Spirocyclic dihydropyranopyridine KRas inhibitors

Abstract

This disclosure provides compounds of formula (Ic) or pharmaceutically acceptable salts thereof that inhibit the 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, for example, increased and / or sustained (e.g., excessive) KRas activation, e.g., KRas activation associated with a mutated 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., human). This disclosure also provides compositions containing compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or compounds of formula (B), or pharmaceutically acceptable salts thereof, as well as methods for using and preparing the same. TIFF2026534205000500.tif29128

Description

[Technical Field]

[0001] Cross-reference of related applications This application is a U.S. Provisional Application No. 63 / 685,160 filed on August 20, 2024; a U.S. Provisional Patent Application No. 63 / 675,512 filed on July 25, 2024; a U.S. Provisional Patent Application No. 63 / 653,043 filed on May 29, 2024; a U.S. Provisional Patent Application No. 63 / 650,239 filed on May 21, 2024; and a U.S. Provisional Patent Application No. 63 / 650,239 filed on March 19, 2024. This invention claims priority to U.S. Provisional Patent Application No. 63 / 567,238; U.S. Provisional Patent Application No. 63 / 559,588 filed on 29 February 2024; U.S. Provisional Patent Application No. 63 / 614,278 filed on 22 December 2023; and U.S. Provisional Patent Application No. 63 / 539,749 filed on 21 September 2023, each of which is incorporated herein by reference in whole.

[0002] Description of the electronically submitted text file This application includes a sequence listing submitted electronically in XML format. The sequence listing XML is incorporated herein by reference. The filename of the XML file created on September 9, 2024, is TRLN-008-017WO1_ST26_SL.xml, and its size is 2,075 bytes.

[0003] Technical field This disclosure provides compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B) or pharmaceutically acceptable salts thereof that inhibit KRas GTPases (e.g., dysregulated KRas GTPases, collectively referred to herein as dysregulated KRas proteins). In some embodiments, the KRas protein is a mutated dysregulated KRas protein (collectively referred to herein as a mutant KRas protein). These compounds are useful in treating diseases, disorders, or conditions in which increased and / or persistent (e.g., excessive) KRas activation, such as KRas activation associated with a mutant KRas protein, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., human). This disclosure also provides compositions containing compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))), or compounds of formula (B), or pharmaceutically acceptable salts thereof, as well as methods for using and preparing the 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 the maintenance of KRas activation (GTP-bound state), for example, due to a deficiency in endogenous GTPase activity and / or insensitivity to GTPase-activating protein (GAP), and consequently 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; mutations at position 13 (hereinafter referred to as G13X), such as G13C, G13D, and G13V; and mutations at position Q61 (hereinafter referred to as Q61X), such as Q61E, Q61H, Q61K, Q61L, Q61P, and Q61R.

[0005] KRas are widely recognized as targets for the design and development of therapies that can specifically bind to and inhibit KRas signaling in cancer cells, but they have long been considered undruggable. Currently, there are very few approved KRas-targeted therapies.

[0006] In some embodiments, the KRas protein is a mutated, dysregulated KRas protein (hereinafter referred to as a mutant KRas protein). These compounds are useful in treating diseases, disorders, or conditions in which increased and / or sustained (e.g., excessive) KRas activation, such as KRas activation associated with the 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., human). This disclosure also provides compositions containing the same, as well as methods for using and producing the same. [Overview of the project]

[0007] overview The present disclosure provides a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d) or (I-e))) or Formula (B), or a pharmaceutically acceptable salt thereof, that inhibits a KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein). These compounds are useful for treating a disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human), wherein increased KRas activation, such as KRas activation associated with mutant KRas protein or KRas activation associated with KRas amplification, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. The present disclosure also provides compositions containing a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e))), or a compound of Formula (B), or a pharmaceutically acceptable salt thereof, as well as methods of using and methods of making the same.

[0008] Provided herein are compounds of Formula (A): TIFF2026534205000002.tif37128, or a pharmaceutically acceptable salt thereof, wherein, E 1 is selected from the group consisting of CH and CR 4 ; R 4 is selected from the group consisting of -CN, halo, C 1-3 alkyl, C 1-3 haloalkyl, and C 3-6 cycloalkyl, R 1 is (i) a 4-10 membered heterocyclyl, which is optionally substituted with 1 to 4 R 7 groups, (ii) TIFF2026534205000003.tif24128, wherein b2 is 0, 1, 2, or 3, and A 1 and A 2 are selected from the group consisting of N, CH, and CR 7(Selected independently from the group consisting of) (iii)-N(R 2 )2(in the formula, each R 2 -H, and 1 to 3 R c Even if replaced by C 1-6 (Independently selected from the group consisting of alkyls), and (iv)-H Selected from the group consisting of, Each R 7 R a and R b Independently selected from the group consisting of, Ring B is The filename is TIFF2026534205000004.tif26128, and in the formula, * is ring B and Both TIFF2026534205000005.tif21128 show a common ring carbon atom, X 1 is a bond, S(O) 0-2 CH2, CHR L , C(R L ) Selected from the group consisting of 2 and O, X 2 and X 3 CH2, CHR L , C(R L )2, O, and S(O) 0-2 Independently selected from the group consisting of, where X 1 , X 2 , and X 3 One or fewer of these are O and S(O) 0-2 The condition is that the group is selected from the group consisting of the following: b1 is 0, 1, or 2. R 9 -H, -OH, -NR d R e Selected from the group consisting of and halos, Each R 10 R a and R b Independently selected from the group consisting of, Each R L C 1-3 Alkoxy, -F, CN, and 1-3 R cEven if replaced by C 1-3 Independently selected from the group consisting of alkyls, or A pair of R on the same or different ring carbon atoms L Together with the ring atoms that connect them, C 3-6 Forming a cycloalkyl ring, Y 2 This is a bond or 1 to 6 R Y Linear C may be substituted with 1-6 It is alkylene, Each R Y These are halo, cyano, -OH, oxo, and C. 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl and C 1-6 Independently selected from the group consisting of haloalkyls, or A pair of R on the same or different carbon atoms Y Together with the atoms that connect them, C 3-6 They form a cycloalkyl ring or a 4-6 membered heterocyclyl ring, each of which has 1-3 independently selected C atoms. 1-3 It may also be substituted with alkyl groups. R 3 teeth, (a)R a and R b A 4-15 member heterocycline which may be substituted with 1-6 substituents independently selected from the group consisting of, and (b)-NR d R e Selected from the group consisting of, Each R a Independently, (a) Hello, (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 1-6alkyl, (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) each of which is optionally substituted with 1 to 6 R c is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, each R b is independently selected from the group consisting of -(L b ) b -R b1 and R b1 , is independently selected from the group consisting of b is 1, 2, or 3, each L b is independently selected from the group consisting of O, N(H), N(C 1-3 alkyl), S(O) 0-2 , C(=O), and C 1-3 alkylene, each R b1 is independently selected from the group consisting of C 3-10 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, and 5 to 10 membered heteroaryl, each of which is optionally substituted with 1 to 3 R g , each R c is selected from halo, cyano, -OH, C 1-6 alkoxy, C 1-6 haloalkoxy, -NR d Re , 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 ) Independently selected from the group consisting of 2, Each R d and R e 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 Even if replaced by C 1-6 Independently selected from the group consisting of alkyls, Each R f This consists of -H and 1 to 3 R h Even if replaced by C 1-6 Independently selected from the group consisting of alkyl and, Each R g R h , C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-5 Independently selected from the group consisting of cycloalkyl and 4-5 membered heterocyclyl, Each R h is halo, cyano, -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NH2, -N(H)(C) 1-3Alkyl), and -N(C 1-3 It is independently selected from the group consisting of alkyl)2.

[0009] Pharmaceutical compositions comprising compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B), or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers are also provided herein.

[0010] A method for treating cancer in a subject in need thereof is provided herein, comprising the step of administering a therapeutically effective amount of a compound of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, to the subject.

[0011] Furthermore, this specification provides a method for treating cancer in a subject where such treatment is needed, the method comprising: (a) determining that the cancer has a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, or a KRas G12V mutation)); and (b) administering a therapeutically effective amount of a compound of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, to the subject.

[0012] A method for treating a subject having a KRas-related disease or disorder (e.g., mutant KRas-related disease or disorder (e.g., KRas G12A-related cancer, KRas G12C-related cancer, KRas G12D-related cancer, KRas G12R-related cancer, KRas G12S-related cancer, or KRas G12V-related cancer)) is provided herein, comprising the step of administering a therapeutically effective amount of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, to a subject identified or diagnosed with a KRas-related disease or disorder.

[0013] This disclosure also provides a method for treating a KRas-related disease or disorder in a subject (e.g., mutant KRas-related disease or disorder (e.g., KRas G12A-related disease or disorder, KRas G12C-related disease or disorder, KRas G12D-related disease or disorder, KRas G12R-related disease or disorder, KRas G12S-related disease or disorder, or KRas G12V-related disease or disorder)) in which the disease or disorder in the subject is treated by the method. The process includes the steps of determining whether the condition is a G12V-related disease or disorder, and administering a therapeutically effective amount of a compound of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0014] Methods for treating target KRas-related cancers (e.g., mutated KRas-related cancers (e.g., KRas G12A-related cancer, KRas G12C-related cancer, KRas G12D-related cancer, KRas G12R-related cancer, KRas G12S-related cancer, or KRas G12V-related cancer)) are further provided herein, and KRas-related cancers (e.g., mutated KRas-related cancers (e.g., KRas G12A-related cancer, KRas G12C-related cancer, mutated KRas-related cancers (e.g., KRas G12D-related cancer, KRas G12R-related cancer, KRas G12S-related cancer, or KRas The procedure includes administering to a subject identified or diagnosed with a G12V-related cancer a therapeutically effective dose of a compound of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0015] This disclosure also provides a method for treating target KRas-related cancers (e.g., mutated KRas-related cancers (e.g., KRas G12A-related cancer, KRas G12C-related cancer, KRas G12D-related cancer, KRas G12R-related cancer, KRas G12S-related cancer, or KRas G12V-related cancer)) in which the target cancer is due to KRas dysregulation (e.g., KRas G12A mutation, KRas G12C mutation, KRas G12D mutation, KRas G12R mutation, KRas G12S mutation, or KRas The process includes the steps of determining that the compound has the G12V mutation, and administering a therapeutically effective amount of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0016] To facilitate understanding of the disclosures described herein, several terms are provided. In general, the nomenclature used herein, as well as 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 have the same meaning as generally understood by those skilled in the art in which this disclosure pertains. Each of the patents, applications, published applications, and other publications referenced herein and in their appendices is incorporated herein in their entirety by reference. In the event of any conflict between this disclosure and any content incorporated by reference, this disclosure shall prevail.

[0017] Details of one or more embodiments of the present invention are described in the accompanying drawings and the following description. Other features and advantages of the present invention will become apparent from the specification and drawings and the claims. [Modes for carrying out the invention]

[0018] Detailed explanation This disclosure provides compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B) or pharmaceutically acceptable salts thereof that inhibit KRas proteins (e.g., dysregulated KRas proteins, e.g., mutant KRas proteins). These compounds are useful, for example, for treating diseases, disorders, or conditions associated with KRas dysregulation (e.g., KRas mutation or amplification) in which increased and / or sustained (e.g., excessive) KRas activation contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., human). These compounds may also be useful for treating diseases, disorders, or conditions in which a mutant KRas protein (e.g., a resistance mutation) confers endogenous resistance to one or more KRas inhibitors (e.g., KRas inhibitors selective for the KRas G12C mutant protein) or non-KRas-targeted therapeutic agents. See, for example, Misale, et al., Nature 486.7404(2012):532-536 and Awad, et al., New England Journal of Medicine 384.25(2021):2382-2393. This disclosure also provides compositions containing the compounds provided herein, as well as methods for using and preparing them.

[0019] The Ras family genes (e.g., KRAS, NRAS, and HRAS) were among 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. The Ras family are guanine nucleotide-binding proteins commonly 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 allow GDP to dissociate from the Ras protein and GTP to bind. When bound to GTP, the Ras protein can interact with effector proteins such as cRAF. Hydrolysis of GTP to form GDP can inactivate Ras proteins, and this hydrolysis can be achieved via intrinsic GTPase activity, which can be enhanced by binding to GTPase-activating protein (GAP). Humans have three major RAS proteins: KRas, HRas, and NRas.

[0020] Some oncogenic KRas missense mutations can prevent or delay GTP hydrolysis, leading to the accumulation of active KRas. KRas-related 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.

[0021] Mutant KRas proteins often possess altered Raf affinity and / or altered endogenous GTPase activity. See, for example, Table 1, reproduced from Hunter et al. Mol Cancer Res. 2015;13(9):1325-35. These changes and other factors may contribute to increased KRas signaling in mutant KRas proteins.

[0022] [Table 1]

[0023] KRas inhibitors are described, for example, in International Publication Nos. 2024 / 112654, 2023 / 154766, 2023 / 143623, 2022 / 240971, 2020 / 236940, 2022 / 115439, 2023 / 086383, 2021 / 093758, 2022 / 135546, 2021 / 139748, 2022 / 251576, and 2023 / 025116.

[0024] Further examples of KRas inhibitors are, for example, International Publication Nos. 2022 / 132200, 2022 / 133038, 2023 / 150284, 2022 / 261154, 2023 / 183585, 2023 / 099592, 2023 / 099623, 2023 / 099624, 2023 / 099608, and 2022 / 2 International Publication No. 50170, International Publication No. 2022 / 173870, International Publication No. 2022 / 236578, International Publication No. 2022 / 237649, International Publication No. 2022 / 248885, International Publication No. 2022 / 256459, International Publication No. 2022 / 258974, International Publication No. 2022 / 266015, International Publication No. 2023 / 018809, International Publication No. 2023 / 018810, International Publication No. 2023 / 018812, International Publication International Publication No. 2023 / 020518, International Publication No. 2023 / 020519, International Publication No. 2023 / 020521, International Publication No. 2023 / 020523, International Publication No. 2023 / 046135, International Publication No. 2023 / 061294, International Publication No. 2023 / 097227, International Publication No. 2023 / 114733, International Publication No. 2023 / 137223, International Publication No. 2023 / 141300, International Publication No. 2023 / 13858 This is described in Patent No. 3, International Publication Nos. 2023 / 159086, 2023 / 159087, 2023 / 173016, 2023 / 173017, 2023 / 179703, 2023 / 125627, 2022 / 216762, 2024 / 030633, 2023 / 230190, and Chinese Patent No. 116143806.

