylene optionally substituted by The compound according to any one of claims 1 to 4.

6. Ring C or and c1 is 0, 1, or 2; Each R ７ａ and R ７ｂ are independently selected R ７ and cc is -(L Ａ ) ｐ - represents the point of attachment to The compound according to any one of claims 1 to 5.

7. The compound of claim 6, wherein c1 is 0.

8. Ring C is or Ring C is and R ７ａ C optionally substituted with 1 to 3 F １～３ alkyl, or Ring C is and R ７ａ is —OH; 8. The compound according to claim 6 or 7.

9. Ring C is a ring having 1 to 3 R ７ The compound according to any one of claims 1 to 5, which is a 7- to 10-membered heterocyclylene optionally substituted by:

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

11. Ring C is where c1 is 0, 1, or 2, and cc is -(L Ａ ) ｐ 11. The compound of any one of claims 1 to 5 or 9 to 10, wherein - represents the point of attachment to -.

12. p is 4, 5, or 6; or p is 6, 7, or 8; The compound according to any one of claims 1 to 11.

13. L Ａ Each of the Ａ１ , L Ａ３ , and L Ａ４ The compound of any one of claims 1 to 12, independently selected from the group consisting of:

14. L Ａ 0 to 1 occurrences of L Ａ４ and each of the remaining L Ａ But, L Ａ１ and L Ａ３ The compound of any one of claims 1 to 13, independently selected from the group consisting of:

15. L Ａ One occurrence of L Ａ４ and each of the remaining L Ａ But independently Ａ１ The compound according to any one of claims 1 to 14,

16. Each L Ａ But independently Ａ１ The compound according to any one of claims 1 to 14,

17. L Ａ One or two occurrences of L Ａ３ and each of the remaining L Ａ Each of the following independently represents L Ａ１ The compound according to any one of claims 1 to 14,

18. p is 4, 5, or 6; Ａ One occurrence of L Ａ４ and each of the remaining L Ａ But independently Ａ１ The compound according to any one of claims 1 to 11,

19. p is 6, 7, or 8, and each L Ａ is independent and L Ａ１ The compound according to any one of claims 1 to 11,

20. Each L Ａ Ga-CH ２ The compound of claim 19, wherein

21. p is 6, 7, or 8; Ａ One occurrence of is C(=O) and L Ａ The second occurrence of N(R ｄ ) (e.g., NH), and each remaining L Ａ are each independently L Ａ１ The compound according to any one of claims 1 to 11,

22. - (L Ａ ) ｐ - but - (L Ａ１ａ ) ａ１ａ -C(=O)NH-(L Ａ１ｂ ) ａ１ｂ - ｂｂ and where: a1a and a1b are independently an integer from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and bb represents the point of attachment to ring C; 27. The compound of any one of claims 1 to 11 or 26.

23. a1b is 2 and a1a is 2, 3, or 4; or a1b is 1 and a1a is 3, 4, or 5; 23. The compound of claim 22.

24. L Ａ１ａ and L Ａ１ｂ Each of ２ The compound according to any one of claims 22 to 23, wherein

25. m is 0, Ring C or and where: c1 is 0, 1, or 2; Each R ７ａ and R ７ｂ are independently selected R ７ and cc is -(L Ａ ) ｐ represents the point of attachment to -, - (L Ａ ) ｐ - but - (L Ａ１ａ ) ａ１ａ -C(=O)NH-(L Ａ１ｂ ) ａ１ｂ - ｂｂ and a1a and a1b are independently an integer from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and bb represents the point of attachment to ring C; The compound according to any one of claims 1 to 3.

26. a1b is 2 and a1a is 2, 3, or 4; or a1b is 1 and a1a is 3, 4, or 5; 26. The compound of claim 25.