[0025] Embodiments of the compound Provided herein is formula (A): A compound of TIFF2026534205000007.tif37128, or a pharmaceutically acceptable salt thereof, wherein the formula is: E 1 CH and CR 4 Selected from the group consisting of R 4 -CN, Haro, C1-3 Alkyl, C 1-3 Haloalkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 1 teeth, (i) 1 to 4 R 7 A 4-10 member heterocycline which may be substituted with (ii) TIFF2026534205000008.tif24128(In the formula, b2 is 0, 1, 2, or 3, A 1 and A 2 These are N, CH, and CR 7 (Selected independently from the group consisting of) (iii)-N(R 2 )2(in the formula, each R 2 -H, and 1 to 3 R c Even if replaced by C 1-6 (Independently selected from the group consisting of alkyls), and (iv)-H Selected from the group consisting of, Each R 7 R a and R b Independently selected from the group consisting of, Ring B is The filename is TIFF2026534205000009.tif26128, and in the formula, * is ring B and Both TIFF2026534205000010.tif21128 show a common ring carbon atom, X 1 is a bond, S(O) 0-2 CH2, CHR L , C(R L ) Selected from the group consisting of 2 and O, X 2 and X 3 CH2, CHR L , C(R L )2, O, and S(O) 0-2 Independently selected from the group consisting of, where X 1 , X 2 , and X 3 One or fewer of these are O and S(O)0-2 The condition is that the group is selected from the group consisting of the following: b1 is 0, 1, or 2. R 9 -H, -OH, -NR d R e Selected from the group consisting of and halos, Each R 10 R a and R b Independently selected from the group consisting of, Each R L C 1-3 Alkoxy, -F, CN, and 1-3 R c Even if replaced by C 1-3 Independently selected from the group consisting of alkyls, or A pair of R on the same or different ring carbon atoms L Together with the ring atoms that connect them, C 3-6 Forming a cycloalkyl ring, Y 2 This is a bond or 1 to 6 R Y Linear C may be substituted with 1-6 It is alkylene, Each R Y These are halo, cyano, -OH, oxo, and C. 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl and C 1-6 Independently selected from the group consisting of haloalkyls, or A pair of R on the same or different carbon atoms Y Together with the atoms that connect them, C 3-6 They form a cycloalkyl ring or a 4-6 membered heterocyclyl ring, each of which has 1-3 independently selected C atoms. 1-3 It may also be substituted with alkyl groups. R 3 teeth, (a)R a and R b A 4-15 member heterocycline which may be substituted with 1-6 substituents independently selected from the group consisting of, and (b)-NR d R e Selected from the group consisting of, Each R a Independently, (a) Hello, (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 them is replaced in C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Selected from the group consisting of alkinyl, Each R b is, -(L b ) b -R b1 and R b1 Independently selected from the group consisting of, b is 1, 2, or 3. Each L b O, N(H), N(C) 1-3 Alkyl), S(O) 0-2, C(=O), and C 1-3 Independently selected from the group consisting of alkylenes, Each R b1 C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 They are independently selected from the group consisting of aryls and 5-10 membered heteroaryls, each of which has 1-3 R g It may also be replaced 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 ) Independently selected from the group consisting of 2, Each R d and R e 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 Even if replaced by C 1-6 Independently selected from the group consisting of alkyls, Each R f This consists of -H and 1 to 3 R hEven if replaced by C 1-6 Independently selected from the group consisting of alkyl and, Each R g R h , C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-5 Independently selected from the group consisting of cycloalkyl and 4-5 membered heterocyclyl, Each R h is halo, cyano, -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NH2, -N(H)(C) 1-3 Alkyl), and -N(C 1-3 It is independently selected from the group consisting of alkyl)2.

[0026] In some embodiments of formula (A), E 1 CH and CR 4 Selected from the group consisting of R 4 -CN, Haro, C 1-3 Alkyl, C 1-3 Haloalkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 1 teeth, (i) 1 to 4 R 7 A 4-10 member heterocyclyl which may be substituted with, and (ii) TIFF2026534205000011.tif24128(In the formula, b2 is 0, 1, 2, or 3, A 1 and A 2 These are N, CH, and CR 7 (Independently selected from the group consisting of), selected from the group consisting of, Each R 7 R a and R b Independently selected from the group consisting of, Ring B is The filename is TIFF2026534205000012.tif26128, and in the formula, * is ring B and Both TIFF2026534205000013.tif18128 show a common ring carbon atom, X 1 is a bond, S(O) 0-2 CH2, CHR L , C(R L ) Selected from the group consisting of 2 and O, X 2 and X 3 CH2, CHR L , C(R L )2, O, and S(O) 0-2 Independently selected from the group consisting of, where X 1 , X 2 , and X 3 One or fewer of these are O and S(O) 0-2 The condition is that the group is selected from the group consisting of the following: b1 is 0, 1, or 2. R 9 -H, -OH, -NR d R e Selected from the group consisting of and halos, Each R 10 R a and R b Independently selected from the group consisting of, Each R L C 1-3 Alkoxy, -F, CN, and 1-3 R c Even if replaced by C 1-3 Independently selected from the group consisting of alkyls, or A pair of R on the same or different ring carbon atoms L Together with the ring atoms that connect them, C 3-6 Forming a cycloalkyl ring, Y 2 This is a bond or 1 to 6 R Y Linear C may be substituted with 1-6 It is alkylene, Each R Y These are halo, cyano, -OH, oxo, and C. 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl and C 1-6Independently selected from the group consisting of haloalkyls, or A pair of R on the same or different carbon atoms Y Together with the atoms that connect them, C 3-6 They form a cycloalkyl ring or a 4-6 membered heterocyclyl ring, each of which has 1-3 independently selected C atoms. 1-3 It may also be substituted with alkyl groups. R 3 teeth, (a)R a and R b A 4-15 member heterocycline which may be substituted with 1-6 substituents independently selected from the group consisting of, and (b)-NR d R e Selected from the group consisting of, Each R a Independently, (a) Hello, (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 them is replaced in C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Selected from the group consisting of alkinyl, Each R b is, -(L b ) b -R b1 and R b1 Independently selected from the group consisting of, b is 1, 2, or 3. Each-L b -O-, -N(H)-, -N(C 1-3 Alkyl)-, -S(O) 0-2 -, C(=O), and C 1-3 Independently selected from the group consisting of alkylenes, Each R b1 C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 They are independently selected from the group consisting of aryls and 5-10 membered heteroaryls, each of which has 1-3 R g It may also be replaced 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 ) Independently selected from the group consisting of 2, Each R d and R e H, C(=O)C 1-6 Alkyl, C(=O)C1-6 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 Even if replaced by C 1-6 Independently selected from the group consisting of alkyls, Each R f H and 1 to 3 R h Even if replaced by C 1-6 Independently selected from the group consisting of alkyl and, Each R g R h , C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-5 Independently selected from the group consisting of cycloalkyl and 4-5 membered heterocyclyl, Each R h These 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 Selected from the group consisting of alkyl(2).

[0027] In some embodiments, the compound of formula (A) is of formula (I): The compound TIFF2026534205000014.tif38128, or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments of formula (A) (for example, formula (I)), R 9 -OH and -NR d R e It is selected from the group consisting of the following.

[0029] In some embodiments of formula (A) (for example, formula (I)), R9 -NR d R e That is the case.

[0030] In some embodiments of formula (A) (for example, formula (I)), R 9 It is -NH2.

[0031] In some embodiments of formula (A) (for example, formula (I)), b1 is 1 or 2.

[0032] In some embodiments of formula (A) (for example, formula (I)), each R 10 These are -Cl, -F, -CN, and 1 to 3 R c Even if replaced by C 1-3 Alkyl (for example, C which may be substituted with 1 to 3 -F atoms) 1-3 It is independently selected from the group consisting of alkyls.

[0033] In some embodiments, the compound of formula (A) (for example, formula (I)) is formula (Ia): A compound of TIFF2026534205000015.tif38128, or a pharmaceutically acceptable salt thereof, wherein the formula is: b1 is either 1 or 2.

[0034] In some embodiments of equation (Ia), each R 10 These are -Cl, -F, -CN, and 1 to 3 R c Even if replaced by C 1-3 Alkyl (for example, C which may be substituted with 1 to 3 -F atoms) 1-3 It is independently selected from the group consisting of alkyls. In some embodiments of formula (Ia), b1 is 1.

[0035] In some embodiments, the compound of formula (A) (for example, formula (I)) is formula (Ib): A compound of TIFF2026534205000016.tif38128, or a pharmaceutically acceptable salt thereof, wherein the formula is: b4 is either 0 or 1. R10 These are -Cl, -F, -CN, and 1 to 3 R c Even if replaced by C 1-3 Alkyl (for example, C which may be substituted with 1 to 3 -F atoms) 1-3 Selected from the group consisting of alkyl groups.

[0036] In some embodiments of equation (Ib), R 9 -NR d R e (For example, -NH2). In some embodiments of equation (Ib), b4 is 0.

[0037] In some embodiments of equation (Ib), R 9 -NR d R e (For example, -NH2), and b4 is 0.

[0038] In some embodiments, the compound of formula (A) (e.g., formula (I)) is formula (Ic): A compound of TIFF2026534205000017.tif38128 or a pharmaceutically acceptable salt thereof, wherein the formula is: b4 is either 0 or 1. R 10 These are -Cl, -F, -CN, and 1 to 3 R c Even if replaced by C 1-3 Alkyl (for example, C which may be substituted with 1 to 3 -F atoms) 1-3 Selected from the group consisting of alkyl groups.

[0039] In some embodiments of equation (Ic), b4 is 0.

[0040] In some embodiments of compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), or (Ic))), X 1 It is -CH2-.

[0041] In some embodiments of compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), or (Ic))), X2 and X 3 -CH2-, -CHR L -, -C(R L It is independently selected from the group consisting of )2- and -O-.

[0042] In some embodiments of compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), or (Ic))), X 1 It is -CH2- and X 2 and X 3 All of these are -CH-2-.

[0043] In some embodiments of compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), or (Ic))), X 1 It is -CH2-, X 2 It is -CH2- and X 3 However, -CHR L -In some embodiments, R L The group is selected from -CH3, -CF3, -CHF2, and -CH2F (for example, -CH3).

[0044] In some embodiments of compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), or (Ic))), X 1 It is -CH2- and X 2 is -O- and X 3 -CH2-, -CHR L -Selected from the group consisting of -C(R L )2-(For example, X 3 is, -CH 2- or -CHR L Selected from the group consisting of -).

[0045] In some embodiments of compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), or (Ic))), each R L The group is independently selected from the group consisting of -CH3, -CF3, -CHF2, and -CH2F (for example, -CH3).

[0046] In some embodiments of compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), or (Ic))), X 1 -CHR L - and X 2 is -O- or -CH2-, X 3 ha-CHR L -and here, R L The pair, together with the ring atom connecting them, C 3-4 (For example, C4) forms a cycloalkyl ring. For example, The part TIFF2026534205000018.tif29128 It could be TIFF2026534205000019.tif28128.

[0047] In some embodiments, the compound of formula (A) (e.g., formula (I)) is formula (Id): A compound of TIFF2026534205000020.tif38128, or a pharmaceutically acceptable salt thereof, wherein the formula is: X 1 This is a bond, -S(O) 0-2 -, -CH2-, -CHR L -, -C(R L Selected from the group consisting of )2- and -O-, X 2 and X 3 -CH2-, -CHR L -, -C(R L )2-, -O-, and -S(O) 0-2 Independently selected from the group consisting of, however, X 1 , X 2 , and X 3 At least one of them is -CHR L -or -C(R L )2, X 1 , X 2 , and X 3 One or fewer of these are -O- and -S(O) 0-2 - Selected from the group consisting of these.

[0048] In some embodiments of formula (Id), X 1 is -CH2-, X 2 It is -CH2- and X 3 However, -CHR L - is

[0049] In some embodiments of equation (Id), R L The group is selected from the group consisting of -CH3, -CF3, -CHF2, and -CH2F (for example, CH3).

[0050] In some embodiments of formula (Id), X 1 is -CH2-, X 2 It is -CH2- and X 3 -CHR L - and R L The group is selected from -CH3, -CF3, -CHF2, and -CH2F (for example, -CH3).

[0051] In some embodiments, the compound of formula (A) (e.g., formula (I)) is formula (Ie): A compound of TIFF2026534205000021.tif38128, or a pharmaceutically acceptable salt thereof, wherein the formula is: X 1 This is a bond, -S(O) 0-2 -, -CH2-, -CHR L -, -C(R L Selected from the group consisting of )2- and -O-, X 2 and X 3 -CH2, -CHR L , -C(R L )2, -O-, and -S(O) 0-2 Independently selected from the group consisting of, where X 1 , X 2 , and X 3 Two to three of these are independently -CHR L or -C(R L ) Provided that it is 2, A pair of R on the same or different ring carbon atoms LTogether with the ring atoms that connect them, C 3-6 Forming a cycloalkyl ring, Each additional R L C 1-3 Alkoxy, -F, CN, and 1-3 R c Even if replaced by C 1-3 Alkyl (for example, C which may be substituted with 1 to 3 -F atoms) 1-3 It is independently selected from the group consisting of alkyls.

[0052] In some embodiments of equation (Ie), X 2 is -CH2- or -O- (for example, -CH2-).

[0053] In some embodiments of equation (Ie), X 1 ha-CHR L - is X 3 ha-CHR L - and the pair R L Together with the ring atoms that connect them, C 3-4 (For example, it forms a C4)cycloalkyl ring.

[0054] In some embodiments of formula (Id) or (Ie), R 9 -NR d R e (For example, -NH2).

[0055] In some embodiments of formula (Id) or (Ie), b1 is 1 or 2, and each R 10 These are -Cl, -F, -CN, and 1 to 3 R c Even if replaced by C 1-3 Alkyl (for example, C which may be substituted with 1 to 3 -F atoms) 1-3 It is independently selected from the group consisting of alkyls.

[0056] In some embodiments of formula (Id) or (Ie), The part TIFF2026534205000022.tif28128 is The file is TIFF2026534205000023.tif28128, and in the formula, b4 is 0 or 1, R 10 These are -Cl, -F, -CN, and 1 to 3 R c Even if replaced by C 1-3 Alkyl (for example, C which may be substituted with 1 to 3 -F atoms) 1-3 Selected from the group consisting of alkyls. In some embodiments, b4 is 0.

[0057] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), E 1 It is CH.

[0058] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), E 1 CR 4 For example, E 1 This could be a CF.

[0059] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie)), Y 2 is -CH2-, and R 3 However, it is a 4-10 membered heterocycline having one ring nitrogen atom and 0-1 additional ring heteroatoms selected from the group consisting of oxygen and nitrogen, and the heterocycline has 1-6 R a It may be replaced with .

[0060] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie)), Y 2 is -CH2-, and R 3 is -F, C 1-3 Alkoxy, and C 1-3 They may be substituted with one or two substituents independently selected from the group consisting of haloalkoxys. The filename is TIFF2026534205000024.tif18128.

[0061] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie)), Y 2 is -CH2-, and R 3 It may be replaced by 1 or 2 -F values. It is TIFF2026534205000025.tif18128 (for example, R 3 teeth, (This is TIFF2026534205000026.tif25128).

[0062] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 3 teeth, TIFF2026534205000027.tif24128 (for example, This is TIFF2026534205000028.tif24128.

[0063] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie)), R 1 teeth The file is TIFF2026534205000029.tif24128, where b2 is 0, 1, or 2, and A 1 and A 2 These are N, CH, and CR 7 It is independently selected from the group consisting of [the specified elements].

[0064] In some embodiments of formula A (e.g., formula I) (e.g., formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie)), R 1 teeth The filename is TIFF2026534205000030.tif27128.

[0065] In some embodiments of formula A (e.g., formula I) (e.g., formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie)), R 1 teeth The filename is TIFF2026534205000031.tif27128. R 7a is -C(=O)N(R f )2, -C(=O)N(C 1-3 Alkyl)R b1 -C(=O)N(H)R b1 , R b1 , and -C(=O)R b1 Selected from the group consisting of, R 7b This includes halo, cyano, and 1-3 R c Even if replaced by C 1-3 Alkyl (for example, C which may be substituted with 1 to 3 -F atoms) 1-3 Selected from the group consisting of alkyl groups.

[0066] In some embodiments, R 7a The following: (a)-C(=O)N(R f )2(in the formula, each R f These are independently H, or 1 to 3 R h Even if replaced by C 1-3 It is alkyl; (b)-C(=O)N(C 1-3 Alkyl)R b1 Or -C(=O)N(H)R b1 (In the formula, R b1 C 3-6 They are cycloalkyl or 4-6 membered heterocyclines, each containing 1-3 R groups. g It may be replaced with); and (c)-C(=O)R b1 (In the formula, R b1 This is 1 to 3 R g A 4-10 member heterocyclyl which may be substituted with R b1 The group is selected from those that are bonded to C(=O) via a cyclic nitrogen atom.

[0067] In some embodiments, R 7b is a halo or C 1-3 It is an alkyl group (for example, -F, -Cl, or methyl).

[0068] In some embodiments, R 7a C(=O)N(R f )2, and each R f These are independently H, or 1 to 3 R h Even if replaced by C 1-3 It is alkyl.

[0069] In some embodiments, R 7b This is a halo (for example, -Cl).

[0070] In some embodiments of formula A (e.g., formula I) (e.g., formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie)), R 1 teeth The file is TIFF2026534205000032.tif31128, and in the formula, each R f These are independently 1 to 3 R h Even if replaced by C 1-3 It is alkyl. For example, R 1 teeth, It could be TIFF2026534205000033.tif31128.

[0071] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 This is a 7-10 (e.g., 7) membered heterocycline having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, where the 7-10 membered heterocycline has 1-4 R 7 It may be replaced by. In some embodiments, each R 7 It consists of -OH, -CN, -F, and 1 to 3 R c Even if replaced by C 1-3 Independently selected from the group consisting of alkyl, R 7Each R that exists above c The group is independently selected from the group consisting of -F, -OH, and -CN.

[0072] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 This is a 7-10 (e.g., 7) member monocyclic heterocycline having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, where the 7-10 member monocyclic heterocycline has 1-4 (e.g., 1-2) R 7 It may be replaced by. In some embodiments, each R 7 It consists of -OH, -CN, -F, and 1 to 3 R c Even if replaced by C 1-3 Independently selected from the group consisting of alkyl, R 7 Each R that exists above c The group is independently selected from the group consisting of -F, -OH, and -CN.

[0073] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 This refers to 1 to 4 R atoms in one or more ring carbon atoms. 7 It may be replaced with This is TIFF2026534205000034.tif21128. In some embodiments, each R 7 It consists of -OH, -CN, -F, and 1 to 3 R c Even if replaced by C 1-3 Independently selected from the group consisting of alkyl, R 7 Each R that exists above c The group is independently selected from the group consisting of -F, -OH, and -CN.

[0074] In some embodiments of formula A (e.g., formula I) (e.g., formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie)), R 1 teeth The filename is TIFF2026534205000035.tif21128.

[0075] In some embodiments of formula (A) (for example, formula (I) (for example, formulas (Ia), (Ib), (Ic), (Id), or (Ie))), each R 7 It consists of -OH, -CN, -F, and 1-3 R c Even if replaced by C 1-3 Independently selected from the group consisting of alkyl, R 7 Each R that exists above c The group is independently selected from the group consisting of -F, -OH, and -CN.

[0076] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 teeth TIFF2026534205000036.tif21128 (for example) TIFF2026534205000037.tif21128) and in the formula, R 7 This is 1 to 3 R g It is a 5-membered heteroaryl which may be substituted with R. In some embodiments, 7 This is 1-2 R g It is a pyrazolyl which may be substituted with (for example, R 7 is one R g It may be replaced with (TIFF2026534205000038.tif11128). Or, R 7 This is one R g It is an oxazolyl which may be substituted with (for example, R 7 This is one R g It may be replaced with (TIFF2026534205000039.tif13128). In some embodiments, R 7 teeth, The filename is TIFF2026534205000040.tif14128.

[0077] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 This is a 7-10 (e.g., 7) membered spirocyclic bicyclic heterocycline having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, where the 7-10 membered spirocyclic bicyclic heterocycline has 1-4 (e.g., 1-2) R 7 It may be replaced with .

[0078] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 teeth, The compound is TIFF2026534205000041.tif23128, where ring A1 is a 4- to 7-membered heterocyclyl ring having one ring oxygen atom and no additional ring heteroatoms. n4 is 0, 1, or 2, n5 is 0, 1, or 2, however n4+n5 is 0, 1, or 2, as described in any one of Embodiments 1-8 or 22-23. In some embodiments, each R 7 It consists of -OH, -CN, -F, and 1 to 3 R c Even if replaced by C 1-3 Independently selected from the group consisting of alkyl, R 7 Each R that exists above c The group is independently selected from the group consisting of -F, -OH, and -CN.

[0079] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 This is 1-2 R 7 It may be replaced with The filename is TIFF2026534205000042.tif16128. For example, R 1 teeth, It could be TIFF2026534205000043.tif16128.

[0080] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 teeth, The filename is TIFF2026534205000044.tif17128, and each of these contains 1 to 2 R values. 7 It may be replaced with R. 1 teeth TIFF2026534205000045.tif16128 (for example, TIFF2026534205000046.tif17128) or TIFF2026534205000047.tif16128 (for example, This could be TIFF2026534205000048.tif17128).

[0081] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 This is a 4- to 7 (e.g., 4 or 7) membered heterocyclil having one ring nitrogen atom, or having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, where a 4- to 7 membered monocyclic heterocyclil is 1- to 4 (e.g., 1-2) R 7 It may be replaced by. In some embodiments, each R 7 It consists of -OH, -CN, -F, and 1 to 3 R c Even if replaced by C 1-3 Independently selected from the group consisting of alkyl, R 7 Each R that exists above c R is independently selected from the group consisting of -F, -OH, and -CN. In some embodiments, R 1 It is a monocyclic heterocycline. In some embodiments, R 1 It is a spirocyclic bicyclic heterocycline.

[0082] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R1 This is 1 to 4 (for example, 1 to 2) R 7 It may be replaced with This is TIFF2026534205000049.tif16128. In some embodiments, each R 7 It consists of -F, -CN, -OH, and 1 to 3 R c Even if replaced by C 1-3 alkyl;-C(=O)N(R f )2 and R b1 Independently selected from the group consisting of R b1 This is 1-2 R g It is a 5-6 member heteroaryl which may be substituted with R. In some embodiments, each R 7 -F, -CN, -OH, R b1 (In the formula, R b1 However, 1-2 R g A 5-6 member heteroaryl that may be substituted with C, which may be substituted with 1-3 -F. 1-3 Alkyl, -OH, or C 1-3 alkoxy-substituted C 1-3 alkyl; and C(=O)N(R f It is independently selected from the group consisting of )2.

[0083] In some embodiments of formula A (e.g., formula I) (e.g., formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie)), R 1 teeth, TIFF2026534205000050.tif16128 (for example, TIFF2026534205000051.tif16128) or This is TIFF2026534205000052.tif16128. In some embodiments, each R 7 It consists of -F, -CN, -OH, and 1 to 3 R c Even if replaced by C 1-3 alkyl;-C(=O)N(R f )2 and R b1 Independently selected from the group consisting of R b1 This is 1-2 R gIt is a 5-6 member heteroaryl which may be substituted with R. In some embodiments, each R 7 -F, -CN, -OH, R b1 (In the formula, R b1 However, 1-2 R g A 5-6 member heteroaryl that may be substituted with C, which may be substituted with 1-3 -F. 1-3 Alkyl, -OH, or C 1-3 alkoxy-substituted C 1-3 alkyl; and C(=O)N(R f It is independently selected from the group consisting of )2.

[0084] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 teeth TIFF2026534205000053.tif16128 (for example) TIFF2026534205000054.tif15128) and in the formula, R 7 is -OH or C 1-3 Alkoxy (for example, C substituted with -OH) 1-3 C substituted with alkyl 1-3 It is alkyl.

[0085] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 teeth TIFF2026534205000055.tif16128 (for example) This is TIFF2026534205000056.tif16128).

[0086] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 teeth The file is TIFF2026534205000057.tif18128, and in the formula, each R 7C may be replaced by 1 to 3 -F values. 1-3 Alkyl and -OH or C 1-3 alkoxy-substituted C 1-3 It is independently selected from the group consisting of alkyl groups.

[0087] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 teeth TIFF2026534205000058.tif18128 (for example) TIFF2026534205000059.tif18128) and here, R 7a C is a C substituted with -OH. 1-3 It is an alkyl group (for example, -CH2OH). 7b teeth, (a) C which may be replaced by 1 to 3 F 1-3 Alkyl (e.g., methyl), (b)-OH or C 1-3 alkoxy-substituted C 1-3 Alkyl, It is selected from the group consisting of the following.

[0088] In some embodiments of formula A (e.g., formula I) (e.g., formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie)), R 1 teeth, TIFF2026534205000060.tif16128 (for example, TIFF2026534205000061.tif16128) or The filename is TIFF2026534205000062.tif16128.

[0089] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 In the ring carbon atoms, -CN and -(C 1-3 Alkylene)-CN, or -(C 3-6A 4- to 10-membered heterocycline substituted with cycloalkylene)-CN, where the heterocycline has 1-3 R groups. 7 It may be further replaced by R. In some embodiments, each R 7 It consists of -OH, -CN, -F, and 1 to 3 R c Even if replaced by C 1-3 Alkyl (for example, C which may be substituted with 1 to 3 -F atoms) 1-3 It is independently selected from the group consisting of alkyls.

[0090] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 In the ring carbon atom, -CN or -(C 1-3 A 6- to 8-membered heterocycline substituted with alkylene)-CN, where the heterocycline has one ring nitrogen atom and 0-1 ring oxygen atoms; the heterocycline has 1-3 R 7 It may be further replaced by R. In some embodiments, each R 7 It consists of -OH, -CN, -F, and 1 to 3 R c Even if replaced by C 1-3 Alkyl (for example, C which may be substituted with 1 to 3 -F atoms) 1-3 It is independently selected from the group consisting of alkyls.

[0091] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 teeth TIFF2026534205000063.tif29128 (for example) This is TIFF2026534205000064.tif29128.

[0092] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie))), R 1 is -N(R 2 )2. In some embodiments, each R2 These are independently methyl or ethyl, and have 1 to 3 R c It may also be replaced with R 2 Each R present above c is -F, cyano, -OH, C 1-6 Alkoxy and C 1-6 It is independently selected from the group consisting of haloalkoxys.

[0093] In some embodiments of formula (A) (for example, formula (I) (for example, formulas (Ia), (Ib), (Ic), (Id), or (Ie)), * The labeled ring carbon atoms have (S)-stereochemistry.

[0094] In some embodiments of formula (A) (for example, formula (I) (for example, formula (Ia), (Ib), (Ic), (Id), or (Ie)), The part TIFF2026534205000065.tif27128 The filename is TIFF2026534205000066.tif29128.

[0095] In some embodiments, the compound of formula (Ic) is formula (I-c1) or (I-c2): A compound of TIFF2026534205000067.tif103128, or a pharmaceutically acceptable salt thereof, wherein the formula is: E 1 CH is, b4 is either 0 or 1. R 10 These are -Cl, -F, -CN, and 1 to 3 R c Even if replaced by C 1-3 Selected from the group consisting of alkyl groups, X 1 It is -CH2-, X 2 and X 3 -O-, -CH2-, -CHR L -, and -C(R L )Independently selected from the group consisting of 2, R 7a teeth, (a)-C(=O)N(R f )2(in the formula, each R f These are independently -H or 1 to 3 R h Even if replaced by C 1-3 It is alkyl; (b)-C(=O)N(C 1-3 Alkyl)R b1 Or -C(=O)N(H)R b1 (In the formula, R b1 C 3-6 These are cycloalkyl or 4-6 membered heterocyclyl groups, each containing 1-3 R groups. g (May be replaced by) (c)-C(=O)R b1 (In the formula, R b1 This is 1 to 3 R g A 4-10 member heterocyclyl which may be substituted with R b1 This is selected from the group consisting of those bonded to C(=O) via a cyclic nitrogen atom, R 7b is a halo or C 1-3 It is an alkyl group (for example, -F, -Cl, or methyl).

[0096] In some embodiments of formula (I-c1) or (I-c2), b4 is 0.

[0097] In some embodiments of formula (I-c1) or (I-c2), X 2 is -CH2-;X 3 -CH2- or -CHR L - is

[0098] In some embodiments of formula (I-c1) or (I-c2), X 2 is -CH2-;X 3 However, it is CH2-.

[0099] In some embodiments of formula (I-c1) or (I-c2), X 2 is -CH2-;X 3 However, -CHR L - is

[0100] In some embodiments of formula (I-c1) or (I-c2), X 2 is -CH2-;X 3 However, it is -CHMe-.

[0101] In some embodiments of formula (I-c1) or (I-c2), R 7a is -C(=O)N(R f )2, and each R f C is selected independently 1-3 It is alkyl, R 7b is -F, -Cl, or methyl. For example, R 7a This can be -C(=O)N(Me)2, and R 7b This can be -F, -Cl, or methyl.

[0102] In some embodiments, the compound of formula (Ic) is formula (I-c3) or (I-c4): A compound of TIFF2026534205000068.tif79128, or a pharmaceutically acceptable salt thereof, wherein the formula is: E 1 CH is, R 7 C is a C substituted with -OH. 1-3 It is alkyl, b4 is either 0 or 1 (for example, 0), R 10 These are -Cl, -F, -CN, and 1 to 3 R c Even if replaced by C 1-3 Selected from the group consisting of alkyl groups, X 1 It is -CH2-, X 2 and X 3 -O-, -CH2-, -CHR L -, and -C(R L ) is independently selected from the group consisting of 2.

[0103] In some embodiments of formula (I-c3) or (I-c4), X 2 is -CH2-, X 3-CH2- or -CHR L - is

[0104] In some embodiments of formula (I-c3) or (I-c4), X 2 is -CH2-, X 3 However, it is CH2-.

[0105] In some embodiments of formula (I-c3) or (I-c4), X 2 is -CH2-, X 3 However, -CHR L - is

[0106] In some embodiments of formula (I-c3) or (I-c4), X 2 is -CH2-, X 3 However, it is -CHMe-.

[0107] In some embodiments of formula (I-c4), The part TIFF2026534205000069.tif16128 The filename is TIFF2026534205000070.tif16128.

[0108] In some embodiments of equation (I-c4), R 7 It is -CH2OH.

[0109] In some embodiments of formulas (I-c1), (I-c2), (I-c3), or (I-c4), Y 2 is -CH2-, and R 3 is -F, C 1-3 Alkoxy, and C 1-3 They may be substituted with one or two substituents independently selected from the group consisting of haloalkoxys. The filename is TIFF2026534205000071.tif19128.

[0110] In some embodiments of formulas (I-c1), (I-c2), (I-c3), or (I-c4), Y 2 is -CH2-, and R 3It may be replaced by 1 or 2 Fs. The filename is TIFF2026534205000072.tif19128.