27. L Ａ１ａ and L Ａ１ｂ Each of ２ 27. The compound of claim 25 or 26,

28. Ring C or Ring C and R ７ａ is —OH; The compound according to any one of claims 23 to 27.

29. The compound according to any one of claims 23 to 28, wherein c1 is 0.

30. m is 0, Ring C and c1 is 0, 1, or 2; cc is -(L Ａ ) ｐ represents the point of attachment to -, - (L Ａ ) ｐ - but - (L Ａ１ａ ) ａ１ａ -C(=O)NH-(L Ａ１ｂ ) ａ１ｂ - ｂｂ and a1a and a1b are independently an integer from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and bb represents the point of attachment to ring C; The compound according to any one of claims 1 to 3.

31. a1b is 2 and a1a is 2, 3, or 4; or a1b is 1 and a1a is 3, 4, or 5; 31. The compound of claim 30.

32. L Ａ１ａ and L Ａ１ｂ Each of these is CH ２ and c1 is 0.

33. Ring B is R ａ and R ｂ C optionally substituted with 1 to 6 substituents independently selected from the group consisting of ６～１０ The compound of any one of claims 1 to 32, which is an arylene.

34. Ring B is a ring having 1 to 4 R ａ The compound according to any one of claims 1 to 33, which is naphthylene optionally substituted by

35. Ring B is where R ２ａ and R ２ｃ are independently H or R ａ and aa is -(L Ａ ) ｐ 35. The compound of any one of claims 1 to 34, wherein - represents a point of attachment to -.

36. R ２ａ is —OH, or R ２ａ is H or -NH ２ That is, 36. The compound of claim 35.

37. R ２ｃ The compound of any one of claims 34 to 36, wherein is halo or H.

38. Ring B is where aa is -(L Ａ ) ｐ 35. The compound of any one of claims 1 to 34, wherein - represents a point of attachment to -.

39. Ring B is where aa is -(L Ａ ) ｐ 35. The compound of any one of claims 1 to 34, wherein - represents a point of attachment to -.

40. Ring B is a ring having 1 to 4 R ａ The compound according to any one of claims 1 to 33, wherein the phenylene is optionally substituted by

41. Ring B is where R ２ａ , R ２ｂ , and R ２ｃ are independently H or R ａ and aa is -(L Ａ ) ｐ represents the point of attachment to -, or Ring B where R ２ａ and R ２ｃ are independently H or R ａ and aa is -(L Ａ ) ｐ - represents the point of attachment to 41. A compound according to any one of claims 1 to 33 or 40.

42. R ２ａ is —OH, or R ２ａ Ga-NH ２ That is, 42. The compound of claim 41.

43. R ２ｃ 43. The compound of claim 41 or 42, wherein is halo (e.g., -Cl).

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

45. Ring B is a ring having 1 to 3 R ａ The compound according to any one of claims 1 to 33 or 44, which is a 9- to 10-membered bicyclic heteroarylene optionally substituted by:

46. Ring B is where R ２ｃ is H or R ａ and aa is -(L Ａ ) ｐ 46. ​​A compound according to any one of claims 1 to 33 or 44 to 45, wherein - represents a point of attachment to.

47. R ２ｃ 47. The compound of claim 46, wherein is halo.

48. Ring B is where aa is -(L Ａ ) ｐ 48. A compound according to any one of claims 1 to 33 or 44 to 47, wherein - represents a point of attachment to -.

49. Y １ The compound of any one of claims 1 to 48, wherein is -O-.

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

51. Y ２ But 1 to 3 R Ｙ A linear C optionally substituted with １～３ The compound of any one of claims 1 to 50, which is alkylene.

52. Y ２ But -CH ２ The compound according to any one of claims 1 to 51, wherein

53. Y ２ but, 52. The compound according to any one of claims 1 to 51, wherein

54. R ３ But, R ａ and R ｂ or a 4- to 10-membered heterocyclyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of R ３ But 1 to 3 R ａ and a monocyclic 4- to 6-membered heterocyclyl optionally substituted by, said heterocyclyl containing at least one ring nitrogen atom. A compound according to any one of claims 1 to 53.