[0111] In some embodiments of formulas (I-c1), (I-c2), (I-c3), or (I-c4), R 3 teeth TIFF2026534205000073.tif24128 (for example) This is TIFF2026534205000074.tif24128.

[0112] In some embodiments of formulas (I-c1), (I-c2), (I-c3), or (I-c4), The part TIFF2026534205000075.tif27128 The filename is TIFF2026534205000076.tif29128.

[0113] In some embodiments, the compound of formula (A) or formula (I) is selected from the group consisting of the compounds shown in Table C1 or pharmaceutically acceptable salts thereof.

[0114] [Table C1] TIFF2026534205000078.tif241132TIFF2026534205000079.tif241132TIFF2026534205000080.tif230132TIFF2026534205000081.tif215132TIFF2026534205000082.tif215132TIFF2026534205000083.tif244132TIFF2026534205000084.tif215132TIFF2026534205000085.tif247132TIFF2026534205000086.tif226132TIFF2026534205000087.tif227132TIFF2026534205000088.tif238132TIFF2026534205000089.tif212132TIFF2026534205000090.tif200132TIFF2026534205000091.tif214132TIFF2026534205000092.tif212132TIFF2026534205000093.tif208132TIFF2026534205000094.tif208132TIFF2026534205000095.tif225132TIFF2026534205000096.tif225132TIFF2026534205000097.tif246132TIFF2026534205000098.tif221132TIFF2026534205000099.tif210132TIFF2026534205000100.tif222132TIFF2026534205000101.tif221132TIFF2026534205000102.tif213132TIFF2026534205000103.tif217132TIFF2026534205000104.tif83132

[0115] For certain compounds in Table C1, one or more stereocenters are indicated by "V3000 enhanced stereochemical notation" (each in its entirety incorporated herein by reference; see support.collaborativedrug.com / hc / en-us / articles / 360020872171-Advanced-Stereochemistry-Registration-Atropisomers-Mixtures-Unknowns-and-Non-Tetrahedral-Chirality, accessed on November 29, 2023 and Accelrys Chemical Representation Guide, Accelrys Software Inc., 2014). Using this stereochemical notation, a particular stereocenter is indicated by "abs", "&x", or "orx", where x is an integer (e.g., 1 or 2). To avoid misunderstanding, the stereochemical notations in Table C1 have the following meanings:

[0116] If the structure does not contain wedge or hash bonds (i.e., each stereocenter is undefined), each stereocenter can independently assume either an (R) or (S) stereochemical configuration. To avoid misunderstanding, such structures also include mixtures of stereoisomers. For example, TIFF2026534205000105.tif14128 is, TIFF2026534205000106.tif16128 and below: This represents a mixture of TIFF2026534205000107.tif16128.

[0117] When a structure contains a stereocenter or multiple stereocenters represented by a wedge and a hash (i.e., one or more stereocenters are defined), the following notation is used: (1) If a defined stereocenter is indicated by "abs" or not by an enhanced stereochemical notation (e.g., "abs", "&x", or "orx"), the defined stereocenter has the absolute configuration shown by the structural formula. For example, Both TIFF2026534205000108.tif14128 refer to (S)-(1-methylpyrrolidine-2-yl)methanol. (2) When a defined stereocenter is represented by "orx" in the structural formula, the defined stereocenter is assigned, but the stereoconfiguration at the defined stereocenter is not determined. For example, TIFF2026534205000109.tif13128 refers to one stereoisomer selected from the group consisting of (S)-(1-methylpyrrolidine-2-yl)methanol and (R)-(1-methylpyrrolidine-2-yl)methanol. (3) When a defined stereocenter is indicated by "&x" in the structural formula, this stereocenter represents a mixture of different stereoisomers. For example, structure: TIFF2026534205000110.tif14128 represents a mixture of (S)-(1-methylpyrrolidine-2-yl)methanol and (R)-(1-methylpyrrolidine-2-yl)methanol. As another example, the structure: TIFF2026534205000111.tif18128 represents a mixture of ((2S,3S)-1,3-dimethylpyrrolidine-2-yl)methanol and ((2R,3S)-1,3-dimethylpyrrolidine-2-yl)methanol. (4) When two or more defined stereocenters are represented by "orx" in the structural formula, each of these defined stereocenters is assigned, but the stereoconfiguration at the defined stereocenters is not determined. a. For any pair of defined stereocenters represented by "orx" in a structural formula, if the numerical parts in the notation are different (for example, two defined stereocenters represented by "or1" and "or2" respectively), each defined stereocenter should be interpreted independently according to "(2)" above. For example, structure TIFF2026534205000112.tif23128 is, This refers to one stereoisomer selected from the group consisting of TIFF2026534205000113.tif25131. b. For any pair of defined stereocenters represented by "orx" in a structural formula, if the numerical part of the notation is the same (for example, two defined stereocenters are each represented by "or1"), the structural formula refers to one stereoisomer having the relative stereochemistry of these stereocenters shown in the structural formula, but the absolute configuration of these stereocenters has not been determined. For example, TIFF2026534205000114.tif23128 is two "syn" stereoisomers: This refers to one of the TIFF2026534205000115.tif24128 files. Another example is the structure TIFF2026534205000116.tif23128 is an "anti" stereoisomer: This refers to one of the files named TIFF2026534205000117.tif25128. (5) When two or more defined stereocenters are represented by "&x" in a structural formula, the structural formula refers to a mixture of stereoisomers with different arrangements of defined stereocenters. Specifications: a. For any pair of defined stereocenters represented by "&x" in a structural formula, if the numerical parts in the notation are different (for example, two defined stereocenters represented by "&1" and "&2" respectively), the structural formula refers to a mixture of stereoisomers at these two defined stereocenters, and the stereoconfigurations at each of the defined stereocenters can change independently of each other. For example, structure TIFF2026534205000118.tif21128 has four stereoisomers: This refers to a mixture of TIFF2026534205000119.tif25131. b. For any pair of defined stereocenters represented by "&x" in a structural formula, if the numerical part of the notation is the same (for example, two defined stereocenters are each represented by "&1"), the structural formula refers to a mixture of stereoisomers at these two defined stereocenters, and the relative configuration is as shown in the structural formula. For example, TIFF2026534205000120.tif23128 is a "syn" stereoisomer: This refers to a mixture of TIFF2026534205000121.tif24128. Another example is the structure TIFF2026534205000122.tif23128 is an "anti" stereoisomer: This refers to a mixture of TIFF2026534205000123.tif24128.

[0118] Certain examples of formula (A) or formula (I) were synthesized using methods involving the resolution of stereoisomer mixtures (e.g., SFC separation of stereoisomers). In Table C1, the resolved stereocenters in these compounds are labeled with the enhanced stereochemical annotations "or1" and / or "or2". In some cases, stereoisomer resolution is performed during the final step of synthesis, thereby providing individual stereoisomers of the compound. Alternatively, in some other cases, the resolution is performed on an intermediate or starting material, where each of the constituent stereoisomers of the intermediate or starting material is subjected separately to subsequent steps of synthesis, providing each compound as a separate stereoisomer. Those skilled in the art will understand that under either approach for stereoisomer resolution, stereoisomers having both (R) and (S) configurations in the resolved stereocenter are provided. Please refer to Table C2 (in Table C1, compounds whose stereoisomers include or1 and / or or2 stereochemical notations are provided in a non-stereoforming form, followed by the respective stereoisomers having (R)- and (S)- configurations).

[0119] [Table C2] TIFF2026534205000125.tif238128TIFF2026534205000126.tif226128TIFF2026534205000127.tif155128

[0120] In some embodiments, the compound of formula (A) or formula (I) is selected from the group consisting of: [Table 4] or their pharmaceutically acceptable salts.

[0121] In some embodiments, compounds of formula (A) or formula (I) are used in U.S. Provisional Application No. 63 / 685,160 filed on August 20, 2024; U.S. Provisional Patent Application No. 63 / 675,512 filed on July 25, 2024; U.S. Provisional Patent Application No. 63 / 653,043 filed on May 29, 2024; U.S. Provisional Patent Application No. 63 / 650,239 filed on May 21, 2024; and filed on March 19, 2024. Selected from the group of compounds shown in Table C1 of U.S. Provisional Patent Application No. 63 / 567,238 filed; U.S. Provisional Patent Application No. 63 / 559,588 filed on 29 February 2024; U.S. Provisional Patent Application No. 63 / 614,278 filed on 22 December 2023; and U.S. Provisional Patent Application No. 63 / 539,749 filed on 21 September 2023, Table C1 is incorporated herein by reference in its entirety.

[0122] Furthermore, provided herein is formula (B): A compound of TIFF2026534205000129.tif43128, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein in the formula, E 1 CH and CR 4 Selected from the group consisting of R 4 -CN, Haro, C 1-3 Alkyl, C 1-3 Haloalkyl and C 3-6 Selected from the group consisting of cycloalkyl groups, R 1 teeth, (i) 1 to 4 R 7 A 4-10 member heterocycline which may be substituted with (ii) TIFF2026534205000130.tif24128(In the formula, b2 is 0, 1, 2, or 3, A 1 and A 2 These are N, CH, and CR 7 (Selected independently from the group consisting of) (iii)-N(R 2)2(in the formula, each R 2 -H, and 1 to 3 R c Even if replaced by C 1-6 (Independently selected from the group consisting of alkyls), and (iv)-H Selected from the group consisting of, Each R 7 R a and R b Independently selected from the group consisting of, R 2a and R 2b is -H, C 1-3 Alkyl, C 1-3 Haloalkyl and C 3-6 Independently selected from the group consisting of cycloalkyls, or R 2a and R 2b Each of them, together with the ring carbon atoms to which it is bonded, C 3-6 Forming a cycloalkyl ring or a 4-6 membered heterocyclyl ring, R 2c and R 2d -H, Halo, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl and C 3-6 Independently selected from the group consisting of cycloalkyls, or R 2c and R 2d Each of them, together with the ring carbon atoms to which it is bonded, C 3-6 Forming a cycloalkyl ring or a 4-6 membered heterocyclyl ring, Ring B is The filename is TIFF2026534205000131.tif26128, and in the formula, * is ring B and Both TIFF2026534205000132.tif26128 show a common ring carbon atom, X 1 This is a bond, -S(O) 0-2 -, -CH2-, -CHR L -, -C(R L Selected from the group consisting of )2- and -O-, X 2 and X 3-CH2-, -CHR L -, -C(R L )2-, O-, and -S(O) 0-2 Independently selected from the group consisting of, where X 1 , X 2 , and X 3 One or fewer of these are -O- and -S(O) 0-2 - The condition is that it is selected from the group consisting of b1 is 0, 1, or 2. R 9 -H, -OH, -NR d R e Selected from the group consisting of and halos, Each R 10 R a and R b Independently selected from the group consisting of, Each R L C 1-3 Alkoxy, -F, CN, and 1-3 R c Even if replaced by C 1-3 Independently selected from the group consisting of alkyls, or A pair of R on the same or different ring carbon atoms L Together with the ring atoms that connect them, C 3-6 Forming a cycloalkyl ring, Y 2 This is a bond or 1 to 6 R Y Linear C may be substituted with 1-6 It is alkylene, Each R Y These are halo, cyano, -OH, oxo, and C. 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl and C 1-6 Haloalkyl and Independently selected from the group consisting of TIFF2026534205000133.tif15128, or A pair of R on the same or different carbon atoms Y Together with the atoms that connect them, C 3-6 They form a cycloalkyl ring or a 4-6 membered heterocyclyl ring, each of which is F and C1-3 It may be substituted with 1 to 3 substituents independently selected from the group consisting of alkyl groups. R 3 teeth, (a)R a , R b , A 4- to 15-membered heterocycline which may be substituted with 1 to 6 substituents independently selected from the group consisting of TIFF2026534205000134.tif16128, and (b)-NR d R e Selected from the group consisting of, Each R o -H, -F, C 1-3 Alkyl and C 1-3 Independently selected from the group consisting of haloalkyls, R ox is -H or C 1-3 It is alkyl, Each R a Independently, (a) Hello, (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) C each optionally substituted with 1 to 6 R c groups, 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, are selected from the group consisting of, each R b is independently selected from the group consisting of -(L b ) b -R b1 and R b1 , b is 1, 2, or 3, each -L b is independently selected from the group consisting of -O-, -N(H)-, -N(C 1-3 alkyl)-, -S(O) 0-2 , -C(=O)-, and C 1-3 alkylene, each R b1 is independently selected from the group consisting of C 3-10 cycloalkyl, 4 to 10 membered heterocyclyl, C 6-10 aryl, and 5 to 10 membered heteroaryl, each of which may be optionally substituted with 1 to 3 R g groups, 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) Independently selected from the group consisting of 2, 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 Even if replaced by C 1-6 Independently selected from the group consisting of alkyls, Each R f This consists of -H and 1 to 3 R h Even if replaced by C 1-6 Independently selected from the group consisting of alkyl and, Each R g R h , C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-5 Independently selected from the group consisting of cycloalkyl and 4-5 membered heterocyclyl, Each R h is halo, cyano, -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NH2, -N(H)(C) 1-3 Alkyl), and -N(C 1-3 It is independently selected from the group consisting of alkyl)2.

[0123] As used herein, the term “prodrug” refers to a derivative of the compound of formula (B) that releases the compound of formula (B) under appropriate conditions (e.g., in vivo conditions) via a non-enzymatic process (e.g., chemical reduction, oxidation, or hydrolysis (e.g., acid-catalyzed hydrolysis)) or an enzymatic process (e.g., esterase, nuclease, lipase, amidase, or protease-catalyzed reaction). Prodrugs can be used to alter the biological distribution or pharmacokinetics of the compound of formula (B). Various groups have been used to modify the compound to form prodrugs, such as esters (e.g., benzoates, acetates, etc.), ethers, carbamates, carbonates, N,O-acetals, phosphate esters / salts, etc. The compound of formula (B) is -NH2 (e.g., R 9 If R is -NH2, 9 (in) or -OH (for example, R 7 C is substituted with -OH or -OH. 1-3 If it is alkyl, R 7 (In this context) functional groups can form prodrugs. Further information regarding the use of prodrugs can be found below: International Patent No. 2024 / 050640; ACS Omega 2023, 8, 7, 7211-7221, doi:10.1021 / acsomega.3c00329; Nat Rev Drug Discov 7, 255-270 (2008), doi:10.1038 / nrd246; Chem Biol Drug Des 82:643-668 (2013), doi:10.1111 / cbdd.12224; Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series; Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E.B. Roche, American Pharmaceutical Association).

[0124] In some embodiments of formula (B), ring B is: TIFF2026534205000135.tif26128, X3 is -CH2-, -CHR L -, or -C(R L )2-. In some embodiments, R 9 is selected from the group consisting of -OH, NR d R e (e.g., -OH and -NH2). In some embodiments, each R L is independently C optionally substituted with 1 to 3 -F 1-3 alkyl.

[0125] In some embodiments of Formula (B), Ring B is: TIFF2026534205000136.tif26128, and X 3 is -CH2-, -CHR L -, or -C(R L )2-. In some embodiments, each R L is independently C optionally substituted with 1 to 3 -F 1-3 alkyl.