55. R ３ has 1 to 3 R on one or more ring carbon atoms ａ may be substituted with or R ３ But 1 to 3 R ａ may be substituted with or R ３ But 1 to 6 R ａ or a bicyclic 7- to 10-membered heterocyclyl optionally substituted by R ３ But 1 to 3 R ａ may be substituted with or R ３ but, or R ３ but, (for example ) or R ３ but, each of which is selected from the group consisting of 1 to 3 R ａ optionally substituted with, 55. A compound according to any one of claims 1 to 54.

56. Y １ is —O—, n is 1, and Y ２ But -CH ２ - and R ３ But 1 to 3 R ａ may be substituted with 56. The compound of any one of claims 1 to 55,

57. R ３ but, 57. The compound of claim 56, selected from the group consisting of:

58. R ３ but, (for example, 58. The compound of claim 56 or 57, wherein

59. Y １ is —O—, n is 1, and Y ２ but and R ３ But 1 to 3 R ａ The compound according to any one of claims 1 to 48, which is a 5- to 8-membered heterocyclyl optionally substituted by:

60. R ３ but, each of which is selected from the group consisting of 1 to 3 R ａ 60. The compound of claim 59, optionally substituted with:

61. R ４ The compound of any one of claims 1 to 60, wherein is H.

62. R ５ The compound of any one of claims 1 to 61, wherein is -F.

63. R ４ is H and R ５ The compound of any one of claims 1 to 60, wherein is -F.

64. E １ is CH or CR ６ and R ６ 64. The compound of any one of claims 1 or 3-63, wherein is halo (e.g., -F or -Cl).

65. Formula (Aa): or a pharmaceutically acceptable salt thereof, During the ceremony, Ring C is a ring having 1 to 4 R ７ wherein Ring C has 1 ring nitrogen atom, 0 to 1 ring oxygen atoms and no additional ring heteroatoms; Ring B is R ａ and R ｂ C, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of ６～１０ selected from the group consisting of arylene and 5- to 10-membered heteroarylene; a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; The compound of claim 1.

66. E １ is N, CH, or C-halo; Ring C is and is selected from the group consisting of where: c1 is 0, 1, or 2; cc is -(L Ａ１ｂ ) ａ１ｂ represents the point of attachment to -, Each R ７ａ and R ７ｂ are independently selected R ７ and Ring B is and R ２ａ is —OH or —NH ２ and R ２ｂ and R ２ｃ is independently H or halo (e.g., —Cl), and aa is —(L Ａ１ａ ) ａ１ａ - represents the point of attachment to 66. The compound of claim 65.

67. Formula (I-c) or (I-cc): or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; Each R ７ａ and R ７ｂ are independently selected R ７ and a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ２ａ and R ２ｃ are independently H or R ａ and Y ２ is -CH ２ -or and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; 3. The compound of claim 1 or 2.

68. Formula (II-c) or (II-cc): or a pharmaceutically acceptable salt thereof, During the ceremony, E １ is CH or CR ６ and c1 is 0, 1, or 2; Each R ７ａ and R ７ｂ are independently selected R ７ and a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ２ａ and R ２ｃ are independently H or R ａ and Y ２ is -CH ２ -or and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; 4. The compound of claim 1 or 3.

69. Formula (I-d) or (I-dd): or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; Each R ７ａ and R ７ｂ are independently selected R ７ and a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ２ａ and R ２ｃ is independently R ａ and Y ２ is -CH ２ -or and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; 3. The compound according to claim 1 or 2.

70. Formula (II-d) or (II-dd): or a pharmaceutically acceptable salt thereof, During the ceremony, E １ is CH or CR ６ and c1 is 0, 1, or 2; Each R ７ａ and R ７ｂ are independently selected R ７ and a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ２ａ and R ２ｃ is independently R ａ and Y ２ is -CH ２ -or and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; 4. The compound of claim 1 or 3.