[0126] In some embodiments of Formula (B), Ring B is TIFF2026534205000137.tif26128. For example, R L can be methyl, ethyl or -CF3. For example, R L can be methyl.

[0127] In some embodiments of Formula (B), Ring B is TIFF2026534205000138.tif26128.

[0128] In some embodiments of Formula (B), Ring B is TIFF2026534205000139.tif26128.

[0129] In some embodiments of Formula (B), Ring B is TIFF2026534205000140.tif27128.

[0130] In some embodiments of equation (B), R 2a , R 2b , R 2c , and R 2d These are each -H.

[0131] In some embodiments of formula (B), E 1 It is CH.

[0132] In some embodiments of formula (B), R 2a , R 2b , R 2c , and R 2d These are -H and E respectively. 1 It is CH.

[0133] In some embodiments of equation (B), R 2a , R 2b , R 2c , and R 2d These are each -H. E 1 is CH, and ring B is, TIFF2026534205000141.tif26128 (for example) TIFF2026534205000142.tif26128) or The filename is TIFF2026534205000143.tif26128.

[0134] In some embodiments of equation (B), R 1 teeth, The compound according to any one of embodiments 1 to 8 or 22 to 23, wherein ring A1 is a 4- to 7-membered heterocyclyl ring having one ring oxygen atom and no additional ring heteroatoms, n4 is 0, 1, or 2, n5 is 0, 1, or 2, provided that n4+n5 is 0, 1, or 2. In some embodiments, n4 is 0. In some embodiments, n5 is 0. In some embodiments, n4 is 0 and n5 is 0. In some embodiments, each R 7 is -F, -OH, oxo, R b1 , and 1 to 3 R cEven if replaced by C 1-3 Independently selected from the group consisting of alkyl, where R b1 This is 1-2 R g It is a 5-6 member heteroaryl that may be substituted with [another compound].

[0135] In some embodiments of equation (B), R 1 Each of these has 1 to 2 R 7 It may be replaced with TIFF2026534205000145.tif17128 (for example, TIFF2026534205000146.tif16128), and TIFF2026534205000147.tif16128 (for example, Selected from the group consisting of TIFF2026534205000148.tif17128).

[0136] In some embodiments of equation (B), R 1 This is 1 to 4 R 7 It is a four-membered heterocycline which may be substituted with R. In some embodiments, each R 7 is -F, -OH, oxo, R b1 , and 1 to 3 R c Even if replaced by C 1-3 Independently selected from the group consisting of alkyl, where R b1 This is 1-2 R g It is a 5-6 member heteroaryl that may be substituted with [another compound].

[0137] In some embodiments of equation (B), R 1 teeth, TIFF2026534205000149.tif15128 contains 1 to 4 (for example, 1 to 2) R 7 It may be replaced by. In some embodiments, each R 7 -F, oxo, -OH, R b1 , and 1 to 3 R c Even if replaced by C 1-3 Independently selected from the group consisting of alkyl, where Rb1 This is 1-2 R g It is a 5-6 member heteroaryl that may be substituted with [another compound].

[0138] In some embodiments of equation (B), R 1 teeth, Selected from the group consisting of TIFF2026534205000150.tif16128. In some embodiments, each R 7 teeth, (a)-F; (b) Cyano, (c)-OH, (d)R b1 (R b1 This is 1-2 R g (It is a 5-6 member heteroaryl that may be substituted with) (e) C which may be replaced by 1 to 3 F 1-3 Alkyl, (f)-OH or C 1-3 alkoxy-substituted C 1-3 Alkyl It is independently selected from the group consisting of [the specified elements].

[0139] In some embodiments of equation (B), R 1 teeth, TIFF2026534205000151.tif15128 (for example) TIFF2026534205000152.tif15128), R 7 is -OH or C 1-3 alkoxy-substituted C 1-3 It is alkyl (for example, C substituted with -OH) 1-3 Alkyl). In some embodiments, R 1 teeth, TIFF2026534205000153.tif15128 (for example, This is TIFF2026534205000154.tif15128).

[0140] In some embodiments of equation (B), R 1 teeth, The file is TIFF2026534205000155.tif18128, and here, R 7a C is a C substituted with -OH. 1-3 It is an alkyl group (for example, -CH2OH). 7b C may be substituted with 1 to 3 -F (e.g., methyl) atoms. 1-3 Alkyl, and -OH or C 1-3 C may be substituted with alkoxy. 1-3 Selected from the group consisting of alkyl groups. For example, R 1 teeth, It could be TIFF2026534205000156.tif15128.

[0141] In some embodiments of equation (B), R 1 teeth, TIFF2026534205000157.tif20128 (for example) TIFF2026534205000158.tif20128) and R 7 This is 1 to 3 R g It is a 5-membered heteroaryl which may be substituted with R. In some embodiments, 7 These are selected from the group consisting of pyrazolyl and oxazolyl, each of which contains 1-2 R g It may be replaced by R. In some embodiments, 7 This is 1-2 R g It is a pyrazolyl which may be substituted with (for example, R 7 This is one R g It may be replaced with (This is TIFF2026534205000159.tif12128). For example, R 7 teeth It could be TIFF2026534205000160.tif12128. In some embodiments, R 7 This is one R g It is an oxazolyl which may be substituted with (for example, R 7 is one R g It may be replaced with TIFF2026534205000161.tif13128). For example, R 7 teeth It could be TIFF2026534205000162.tif12128.

[0142] In some embodiments of formula (B), Y 2 It is -CH2- or -CD2- (for example, -CH2-).

[0143] In some embodiments of formula (B), Y 2 is -CH2- or -CD2- (for example, -CH2-), and R 3 -F, -C 1-3 Alkoxy, and -C 1-3 They may be substituted with one or two substituents independently selected from the group consisting of haloalkoxys. The filename is TIFF2026534205000163.tif18128.

[0144] In some embodiments of formula (B), Y 2 is -CH2- or -CD2- (for example, -CH2-), and R 3 R a , R b , and It is a 9-14 (e.g., 9-12) member heterocycline which may be substituted with 1-3 substituents independently selected from the group consisting of TIFF2026534205000164.tif15128. In some embodiments, R 3 This is 1 to 3 R a It is a 9-12 member heterocycline which may be substituted with R. In some embodiments, 3 is -F, C 1-3 Alkyl and C 1-3 It is a 9-12 member heterocycline which may be substituted with 1-3 substituents independently selected from the group consisting of alkoxys. For example, R 3 teeth, You can choose from the group consisting of TIFF2026534205000165.tif87160.

[0145] In some embodiments of formula (B), Y 2 is -CH2- or -CD2- (for example, -CH2-), and R 3 1-2 Replaced with TIFF2026534205000166.tif15128, and further 1-2 independently selected R a It is an 8-12 member heterocycline which may be substituted with R. In some embodiments, 3 teeth, Selected from the group consisting of TIFF2026534205000167.tif38128. For example, R 3 teeth, You can choose from the group consisting of TIFF2026534205000168.tif55152.

[0146] In some embodiments of formula (B), Y 2 is -CH2- or -CD2- (for example, -CH2-), and R 3 R b Replaced with R a and It is an 8-12 member heterocycline which may be further substituted with 1-2 substituents independently selected from the group consisting of TIFF2026534205000169.tif15128. In some embodiments, R 3 teeth, Selected from the group consisting of TIFF2026534205000170.tif27128. For example, R 3 teeth, You can choose from the group consisting of TIFF2026534205000171.tif238162.

[0147] In some embodiments of formula (B), Y 2 is -CH2- or -CD2- (for example, -CH2-), and R 3 teeth, TIFF2026534205000172.tif27128 (for example) TIFF2026534205000173.tif26128) or TIFF2026534205000174.tif27128 (for example) Selected from the group consisting of TIFF2026534205000175.tif27128), each R a3 This is an independently selected C which may be replaced by 1 to 3 -Fs. 1-3 It is alkyl. For example, R 3 teeth, You can choose from the group consisting of TIFF2026534205000176.tif28128.

[0148] In some embodiments of formula (B), Y 2 is -CH2- or -CD2- (for example, -CH2-), and R 3 teeth, Selected from the group consisting of TIFF2026534205000177.tif49157, each R a3 This is an independently selected C which may be replaced by 1 to 3 -Fs. 1-3 It is alkyl. For example, R 3 teeth, You can choose from the group consisting of TIFF2026534205000178.tif28151.

[0149] In some embodiments of formula (B), Y 2 This is 1-6 R Y Linear C may be substituted with 3-6 It is an alkylene. In some embodiments, Y 2 teeth, Selected from the group consisting of TIFF2026534205000179.tif16128.

[0150] In some embodiments of formula (B), Y 2 This is 1-6 R Y Linear C may be substituted with 3-6 It is alkylene, R 3 -NR d R e In some embodiments, Y 2 teeth, Selected from the group consisting of TIFF2026534205000180.tif16128, R 3 is -N(C 1-3 It is alkyl)2. For example, -OY 2 -R 3 teeth, It could be TIFF2026534205000181.tif22130.

[0151] In some embodiments of formula (B), Y 2 This is 1 to 6 R Y Linear C may be substituted with 3-6 It is alkylene, R 3 R a , It is a 4-8 member heterocycline which may be substituted with 1-3 substituents independently selected from the group consisting of TIFF2026534205000182.tif15128. In some embodiments, Y 2 teeth, Selected from the group consisting of TIFF2026534205000183.tif16128, R 3 teeth, Selected from the group consisting of TIFF2026534205000184.tif27153. For example, -OY 2 -R 3 teeth, It could be TIFF2026534205000185.tif46138.

[0152] KRas proteins (e.g., dysregulated KRas proteins (e.g., mutant KRas proteins)) non-covalently bonded to compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B) or pharmaceutically acceptable salts thereof are also provided herein. In some embodiments, the KRas protein Gly10 is bonded non-covalently to compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B) or pharmaceutically acceptable salts thereof (e.g., the carbonyl and R of Gly10) 1 via hydrogen bonding between the -OH group of and / or between the -NH group of Gly10 and R 1 R (via water-mediated interaction between the -OH group) 1 It interacts with the group non-covalently. Although we do not wish to be bound by theory, in some embodiments, the Gly10 of the KRas protein and the R of a compound of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B) 1 Interactions between the group or its pharmaceutically acceptable salts promote the inhibition of the interaction between the KRas protein and Raf-RBD. In some embodiments, Arg68 of the KRas protein is a compound of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B) or its pharmaceutically acceptable salt (e.g., guanidine of Arg68 and R 1 R (via hydrogen bonding with the CN group) 1 It interacts with the group non-covalently. Although we do not wish to be bound by theory, in some embodiments, the Arg68 of the KRas protein interacts with the R of a compound of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B).1 Interactions between the group or its pharmaceutically acceptable salts promote the inhibition of the interaction between the KRas protein and Raf-RBD.

[0153] chemical definition The term "halo" refers to fluoro(-F), chloro(-Cl), bromo(-Br), or iodine(-I).

[0154] The term "oxo" refers to a divalent double-bonded oxygen atom (i.e., "=O"). As used herein, the oxo group bonds to a carbon atom to form a carbonyl group.

[0155] The term "alkyl" refers to a saturated acyclic hydrocarbon radical that contains the indicated number of carbon atoms and can be linear or branched. For example, C 1-10 This indicates that the group may have 1 to 10 (including 1 and 10) carbon atoms within it. Alkyl groups may be either unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl. As used in this context, the term “saturated” means only single bonds existing between the constituent carbon atoms and other available valencies occupied by hydrogen and / or other substituents as defined herein.

[0156] The term "haloalkyl" refers to an alkyl group (e.g., -CF3, -CHF2, or -CH2F) in which one or more hydrogen atoms are replaced by independently selected halos.

[0157] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3). The term "haloalkoxy" refers to an -O-haloalkyl radical (e.g., -OCF3, -OCHF2, or -OCH2F).

[0158] The term "alkylene" refers to a divalent alkyl group (e.g., -CH2-). Similarly, terms such as "cycloalkylene" and "heterocyclylene" refer to divalent cycloalkyl and heterocyclyl groups, respectively. To avoid ambiguity, in "cycloalkylene" and "heterocyclylene," can the two radicals lie on the same ring carbon atom (e.g., Geminal diradicals such as TIFF2026534205000186.tif19128, or can be on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring carbon and / or nitrogen atoms)) (e.g., TIFF2026534205000187.tif19128).

[0159] The term "alkenyl" refers to an acyclic hydrocarbon chain that may be a straight or branched chain having one or more carbon-carbon double bonds. The alkenyl portion contains the indicated number of carbon atoms. For example, C 2-6 This indicates that the group may have 2 to 6 (including 2 and 6) carbon atoms within it. The alkenyl group may be either unsubstituted or substituted with one or more substituents.

[0160] The term "alkynyl" refers to an acyclic hydrocarbon chain that may be a straight or branched chain having one or more carbon-carbon triple bonds. The alkynyl portion contains the indicated number of carbon atoms. For example, C 2-6 This indicates that the group may have 2 to 6 (including 2 and 6) carbon atoms within it. The alkynyl group may be either unsubstituted or substituted with one or more substituents.

[0161] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbon atoms 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), where 0, 1, 2, 3, or 4 atoms in each ring may be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, and tetrahydronaphthyl.

[0162] As used herein, the term “cycloalkyl” refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated hydrocarbon group having, for example, 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. As used in this context, the term “saturated” means only single bonds present between constituent carbon atoms. Examples of saturated cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Partially unsaturated cycloalkyl groups may have any degree of unsaturation, provided that one or more double bonds are present in the cycloalkyl group, none of the rings in the cyclic system are aromatic, and the partially unsaturated cycloalkyl group is not fully saturated overall. Examples of partially unsaturated cycloalkyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkyls may include multiple fused and / or crosslinked rings. Non-limiting examples of fused / crosslinked 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, and bicyclo[2.2.2]octyl. Cycloalkyls also include spirocyclic rings (e.g., spirocyclic dicyclic rings in which two rings are connected by 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, and spiro[5.5]undecyl.

[0163] As used herein, the term "heteroaryl" means a monocyclic, dicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, or alternatively, 5, 6, 9, 10, or 15 ring atoms, where at least one ring in the system is independently N, O, S( (including oxidation forms such as TIFF2026534205000188.tif15128), and P( (including oxidation forms such as TIFF2026534205000189.tif14128) (e.g., N, O, and S) It contains one or more heteroatoms selected from the group consisting of (including oxidation forms such as TIFF2026534205000190.tif15128), and at least one ring in the system is aromatic (however, it does not have to be a ring containing a heteroatom, e.g., tetrahydroisoquinolinyl). The heteroaryl group may be unsubstituted or substituted with one or more substituents. Examples of heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridadinyl, triazinyl, thiazolylbenzothienyl, benzooxadiazolyl, benzofuranil, benzimidazolyl, benzotriazolyl, sinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthylidinyl, prinyl, thienopyridinyl, and pyrido[2,3-d]pyrim Examples include dinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanil, 2,3-dihydrobenzo[b][1,4]dioxynyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranil, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. To clarify, heteroaryls also include aromatic lactams, aromatic cyclic ureas, or their vinylogous analogs, where each ring nitrogen adjacent to the carbonyl is pyridonyl (e.g., TIFF2026534205000191.tif22128), pyrimidonyl (for example, TIFF2026534205000192.tif22128), pyridazinonyl (for example, TIFF2026534205000193.tif19128), pyrazinonyl (for example, TIFF2026534205000194.tif22128), and imidazolonyl (for example, One or more of the following are tertiary (i.e., all three valencies are occupied by non-hydrogen substituents), and each ring nitrogen adjacent to the carbonyl is tertiary (i.e., the oxo group (i.e., "=O") in this specification is a component of a heteroaryl ring).