71. Formula (I-e) or (I-ee): or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; Each R ７ａ and R ７ｂ are independently selected R ７ and a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ２ｃ is H or R ａ and Y ２ is -CH ２ -or and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; 3. The compound according to claim 1 or 2.

72. Formula (II-e) or (II-ee): or a pharmaceutically acceptable salt thereof, During the ceremony, E １ is CH or CR ６ and c1 is 0, 1, or 2; Each R ７ａ and R ７ｂ are independently selected R ７ and a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ２ｃ is H or R ａ and Y ２ is -CH ２ -or and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; 4. The compound of claim 1 or 3.

73. Formula (If): or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ２ａ and R ２ｃ is independently R ａ and Y ２ is -CH ２ -or and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; 3. The compound according to claim 1 or 2.

74. Formula (II-f): or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ２ａ and R ２ｃ is independently R ａ and Y ２ is -CH ２ -or and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; 4. The compound of claim 1 or 3.

75. Formula (Ig): or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ２ａ and R ２ｃ are independently H or R ａ and Y ２ is -CH ２ -or and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; 3. The compound according to claim 1 or 2.

76. Formula (II-g): or a pharmaceutically acceptable salt thereof, During the ceremony, E １ is CH or CR ６ and c1 is 0, 1, or 2; a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ２ａ and R ２ｃ are independently H or R ａ and Y ２ is -CH ２ -or and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; 4. The compound of claim 1 or 3.

77. Formula (Ih): or a pharmaceutically acceptable salt thereof, During the ceremony, c1 is 0, 1, or 2; a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ２ｃ is H or R ａ and Y ２ is -CH ２ -or and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; 3. The compound according to claim 1 or 2.

78. Formula (II-h): or a pharmaceutically acceptable salt thereof, During the ceremony, E １ is CH or CR ６ and c1 is 0, 1, or 2; a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and R ２ｃ is H or R ａ and Y ２ is -CH ２ -or and R ３ is 1 to 3 R ａ is a 5- to 8-membered heterocyclyl optionally substituted by R ５ is H or halo; 4. The compound of claim 1 or 3.

79. 10. The compound of claim 1 selected from the group consisting of the compounds in Table C1 or a pharmaceutically acceptable salt thereof.

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

81. 81. A method for treating a KRas-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 79 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 80.

82. 81. A method for treating a KRas-associated cancer in a subject in need thereof, comprising: (a) determining that the cancer in the subject has 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 of claim 80.

83. 81. A method of treating a KRas-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a cancer with KRas dysregulation a therapeutically effective amount of a compound of any one of claims 1 to 79 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 80.

84. 1. A method of treating a KRas-associated cancer in a subject, comprising: (a) determining that the cancer in the subject has KRas dysregulation; and (b) administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 79 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 80. The method comprising:

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

86. 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 G12S-associated cancer, or a KRas G12V-associated cancer; or the mutant KRas-associated cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer; or the mutant KRas-associated cancer is a KRas G12D-associated cancer; or the mutant KRas-associated cancer is a KRas G12R-associated cancer; or The mutant KRas-associated cancer is a KRas G12V-associated cancer.

86. The method of claim 85.

87. 85. The method of any one of claims 82 or 84, wherein determining that the cancer in the subject has KRas dysregulation comprises performing an assay to detect the KRas dysregulation (e.g., KRas mutation) in a tumor sample from the subject.

88. 88. The method of claim 87, wherein detecting the KRas dysregulation comprises detecting a KRAS gene having a mutation corresponding to a substitution of glycine 12 in the KRas protein, and / or a KRas protein having a substitution of glycine 12.

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

90. the KRas-associated cancer is selected from the group consisting of blood cancer, 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 cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, urothelial cancer, uterine cancer, and combinations thereof; or The KRas-related cancer is pancreatic cancer.

89. The method of any one of claims 81 to 88.

91. Formula (SI-Aa): or a salt thereof, During the ceremony, Ring C is a ring having 1 to 4 R ７ wherein Ring C has 1 ring nitrogen atom, 0 to 1 ring oxygen atoms and no further ring heteroatoms; R ７ Each of ａ and R ｂ are independently selected from the group consisting of Ring B is R ａ and R ｂ C, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of ６～１０ selected from the group consisting of arylene and 5- to 10-membered heteroarylene; a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and L Ａ１ Each of the is independently —CH ２ --, --CHR Ｌ -, and -C(R Ｌ ) ２ - selected from the group consisting of Each R Ｌ are independently halo, cyano, —OH, —C １～６ Alkoxy, -C １～６ Haloalkoxy, —NR ｄ R ｅ , C(=O)N(R ｆ ) ２ , and 1 to 6 R ｃ C optionally substituted with １～６ independently selected from the group consisting of alkyl, R ３ is 1 to 3 R ａ or -NR ｄ R ｅ (e.g., -NMe ２ ) and Y １ represents a bond, -N(H)-, -N(C １～３ alkyl)-, -N(C ３～６ cycloalkyl)-, —O—, and —S(O) ０～２ - selected from the group consisting of Y ２ is 1 to 6 R Ｙ A linear C optionally substituted with １～６ is alkylene, Each R Ｙ are independently halo, cyano, —OH, oxo, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkyl, and C １～６ haloalkyl; A pair of R on the same or different carbon atoms Ｙ together with the atoms connecting them, represent 1 to 3 independently selected C １～３ C, each of which may be substituted with alkyl ３～６ forming a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, E １ is N, CH, or CR ６ and R ５ is H or halo, R ６ teeth, (a)-H, (b) halo, (c) cyano, (d) C １～６ Alkyl, (e) C １～６ haloalkyl, (f) C １～６ Alkoxy, (g) C １～６ haloalkoxy, (h) C ３～６ The cycloalkyl moiety is 1 to 3 R ｇ -(C ０～３ alkylene)-C ３～６ cycloalkyl, and (i) C ３～６ The cycloalkyl moiety is 1 to 3 R ｇ -O-(C ０～３ alkylene)-C ３～６ cycloalkyl are independently selected from the group consisting of R ａ Each of the (a) halo, (b) cyano, (c) —OH, (d) oxo, (e)-C １～６ Alkoxy, (f)-C １～６ haloalkoxy, (g)-NR ｄ R ｅ 、 (h) C(=O)C １～６ Alkyl, (i) C(=O)C １～６ haloalkyl, (j)C(=O)OH, (k)C(=O)OC １～６ Alkyl, (l)C(=O)OC １～６ haloalkyl, (m)C(=O)N(R ｆ ) ２ 、 (n) S(O) ０～２ (C １～６ alkyl), (o)S(O) ０～２ (C １～６ haloalkyl), (p)S(O) １～２ N (R ｆ ) ２ , and (q) 1 to 6 R ｃ each of which is optionally substituted with １～６ Alkyl, C ２～６ Alkenyl, or C ２～６ Alkynyl are independently selected from the group consisting of R ｂ Each of -(L ｂ ) ｂ -R ｂ１ and -R ｂ１ are independently selected from the group consisting of b is 1, 2, or 3; Each -L ｂ are independently —O—, —N(H)—, —N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ alkylene; R ｂ１ Each of the ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R ｇ may be substituted with Each R ｃ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NR ｄ R ｅ , C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)OH, C(=O)N(R ｆ ) ２ , S(O) ０～２ (C １～６ alkyl), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N (R ｆ ) ２ are independently selected from the group consisting of Each R ｄ and R ｅ is H, C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)N(R ｆ ) ２ , S(O) １～２ (C １～６ alkyl), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N (R ｆ ) ２ , and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, R ｆ Each of the groups is H and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Each R ｇ But independently, R ｈ , C １～３ Alkyl, and C １～３ haloalkyl; Each R ｈ are independently