[0164] 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., 5-8 member monocyclic, 8-12 member bicyclic, or 11-15 member tricyclic ring systems) with 1 to 3 heteroatoms in the case of a monocyclic, 1 to 6 heteroatoms in the case of a bicyclic, or 1 to 9 heteroatoms in the case of a tricyclic or polycyclic system, and the heteroatoms are O, N, S ( (including oxidation forms such as TIFF2026534205000196.tif15128), and P( (including oxidation forms such as TIFF2026534205000197.tif14128) (e.g., N, O, and S) Selected from (including oxidation forms such as TIFF2026534205000198.tif15128) (for example, monocyclic, bicyclic, or tricyclic, with a carbon atom and 1-3, 1-6, or 1-9 N, O, S, or P heteroatoms, respectively), where 0, 1, 2, or 3 atoms in each ring may be substituted by substituents. The term “saturated” as used in this context means only single bonds existing between the constituent ring atoms and other available valencies occupied by hydrogen and / or other substituents as defined herein. Examples of saturated heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl. 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 cyclic 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, dihydropyrazine, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl.

[0165] Heterocyclyls may contain multiple condensed and crosslinked rings. Non-limiting examples of condensed / crosslinked heterocyclyls 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, Examples include 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, and 3-oxabicyclo[3.2.1]octyl. Heterocyclines also include spirocyclic rings (for example, spirocyclic bicycles in which two rings are connected by only one atom).Non-restrictive examples of spirocyclic heterocyclils 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, and 2-oxaspiro[2 Examples include .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, and 3-oxa-9-azaspiro[5.5]undecyl.

[0166] As used herein, when a ring is described as “partially unsaturated,” it means that, provided the ring is not aromatic, the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributable to the ring itself, for example, one or more double or triple bonds between the constituent ring atoms). Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, and dihydrothiophene.

[0167] To avoid ambiguity, unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) containing a sufficient number of ring atoms to form a bicyclic or higher-order cyclic system (e.g., tricyclic, polycyclic cyclic system), such rings and cyclic groups have condensation points on (i) adjacent ring atoms (e.g., [xx0] ring systems, where 0 is an 0-atom bridge (e.g., (TIFF2026534205000199.tif13128) represents), (ii) monocyclic atoms (spiro-condensed ring systems) (for example, (TIFF2026534205000200.tif19128), or (iii) a sequence of consecutive ring atoms (a bridged ring system having all bridge lengths > 0) (for example, It is understood that this includes those having fused rings, including those located at TIFF2026534205000201.tif16128).

[0168] In addition, the atoms constituting the compounds of this embodiment are intended to include all isotopic forms of such atoms. The isotopes used herein include atoms with the same atomic number but different mass numbers. As a general example, but not limited to, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include, 13 C and 14 Includes C.

[0169] In addition, the compounds disclosed herein, either generally or specifically, are intended to include all tautomer forms. Therefore, as an example, partial: The compound containing TIFF2026534205000202.tif16128 is, in part: This includes tautomer forms containing TIFF2026534205000203.tif18128. Similarly, pyridinyl or pyrimidinyl moieties that are described as potentially substituted with hydroxyl include pyridone or pyrimidone tautomer forms.

[0170] The compounds provided herein may encompass a variety of stereochemical forms. The compounds also include diastereomers and optical isomers, such as mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers resulting from structural asymmetry in certain compounds. Unless otherwise indicated, the disclosed compounds are named or described structurally without specifying their stereochemistry, and if they have one or more chiral centers, it is understood that this represents all possible stereoisomers of the compound.

[0171] Certain combinations of heteroatoms (e.g., N, O, S, or halo) define compounds that are more unstable under physiological conditions. Examples include (1) compounds containing acetal or aminal bonds; (2) compounds containing acyclic NO, NN, or NS(O)O bonds; and (3) OO, OS(O) 0-2 N-halo, O-halo, and S(O) 0-2 -Examples include compounds containing halo bonds. Therefore, such compounds are generally undesirable. As used herein, "acyclic bond" means a chemical bond that is not part of a ring. For example, The NO bond in TIFF2026534205000204.tif19128 is an example. To avoid misunderstanding, acyclic NO, NN, or NS(O)O bonds (i.e., bonds that are not part of a ring (e.g., TIFF2026534205000205.tif15128)) is not very desirable, but the compounds provided herein have rings (e.g., It may contain NO, NN, or NS(O)O bonds that form part of the NN bond in TIFF2026534205000206.tif16128.

[0172] Treatment method Indications This specification provides methods for inhibiting KRas proteins. For example, inhibitors of KRas proteins (e.g., dysregulated KRas proteins (e.g., mutant KRas proteins (e.g., KRas G12D mutant protein, KRas G12R mutant protein, or KRas G12V mutant protein)) that are useful in treating or preventing diseases or disorders associated with KRas dysregulation, such as cardiovascular diseases, inflammatory diseases and / or autoimmune diseases, or cancer (e.g., KRas-associated cancers)) are provided herein.

[0173] As used herein, the term “KRas-related disease or disorder” refers to a disease or disorder that is related to, or has a dysregulation of the expression, activity, or level of the KRAS gene, KRas protein, or any one thereof (e.g., one or more of the types of dysregulation of the expression, activity, or level of the KRAS gene, KRas protein, or any of them as described herein). Non-exclusive examples of KRas-related diseases or disorders include, for example, cancer, cardiovascular diseases (e.g., arteriovenous malformations), endometritis, and inflammatory and / or autoimmune diseases (e.g., non-malignant syndromes of autoimmunity and abnormal leukocyte homeostasis). For example, see Adashek et al. Genome Med. 2020;12:16,doi:10.1186 / s13073-020-0714-y; Niemela et al. Blood. 2011;117(10):2883-6,doi:10.1182 / blood-2010-07-295501; Nosan et al. Croat Med J. 2013, 54(6):574-578,doi:10.3325 / cmj.2013.54.574; and Messina et al. Small GTPases 11.5(2020):312-319,10.1080 / 21541248.2018.1502591.

[0174] As used herein, the term “mutant-KRas-related disease or disorder” refers to a disease or disorder associated with, or having, a KRas mutation (e.g., a KRAS gene having a mutation corresponding to a mutation in the KRas protein and / or a KRas protein having a mutation). Non-exclusive examples of mutant-KRas-related diseases or disorders include, for example, cancer, cardiovascular diseases (e.g., arteriovenous malformations), endometritis, and inflammatory and / or autoimmune diseases (e.g., non-malignant syndromes of autoimmunity and abnormal leukocyte homeostasis). For example, see Adashek et al. Genome Med. 2020;12:16,doi:10.1186 / s13073-020-0714-y; Niemela et al. Blood. 2011;117(10):2883-6,doi:10.1182 / blood-2010-07-295501; Nosan et al. Croat Med J. 2013, 54(6):574-578,doi:10.3325 / cmj.2013.54.574; and Messina et al. Small GTPases 11.5(2020):312-319,10.1080 / 21541248.2018.1502591.

[0175] The phrase "dysregulation of the expression, activity, or level of the KRAS gene, KRas protein, or any of them" refers to increased expression (e.g., increased level) of wild-type KRas protein in mammalian cells resulting from gene mutations (e.g., mutations in the KRAS gene resulting in the expression of KRas protein having at least one amino acid deletion compared to wild-type KRas protein, mutations in the KRAS gene resulting in the expression of KRas protein having one or more point mutations compared to wild-type KRas protein, mutations in the KRAS gene resulting in the expression of KRas protein having at least one inserted amino acid compared to wild-type KRas protein, gene duplication resulting in increased levels of KRas protein in cells, or mutations in regulatory sequences (e.g., promoters and / or enhancers) resulting in increased levels of KRas protein in cells), alternative splicing versions of KRas mRNA resulting in KRas protein having at least one amino acid deletion compared to wild-type KRas protein, or increased expression (e.g., increased level) of wild-type KRas protein in mammalian cells resulting from abnormal cellular signaling and / or dysregulated autocrine / parasecretory signaling (e.g., compared to control non-cancerous cells). As an example, dysregulation of the expression, activity, or level of the KRAS gene, KRas protein, or either thereof may be a mutation in the KRAS gene encoding a KRas protein that has lower GTPase activity and / or increased signaling activity compared to the protein encoded by the non-mutated KRAS gene. As another example, dysregulation of the expression, activity, or level of the KRAS gene, KRas protein, or either thereof may be KRas amplification. In some embodiments, KRas amplification is amplification of wild-type KRas. In some embodiments, KRas amplification is amplification of mutant KRas.

[0176] As used herein, “dysregulated KRas protein” means (i) a KRas protein having a mutation (e.g., deletion of at least one amino acid compared to wild-type KRas protein, one or more point mutations compared to wild-type KRas protein, or insertion of at least one amino acid compared to wild-type KRas protein); (ii) a KRas protein resulting from, for example, a gene duplication event of the gene encoding a KRas protein (e.g., wild-type KRas protein), and thus resulting in an increase in the level and / or activity of the KRas protein (e.g., wild-type KRas protein) in a cell; (iii) a KRas protein resulting from a mutation in a regulatory sequence (e.g., promoter and / or enhancer) which may also result in an increase in the level and / or activity of the KRas protein (e.g., wild-type KRas protein) in a cell; (iv) a KRas protein resulting in a KRas protein having a deletion of at least one amino acid in the KRas protein compared to wild-type KRas protein. (v) refers to a KRas protein resulting from an alternative splicing version of mRNA, or a KRas protein resulting from increased expression (e.g., increased levels) of wild-type KRas protein in mammalian cells due to abnormal cellular signaling and / or dysregulated autocrine / parasecretory signaling (e.g., compared to control non-cancerous cells). In some embodiments, the dysregulated KRas protein is a dysregulated human KRas protein.

[0177] As used herein, “mutant KRas protein” refers to a KRas protein that includes substitutions, insertions, deletions, cleavages, and / or fusions to the wild-type human KRas sequence shown in SEQ ID NO: 1. For example, a mutant human KRas protein may include substitutions at any amino acid position (compared to SEQ ID NO: 1).

[0178] As used herein, “KRas G12X mutant protein” refers to a KRas protein that contains a substitution of glycine with any other amino acid at the 12th amino acid position (compared to SEQ ID NO: 1).

[0179] As used herein, "KRas G12A mutant protein" refers to a KRas protein that contains a substitution from glycine to alanine at the 12th amino acid position (relative to SEQ ID NO: 1).

[0180] As used herein, "KRas G12C mutant protein" refers to a KRas protein that contains a substitution from glycine to cysteine ​​at the 12th amino acid position (compared to SEQ ID NO: 1).

[0181] As used herein, "KRas G12D mutant protein" refers to a KRas protein that contains a substitution from glycine to aspartic acid at the 12th amino acid position (compared to SEQ ID NO: 1).

[0182] As used herein, "KRas G12R mutant protein" refers to a KRas protein that contains a substitution from glycine to arginine at the 12th amino acid position (relative to SEQ ID NO: 1).

[0183] 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 (compared to SEQ ID NO: 1).

[0184] As used herein, "KRas G12V mutant protein" refers to a KRas protein that contains a substitution from glycine to valine at the 12th amino acid position (compared to SEQ ID NO: 1).

[0185] As used herein, “KRas G13X mutant protein” refers to a KRas protein that contains a substitution of glycine with any other amino acid at the 13th amino acid position (compared to SEQ ID NO: 1).

[0186] As used herein, "KRas G13C mutant protein" refers to a KRas protein that contains a substitution from glycine to cysteine ​​at the 13th amino acid position (relative to SEQ ID NO: 1).

[0187] As used herein, "KRas G13D mutant protein" refers to a KRas protein that contains a substitution from glycine to aspartic acid at the 13th amino acid position (compared to SEQ ID NO: 1).

[0188] As used herein, "KRas G13V mutant protein" refers to a KRas protein that contains a substitution from glycine to valine at the 13th amino acid position (compared to SEQ ID NO: 1).

[0189] As used herein, “KRas Q61X mutant protein” refers to a KRas protein that contains a substitution of glutamine to any other amino acid at the 61st amino acid position (relative to SEQ ID NO: 1).

[0190] As used herein, "KRas Q61E mutant protein" refers to a KRas protein that contains a glutamine-to-glutamic acid substitution at the 61st amino acid position (relative to SEQ ID NO: 1).

[0191] As used herein, "KRas Q61H mutant protein" refers to a KRas protein that contains a substitution from glutamine to histidine at the 61st amino acid position (relative to SEQ ID NO: 1).

[0192] As used herein, "KRas Q61K mutant protein" refers to a KRas protein that contains a glutamine-to-lysine substitution at the 61st amino acid position (relative to SEQ ID NO: 1).

[0193] As used herein, "KRas Q61L mutant protein" refers to a KRas protein that contains a glutamine-to-leucine substitution at the 61st amino acid position (relative to SEQ ID NO: 1).

[0194] As used herein, "KRas Q61P mutant protein" refers to a KRas protein that contains a glutamine-to-proline substitution at the 61st amino acid position (relative to SEQ ID NO: 1).

[0195] As used herein, "KRas Q61R mutant protein" refers to a KRas protein that contains a substitution from glutamine to arginine at the 61st amino acid position (relative to SEQ ID NO: 1).

[0196] As used herein, “KRas inhibitor” includes any compound that exhibits KRas protein inactivation activity (e.g., inhibiting or reducing KRas signaling activity). In some embodiments, the KRas inhibitors described herein exhibit an IC50 of 1 μM or less in the nucleotide exchange assay described herein. 50 The IC value is 1 μM or less in the Raf kinase interaction assay described herein. 50It has a value, or both. In some embodiments, a KRas inhibitor inhibits the signaling activity of the wild-type KRas protein. In some embodiments, a KRas inhibitor inhibits the signaling activity of a dysregulated KRas protein, resulting in a reduction of other downstream effectors, such as activated Raf or ERK. In some embodiments, a KRas inhibitor inhibits the signaling activity of a mutant KRas protein. In some embodiments, a KRas inhibitor inhibits both the signaling activity of the 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, a KRas inhibitor inhibits one or more mutant KRas proteins and such a KRas inhibitor may be referred to as a “mutant KRas inhibitor”, and may also be referred to by the mutant it inhibits. For example, a KRas inhibitor that inhibits the KRas G12R mutant protein may be referred to as a “KRas G12R inhibitor”. As another example, a KRas inhibitor that inhibits both the KRas G12C mutant protein and the KRas G12D mutant protein may be referred to as a "KRas G12C inhibitor" and / or a "KRas G12D inhibitor." In some embodiments, a "mutant KRas inhibitor" inhibits two or more mutant KRas proteins and may be referred to as a "panmutant KRas inhibitor." In some embodiments, a panmutant KRas inhibitor 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, 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 Q61R mutant protein.For example, a "KRas G12X inhibitor" can inhibit 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. As yet another example, a KRas inhibitor that inhibits the KRas G13D mutant protein may be referred to as a "KRas G13D inhibitor." In some embodiments, a KRas inhibitor can inhibit one or more mutant KRas proteins, and such a KRas inhibitor can be called a "mutant KRas inhibitor," regardless of whether the mutant KRas inhibitor also inhibits 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.