halo, cyano, —OH, —C １～６ Alkoxy, -C １～６ Haloalkoxy, —NH ２ , -N(H)(C １～３ alkyl), and —N(C １～３ alkyl) ２ selected from the group consisting of the compound or a salt thereof, or Formula (SII-Aa): or a salt thereof, During the ceremony, R Ｓ But 1 to 3 R ｃ C optionally substituted with １～６ is alkyl, Ring C is a ring having 1 to 4 R ７ wherein Ring C has 1 ring nitrogen atom, 0 to 1 ring oxygen atoms and no further ring heteroatoms; R ７ Each of ａ and R ｂ are independently selected from the group consisting of Ring B is R ａ and R ｂ C, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of ６～１０ selected from the group consisting of arylene and 5- to 10-membered heteroarylene; a1a and a1b are independently integers from 0 to 5, provided that a1a + a1b is 4, 5, or 6; Each L Ａ１ａ and L Ａ１ｂ are independently selected L Ａ１ and L Ａ１ Each of the is independently —CH ２ --, --CHR Ｌ -, and -C(R Ｌ ) ２ - selected from the group consisting of Each R Ｌ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NR ｄ R ｅ , C(=O)N(R ｆ ) ２ and C optionally substituted with 1 to 6 Rc. １～６ independently selected from the group consisting of alkyl, E １ is N, CH, or CR ６ and R ５ is H or halo, R ６ teeth, (a)-H, (b) halo, (c) cyano, (d) C １～６ Alkyl, (e) C １～６ haloalkyl, (f) C １～６ Alkoxy, (g) C １～６ haloalkoxy, (h) C ３～６ The cycloalkyl moiety is 1 to 3 R ｇ -(C ０～３ alkylene)-C ３～６ cycloalkyl, and (i) C ３～６ The cycloalkyl moiety may be substituted with 1 to 3 Rg groups, ０～３ alkylene)-C ３～６ cycloalkyl are independently selected from the group consisting of R ａ Each of the (a) halo, (b) cyano, (c) —OH, (d) oxo, (e)-C １～６ Alkoxy, (f)-C １～６ haloalkoxy, (g)-NR ｄ R ｅ 、 (h) C(=O)C １～６ Alkyl, (i) C(=O)C １～６ haloalkyl, (j)C(=O)OH, (k)C(=O)OC １～６ Alkyl, (l)C(=O)OC １～６ haloalkyl, (m)C(=O)N(R ｆ ) ２ 、 (n) S(O) ０～２ (C １～６ alkyl), (o)S(O) ０～２ (C １～６ haloalkyl), (p)S(O) １～２ N (R ｆ ) ２ , and (q) 1 to 6 R ｃ each of which is optionally substituted with １～６ Alkyl, C ２～６ Alkenyl, or C ２～６ Alkynyl are independently selected from the group consisting of R ｂ Each of -(L ｂ ) ｂ -R ｂ１ and -R ｂ１ are independently selected from the group consisting of b is 1, 2, or 3; Each -L ｂ are independently —O—, —N(H)—, —N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ alkylene; R ｂ１ Each of the ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R ｇ may be substituted with Each R ｃ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NR ｄ R ｅ , C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)OH, C(=O)N(R ｆ ) ２ , S(O) ０～２ (C １～６ alkyl), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N (R ｆ ) ２ are independently selected from the group consisting of Each R ｄ and R ｅ is H, C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)N(R ｆ ) ２ , S(O) １～２ (C １～６ alkyl), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N (R ｆ ) ２ , and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, R ｆ Each of the groups is H and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Each R ｇ But independently, R ｈ , C １～３ Alkyl, and C １～３ haloalkyl; Each R ｈ are independently halo, cyano, —OH, —C １～６ Alkoxy, -C １～６ Haloalkoxy, —NH ２ , -N(H)(C １～３ alkyl), and —N(C １～３ alkyl) ２ selected from the group consisting of The compound or a salt thereof.

92. Any compound, composition, combination, pharmaceutical composition, method, use, or process substantially as provided herein.

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