[0197] The term "compounds provided herein" refers to compounds of formula (A) (e.g., formula (I) (e.g., formula (Ia), (Ib), (Ic), (I-c1), (I-c2), (I-c3), (I-c4), (Id), or (Ie))) or formula (B) disclosed herein.

[0198] The compounds provided herein, or pharmaceutically acceptable salts thereof, are KRas inhibitors. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are mutant KRas inhibitors. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, or a combination thereof. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12D mutant protein, KRas G12R mutant protein, KRas G12V mutant protein, or a combination thereof. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12D mutant protein, KRas G12V mutant protein, or both. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12R mutant protein, KRas G12V mutant protein, or both. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12A mutant protein.In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12C mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12D mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12S mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12V mutant protein.

[0199] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are KRas G12X inhibitors. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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 compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit four 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 compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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.In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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 compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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 G12V mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit two 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. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit four 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. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12D mutant protein, the KRas G12V mutant protein, or both. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12A mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12C mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, do not inhibit the KRas G12C mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12D mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, do not inhibit the KRas G12D mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12S mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12V mutant protein.

[0200] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are KRas G13X inhibitors. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit one 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G13C mutant protein, KRas G13D mutant protein, and KRas G13V mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G13C mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G13D mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G13V mutant protein.

[0201] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are KRas Q61X inhibitors. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit one or more mutant KRas proteins 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit two or more mutant KRas proteins 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 mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit three or more mutant KRas proteins 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit four or more mutant KRas proteins 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit five or more mutant KRas proteins 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 Q61R mutant protein.In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the 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 compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas Q61E mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas Q61H mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas Q61K mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas Q61L mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas Q61P mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas Q61R mutant protein.

[0202] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit one or more mutant KRas proteins selected from the group consisting of KRas G12X mutant protein, KRas G13X mutant protein, and KRas Q61X mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit two or more mutant KRas proteins selected from the group consisting of KRas G12X mutant protein, KRas G13X mutant protein, and KRas Q61X mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit three or more mutant human KRas proteins selected from the group consisting of KRas G12X mutant protein, KRas G13X mutant protein, and KRas Q61X mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12X mutant protein, KRas G13X mutant protein, and KRas Q61X mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, 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 Q61R mutant protein.In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, 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 Q61R mutant protein.In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit four 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, 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the 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 Q61R mutant protein.In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit the KRas G12A 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 Q61R mutant protein.

[0203] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit one or more mutant KRas proteins 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 Q61H mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit two or more mutant KRas proteins 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 Q61H mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit three or more mutant KRas proteins 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 Q61H mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit two 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit three 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit two 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating bladder cancer.

[0204] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit one 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12C mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12D mutant protein, KRas G12V mutant protein, or both. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating cervical cancer.

[0205] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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 compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating colorectal cancer.

[0206] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12A mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating endometrial cancer.

[0207] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit one or more mutant KRas proteins 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 Q61H mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit two or more mutant KRas proteins 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 Q61H mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit three or more mutant KRas proteins 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 Q61H mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12D mutant protein, KRas G12V mutant protein, or both. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating esophageal cancer or gastric cancer.

[0208] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, 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 Q61R mutant protein.In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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 compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating leukemia.

[0209] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit one or more mutant KRas proteins 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit two or more mutant KRas proteins 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit three or more mutant KRas proteins 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12C mutant protein, KRas G12D mutant protein, and KRas G12R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12D mutant protein, KRas G12R mutant protein, or both. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating melanoma.

[0210] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, KRas G13D mutant protein, and KRas Q61L mutation. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, KRas G13D mutant protein, and KRas Q61L mutation. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, KRas G13D mutant protein, and KRas Q61L mutant. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, and KRas G12S mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, and KRas G12S mutant protein.In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, and KRas G12S mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12C mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12D mutant protein, KRas G12V mutant protein, or both. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating ovarian cancer.

[0211] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12A mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating lung cancer (e.g., non-small cell lung cancer).

[0212] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, KRas G12V mutant protein, KRas G13C mutant protein, KRas Q61H mutant protein, and KRas Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, KRas G12V mutant protein, KRas G13C mutant protein, KRas Q61H mutant protein, and KRas Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, KRas G12V mutant protein, KRas G13C mutant protein, KRas Q61H mutant protein, and KRas Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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 compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating pancreatic cancer.

[0213] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit one or more mutant KRas proteins 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit two or more mutant KRas proteins 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit three or more mutant KRas proteins 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 Q61R mutant protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit two 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, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12A mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating testicular cancer (e.g., seminomas).

[0214] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can bind to the KRas protein in a GTP-bound state. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can selectively bind to the KRas protein in a GTP-bound state.

[0215] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can bind to the KRas protein in a GDP-bound state. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can selectively bind to the KRas protein in a GDP-bound state.

[0216] An exemplary sequence of a mature human KRas protein is shown below (UniProtKB entry P01116) (SEQ ID NO: 1). TIFF2026534205000207.tif27149

[0217] Where used herein, “selective” or “selectively” means, when referring to a compound being assayed, that exhibits at least 5 times (e.g., at least 10 times, at least 25 times, at least 50 times, or at least 100 times) superior performance (e.g., binding affinity and / or potency) in the assay with respect to a comparative protein variant in the assay for specific conditions. For example, if a compound provided herein, or a pharmaceutically acceptable salt thereof, binds “selectively” to a KRas G12X mutant protein than to a wild-type KRas protein, as determined by a surface plasmon resonance (SPR) assay, then the compound provided herein, or a pharmaceutically acceptable salt thereof, will, when measured by an SPR assay, exhibit at least 5 times (e.g., at least 10 times, at least 25 times, at least 50 times, or at least 100 times) lower K than to a wild-type KRas protein for any one or more KRas mutant proteins selected from the group consisting of KRas G12X mutant proteins. D The compound has a value. As a further example, if a compound provided herein, or a pharmaceutically acceptable salt thereof, "selectively" reduces the viability of cells expressing the KRas G12V mutant protein compared to cells expressing the KRas G12C protein, as determined by a cell proliferation assay, then the compound has an EC of at least 5 times (e.g., at least 10 times, at least 25 times, at least 50 times, or at least 100 times) smaller EC than KRas G12C protein-expressing cells when measured by a cell proliferation assay. 50As another example, if a compound or a pharmaceutically acceptable salt thereof provided herein "selectively" inhibits the KRas G13X mutant protein more than the wild-type KRas protein, as determined by a Raf kinase interaction assay, then the compound or a pharmaceutically acceptable salt thereof provided herein, as measured by a Raf kinase interaction assay, will have an IC50 (e.g., at least 10, at least 25, at least 50, or at least 100) smaller IC50 than that of the wild-type KRas G13X protein compared to the KRas G13X protein. 50 As a further example, if a compound or a pharmaceutically acceptable salt thereof provided herein "selectively" inhibits the KRas G12R mutant protein more than the wild-type KRas protein, as determined by a nucleotide exchange assay, then the compound or a pharmaceutically acceptable salt thereof provided herein, as measured by a nucleotide exchange assay, will have an IC50 (e.g., at least 10, at least 25, at least 50, or at least 100) smaller IC50 than that of the wild-type KRas protein compared to the KRas G12R mutant protein. 50 It has a value.

[0218] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are panmutagenic KRas inhibitors (i.e., they can inhibit two or more mutant KRas proteins (e.g., two or more of the KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein)). For example, such compounds inhibit each mutant KRas protein (e.g., two or more mutant KRas proteins) to an IC50 of less than 1 μM. 50 It can be inhibited at concentrations below 750 nM, 500 nM, or 200 nM. As another example, such compounds can be inhibited at independent IC50 levels below 1 μM in at least two of the cell lines. 50These compounds can inhibit ERK phosphorylation in cell lines expressing the respective mutant KRas proteins (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). For example, the compounds provided herein, or their pharmaceutically acceptable salts, inhibit ERK phosphorylation in cell lines expressing the KRas G12R mutant protein to IC50 less than 1 μM. 50 It can be inhibited by the compound provided herein, or a pharmaceutically acceptable salt thereof, which inhibits ERK phosphorylation in cell lines expressing the KRas G12V mutant protein to less than 1 μM IC2. 50 It can be inhibited by... In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are pan-KRas inhibitors (i.e., the compounds can inhibit wild-type KRas and one or more mutant KRas proteins). In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof do not inhibit specific KRas proteins (e.g., wild-type KRas or one or more dysregulated KRas proteins). For example, such compounds inhibit the interaction between a KRas protein (e.g., a dysregulated KRas protein) and one or more Raf proteins at an IC of 1 μM or greater than 1 μM (e.g., greater than 2 μM, greater than 5 μM, greater than 10 μM, or greater than 30 μM). 50 This can inhibit ERK phosphorylation in cell lines expressing KRas proteins (e.g., dysregulated KRas proteins) at IC12 or greater than 1 μM (e.g., greater than 2 μM, greater than 5 μM, greater than 10 μM, or greater than 30 μM). 50 It can be inhibited by this.

[0219] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit KRas G12D mutant proteins and KRas G12V mutant proteins. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit ERK phosphorylation by the compounds in cell lines expressing KRas G12V mutant proteins (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480) as measured by IC2. 50 ICs within approximately 10 times, that is, less than approximately 10 times or more than approximately 10 times (for example, less than approximately 9 times or more than approximately 9 times, less than approximately 8 times or more than approximately 8 times, less than approximately 7 times or more than approximately 7 times, less than approximately 6 times or more than approximately 6 times, less than approximately 5 times or more than approximately 5 times, or less than approximately 2 times or more than approximately 2 times) 50 Therefore, ERK phosphorylation is inhibited in cell lines expressing KRas G12D mutant proteins (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HPAC). For example, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit ERK phosphorylation in cell lines expressing KRas G12D mutant proteins to an IC50 of approximately 150 nM. 50 When inhibited, IC25 is measured for the inhibition of ERK phosphorylation by the compound in cell lines expressing the KRas G12V mutant protein. 50 The C5 is greater than approximately 150 nM by about 10 times, and therefore in the range of approximately 150 nM to approximately 1500 nM, or less than approximately 150 nM by about 10 times, and therefore in the range of approximately 15 nM to approximately 150 nM. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are measured for the inhibition of ERK phosphorylation by the compounds in the SW620 cell line. 50ICs that are within approximately 10 times, i.e., less than approximately 10 times or more than approximately 10 times (for example, less than approximately 9 times or more than approximately 9 times, less than approximately 8 times or more than approximately 8 times, less than approximately 7 times or more than approximately 7 times, less than approximately 6 times or more than approximately 6 times, less than approximately 5 times or more than approximately 5 times, or less than approximately 2 times or more than approximately 2 times) 50 Therefore, ERK phosphorylation in GP2d cell lines can be inhibited. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, have been shown to inhibit ERK phosphorylation in cell lines expressing KRas G12V mutant proteins (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480) as measured by IC2. 50 ERK phosphorylation in cell lines expressing KRas G12D mutant proteins (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HPAC) at a level of less than approximately 10 times (for example, less than approximately 9 times, less than approximately 8 times, less than approximately 7 times, less than approximately 6 times, less than approximately 5 times, or less than approximately 2 times) is controlled by IC. 50 It inhibits by [method]. For example, the compounds provided herein, or their pharmaceutically acceptable salts, have been measured for the inhibition of ERK phosphorylation by the compounds in the SW620 cell line. 50 ERK phosphorylation in GP2d cell lines is less than approximately 10 times (for example, less than approximately 9 times, less than approximately 8 times, less than approximately 7 times, less than approximately 6 times, less than approximately 5 times, or less than approximately 2 times) and IC 50 It can be inhibited by IC. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are used to measure the inhibition of ERK phosphorylation by the compounds in cell lines expressing KRas G12V mutant proteins (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480). 50ERK phosphorylation in cell lines expressing KRas G12D mutant proteins (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HPAC) that are within approximately 10 times (for example, within approximately 9 times, within approximately 8 times, within approximately 7 times, within approximately 6 times, within approximately 5 times, or within approximately 2 times) is performed by IC. 50 It inhibits by [method]. For example, the compounds provided herein, or their pharmaceutically acceptable salts, have been measured for the inhibition of ERK phosphorylation by the compounds in the SW620 cell line. 50 ERK phosphorylation in GP2d cell lines is within approximately 10 times (for example, within approximately 9 times, within approximately 8 times, within approximately 7 times, within approximately 6 times, within approximately 5 times, or within approximately 2 times) when IC 50 It can be inhibited by this.

[0220] In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, have an IC content of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). 50 Therefore, ERK phosphorylation is inhibited in cell lines expressing the KRas G12V mutant protein (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480). For example, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit IC50 at concentrations below 250 nM (e.g., <200 nM, <150 nM, <125 nM, <100 nM, <75 nM, <50 nM, <30 nM). 50 Therefore, ERK phosphorylation in the SW620 cell line can be inhibited. In some further embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof are IC250 nM or less (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM) 50Therefore, ERK phosphorylation is inhibited in cell lines expressing the KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HPAC). For example, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit IC50 at concentrations below 250 nM (e.g., <200 nM, <150 nM, <125 nM, <100 nM, <75 nM, <50 nM, <30 nM). 50 This allows for the inhibition of ERK phosphorylation in GP2d cell lines.

[0221] In some embodiments, the compounds provided herein or pharmaceutically acceptable salts thereof inhibit ERK phosphorylation in cell lines expressing KRas G12D mutant proteins (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HPAC) and inhibit ERK phosphorylation by the compounds in cell lines expressing KRas G12V mutant proteins (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480) as measured by IC2. 50 ICs within approximately 10 times, i.e., within approximately 10 times less or within approximately 10 times more (for example, within approximately 9 times less or within approximately 9 times more, within approximately 8 times less or within approximately 8 times more, within approximately 7 times less or within approximately 7 times more, within approximately 6 times less or within approximately 6 times more, within approximately 5 times less or within approximately 5 times more, or within approximately 2 times less or within approximately 2 times more) 50 The compounds provided herein or their pharmaceutically acceptable salts inhibit ERK phosphorylation in cell lines expressing KRas G12V mutant proteins (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480) at IC250 nM (e.g., <200 nM, <150 nM, <125 nM, <100 nM, <75 nM, <50 nM, <30 nM). 50Inhibits IC at concentrations below 250 nM (e.g., below 200 nM, below 150 nM, below 125 nM, below 100 nM, below 75 nM, below 50 nM, below 30 nM). 50 Therefore, it inhibits ERK phosphorylation in cell lines expressing the KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HPAC).

[0222] For example, the compounds provided herein, or pharmaceutically acceptable salts thereof, can inhibit ERK phosphorylation in GP2d cell lines with an IC50 of less than 10 times the IC50 measured for inhibition of ERK phosphorylation by the compounds in SW620 cell lines, i.e., less than 10 times or more than 10 times (e.g., less than 9 times or more than 9 times, less than 8 times or more than 8 times, less than 7 times or more than 7 times, less than 6 times or more than 6 times, less than 5 times or more than 5 times, or less than 2 times or more than 2 times). The compounds provided herein, or pharmaceutically acceptable salts thereof, have an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). 50 This inhibits ERK phosphorylation in the SW620 cell line. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, have an IC50 concentration of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). 50 This inhibits ERK phosphorylation in GP2d cell lines. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are measured for the inhibition of ERK phosphorylation by the compounds in cell lines expressing Ras G12V mutant proteins (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480) by IC2. 50ICs that are less than approximately 10 times (for example, less than approximately 9 times, less than approximately 8 times, less than approximately 7 times, less than approximately 6 times, less than approximately 5 times, or less than approximately 2 times) 50 The compounds provided herein inhibit ERK phosphorylation in cell lines expressing KRas G12D mutant proteins (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HPAC), and the compounds provided herein or their pharmaceutically acceptable salts inhibit ERK phosphorylation in cell lines expressing KRas G12V mutant proteins (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480) with an IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, have an IC content of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). 50 Therefore, it inhibits ERK phosphorylation in cell lines expressing the KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HPAC).

[0223] For example, the compounds provided herein, or their pharmaceutically acceptable salts, have been measured for the inhibition of ERK phosphorylation by the compounds in the SW620 cell line. 50 ICs that are less than approximately 10 times (for example, less than approximately 9 times, less than approximately 8 times, less than approximately 7 times, less than approximately 6 times, less than approximately 5 times, or less than approximately 2 times) 50 Therefore, the compounds provided herein, or their pharmaceutically acceptable salts, can inhibit ERK phosphorylation in GP2d cell lines and have an IC50 concentration of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). 50This inhibits ERK phosphorylation in the SW620 cell line. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, have an IC50 concentration of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). 50 This inhibits ERK phosphorylation in GP2d cell lines.

[0224] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are measured for the inhibition of ERK phosphorylation by the compounds in cell lines expressing KRas G12V mutant proteins (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480) in IC2. 50 ICs that are more than 10 times (for example, more than 9 times, more than 8 times, more than 7 times, more than 6 times, more than 5 times, or more than 2 times) 50 Therefore, ERK phosphorylation is inhibited in cell lines expressing KRas G12D mutant proteins (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HPAC), and the compounds provided herein or their pharmaceutically acceptable salts inhibit IC50 at concentrations of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). 50 Therefore, ERK phosphorylation is inhibited in cell lines expressing KRas G12V mutant proteins (e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480). In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, inhibit IC50 at less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). 50Therefore, it inhibits ERK phosphorylation in cell lines expressing the KRas G12D mutant protein (e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HPAC).

[0225] For example, the compounds provided herein, or their pharmaceutically acceptable salts, have been measured for the inhibition of ERK phosphorylation by the compounds in the SW620 cell line. 50 ICs that are within approximately 10 times (for example, within approximately 9 times, within approximately 8 times, within approximately 7 times, within approximately 6 times, within approximately 5 times, or within approximately 2 times) 50 Therefore, the compounds provided herein, or their pharmaceutically acceptable salts, can inhibit ERK phosphorylation in GP2d cell lines and have an IC50 concentration of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). 50 This inhibits ERK phosphorylation in the SW620 cell line. In some such embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, have an IC50 concentration of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM, less than 75 nM, less than 50 nM, less than 30 nM). 50 This inhibits ERK phosphorylation in GP2d cell lines.

[0226] The ability of the compounds provided herein, or their pharmaceutically acceptable salts, to bind to KRas proteins can be measured, for example, by direct determination methods (e.g., surface plasmon resonance or isothermal titration calorimetry). This involves radiolabeling the compound before binding, isolating the compound / protein complex, and determining the amount of radiolabeled material bound. Alternatively, it can be done by performing competitive experiments incubating novel compounds with proteins bound to known radioligands. As another example, the occupancy of the compounds provided herein, or their pharmaceutically acceptable salts, 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 can be used, along with an antibody that binds to a site on the protein other than where the compounds provided herein, or their pharmaceutically acceptable salts, bind (e.g., an antibody that binds to an N-terminal tag). It is 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. Patent Application Publication No. 2021 / 0179633.

[0227] In some cases, the binding affinity (e.g., dissociation constant K) of the compounds provided herein, or their pharmaceutically acceptable salts, to GDP-bound and / or GTP-bound KRas proteins (e.g., wild-type KRas protein or mutant KRas protein) is determined by the dissociation constant K. D The binding affinity (such as that measured by) can be measured using methods known in the art (e.g., using SPR (e.g., using one or more of the methods described herein (e.g., using the methods described in Example B1 or Example B5 herein))). The binding affinity to the GDP-bound KRas protein can be measured by loading the KRas protein with GDP (e.g., at the concentrations described in Example B1 or Example B5). The binding affinity to the GTP-bound KRas protein can be measured by loading the KRas protein with GMPPNP (e.g., at the concentrations described in Example B1).

[0228] Exemplary assays for determining the potency of the compounds provided herein, or pharmaceutically acceptable salts thereof, include measuring the effect of the compounds provided herein, or pharmaceutically acceptable salts thereof, on cell proliferation. Cell proliferation assays can be performed in several forms, including 2D and 3D. Similarly, cell proliferation assays can be performed using any suitable cell line, including, for example, A375, A427, A549, AGS, ASPC1, CAL62, CALU1, CAPAN1, CAPAN2, CFPAC1, GP2D, H358, H441, H460, H727, HCT116, HKA1, HPAC, HPAFII, HTK, HUPT3, KMS20, KP2, LS123, LS180, MIAPaCa-2, MKN1, NCI-H1993, NCI-H211, NCI-H424, NCI-H526, Panc02.03, Panc04.03, PATC50, PC9, PK8, PSN1, RKN, SW480, SW620, and / or TCCPAN2. In some embodiments, the cell line may be AGS, A375, A427, ASPC1, H727, H441, RKN, and / or SW620. As an exemplary example, a 3D cell proliferation assay may include growing cells in 3D medium, contacting the cells with a compound provided herein or a pharmaceutically acceptable salt thereof, measuring cell proliferation using a suitable reagent (e.g., CELLTITERGLO® 3D), and then comparing the signal from the experiment with the compound provided herein or a pharmaceutically acceptable salt thereof to the signal from a control experiment (e.g., lacking the compound provided herein).As another exemplary example, a 2D cell proliferation assay may include plating cells onto a growth surface, optionally growing the cells for a certain period of time, contacting the cells with a compound provided herein or a pharmaceutically acceptable salt thereof, measuring cell proliferation using a suitable reagent (e.g., CELLTITERGLO®), and then comparing the signal from the experiment with the compound provided herein or a pharmaceutically acceptable salt thereof to the signal from a control experiment (e.g., lacking the compound provided herein or a pharmaceutically acceptable salt thereof). See, for example, Example B7 of this specification. In some embodiments, cell proliferation can be evaluated using a platform for live cell imaging (e.g., INCUCYTE® SX5 Live-Cell Analysis Instrument). See, for example, U.S. Patent Application Publication 2021 / 0179633, U.S. Patent Application Publication 2021 / 0230142, and U.S. Patent Application Publication 2019 / 0284144.

[0229] As another example, the potency and / or efficacy of the compounds provided herein, or their pharmaceutically acceptable salts, can be evaluated in animal models, for example, xenograft models (using established cancer cell lines such as AGS, A375, A427, ASPC1, H727, H441, RKN, and / or SW620, or patient-derived xenograft (PDX) models). See, for example, U.S. Patent Application Publication No. 2021 / 0179633.

[0230] In some embodiments, the potency and / or efficacy of the compounds provided herein, or their pharmaceutically acceptable salts, can be evaluated in a cell-derived xenograft (CDX) model. In some embodiments, the compounds provided herein, or their pharmaceutically acceptable salts, are evaluated in a CDX (e.g., H727, RKN, or SW620) mouse model. For example, a cell line of interest (e.g., H727, RKN, or SW620) can be transplanted into a mouse, a tumor can be grown for a period of time, and then the compounds provided herein, or their pharmaceutically acceptable salts, can be administered to the mouse. The effect of the compounds provided herein, or their pharmaceutically acceptable salts, can be determined by measuring tumor growth (or regression). An exemplary protocol is as follows:

[0231] All procedures related to the handling, management, and treatment of animals in efficacy studies are carried out in accordance with the guidance of the Association for the Evaluation and Accreditation of Laboratory Animal Management (AAALAC) and the guidelines approved by the Animal Management and Use Committee (IACUC). In the right flank of 6-8 week old BALB / c nude female mice, 5 × 10¹⁴ cells in 0.1 mL of 1:1 medium / Matrigel were used to induce tumor development. 6 Individual H727, RKN, or SW620 tumor cells are subcutaneously inoculated. The average tumor volume is approximately 175-225 mm². 3 Treatment is initiated and group assignments are made when the tumor volume reaches a certain level. Based on tumor volume, mice are randomly assigned to each treatment group such that the mean starting tumor size is the same for each group. Mice with tumors are treated orally twice daily with the compounds provided herein or pharmaceutically acceptable salts thereof (e.g., doses of approximately 1 mg / kg to approximately 200 mg / kg, e.g., 1 mg / kg, 3 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 50 mg / kg, 75 mg / kg, 100 mg / kg, 150 mg / kg, or 200 mg / kg). The body weight of each animal is measured and recorded twice a week throughout the study. Tumor size is measured and recorded twice a week using a calipas. Tumor volume (mm 3 ) is the formula: TV = a × b2 It is estimated using / 2, where "a" and "b" are the major and minor diameters of the tumor, respectively. In some embodiments, the tumor volume is plotted as a function of time.

[0232] Further assays may include, for example, assays based on hydrogen exchange (HX) mass spectrometry. Such assays may be useful, for example, to evaluate whether a compound (e.g., the compounds provided herein, or their pharmaceutically acceptable salts) stabilizes the GTP-bound state or GDP-bound state of a KRas protein (e.g., a dysregulated KRas protein, e.g., a mutant KRas protein (e.g., KRas G12D mutant protein, KRas G12R mutant protein, or KRas G12V mutant protein)). In such assays, the hydrogen exchange rate of skeletal amide hydrogens can be measured for KRas proteins (e.g., dysregulated KRas proteins, e.g., mutant KRas proteins (e.g., KRas G12D mutant protein, KRas G12R mutant protein, or KRas G12V mutant protein)) bound to non-hydrolyzable GTP mimetic (GMPPNP), GDP, or the compounds provided herein, or their pharmaceutically acceptable salts. For example, see Lim et al. Angew Chem Int Ed Engl. 2014, 53(1):199-204, doi:10.1002 / anie.201307387.

[0233] In some embodiments, the potency of the compounds provided herein, or their pharmaceutically acceptable salts, is as provided herein, EC 50 It can be determined by the value. If determined under substantially similar conditions, a lower EC 50 Compounds with a higher EC value 50 It is a more potent inhibitor compared to compounds with the same value. In some embodiments, EC 50The values ​​represent KRas proteins, for example, dysregulated KRas proteins (e.g., mutant KRas proteins or amplified KRas proteins), or cells expressing fragments thereof (e.g., tumor cells, (e.g., A375, A427, A549, AGS, ASPC1, CAL62, CALU1, CAPAN1, CAPAN2, CFPAC1, GP2D, H358, H441, H460, H727, HCT116, HKA1, HPAC, HPAFII, HTK, HUPT3, KMS20, KP2, LS123, LS1 This can be determined in cell lines such as 80, MIAPaCa-2, MKN1, NCI-H1993, NCI-H211, NCI-H424, NCI-H526, Panc02.03, Panc04.03, PATC50, PC9, PK8, PSN1, RKN, SW480, SW620, and / or TCCPAN2 (for example, using KRas-dependent phosphorylation levels (e.g., phosphorylated ERK levels, sometimes called "pERK" levels)) or by using cell viability assays).

[0234] In some embodiments, the potency of the compounds provided herein, or their pharmaceutically acceptable salts, is as provided herein, IC 50 It can also be determined by the value. If determined under substantially the same conditions, the lower IC 50 Compounds with a higher IC value 50 It is a more potent inhibitor compared to compounds with the same value. In some embodiments, IC 50The values ​​represent KRas proteins, for example, dysregulated KRas proteins (e.g., mutant KRas proteins or amplified KRas proteins), or cells expressing fragments thereof (e.g., tumor cells, (e.g., A375, A427, A549, AGS, ASPC1, CAL62, CALU1, CAPAN1, CAPAN2, CFPAC1, GP2D, H358, H441, H460, H727, HCT116, HKA1, HPAC, HPAFII, HTK, HUPT3, KMS20, KP2) This can be determined in cell lines such as LS123, LS180, MIAPaCa-2, MKN1, NCI-H1993, NCI-H211, NCI-H424, NCI-H526, Panc02.03, Panc04.03, PATC50, PC9, PK8, PSN1, RKN, SW480, SW620, and / or TCCPAN2 (for example, using KRas-dependent phosphorylation levels (e.g., phosphorylated ERK levels) or using cell viability assays).

[0235] In some embodiments, measuring the potency of the compounds provided herein, or pharmaceutically acceptable salts thereof, involves measuring the phosphorylation of downstream kinases such as ERK (e.g., ERK1 and / or ERK2) or MEK. Using such assays, for example, cell lines (e.g., A375, A427, A549, AGS, ASPC1, CAL62, CALU1, CAPAN1, CAPAN2, CFPAC1, GP2D, H358, H441, H460, H727, HCT116, HKA1, HPAC, HPAFII, HTK, HUPT3, KMS20, KP2, LS123, LS180, MIAPaCa-2, MKN1, NCI) can be used. The inhibition of KRas signaling activity can be measured in H1993, NCI-H211, NCI-H424, NCI-H526, Panc02.03, Panc04.03, PATC50, PC9, PK8, PSN1, RKN, SW480, SW620, and / or TCCPAN2 (e.g., AGS, A375, A427, ASPC1, H727, H441, RKN, and / or SW620). For example, the compounds provided herein, or pharmaceutically acceptable salts thereof, can be brought into contact with cells for a certain period of time, followed by lysis or permeabilization to determine the total ERK or MEK and phosphoERK or phosphoMEK content (e.g., using antibodies or kits such as Invitrogen InstantOne 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, dose-response curves can be constructed using multiple concentrations of the compounds provided herein, or pharmaceutically acceptable salts thereof. See, for example, Example B6 herein.For example, see International Publication No. 2021 / 041671, U.S. Patent Application Publication No. 2021 / 0122764, U.S. Patent Application Publication No. 2018 / 0334454, U.S. Patent Application Publication No. 2021 / 0179633, U.S. Patent Application Publication No. 2018 / 0334454, and U.S. Patent Application Publication No. 2019 / 0144444.

[0236] 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 are seeded at the desired concentration one day prior to treatment with the compound provided herein or a pharmaceutically acceptable salt thereof in a plate (e.g., white opaque bottom Perkin Elmer CulturPlate-384 (product no. 6007680)) and incubated overnight in a standard 37°C, 5% CO2 humidified incubator. The cells are MIAPACA-2 (KRas G12C), H358 (KRas G12C), AGS (KRas G12D), ASPC1 (KRas G12D), GP2D (KRas G12D), LS180 (KRas G12D), Panc04.03 (KRas G12D), HPAFII (KRas G12D), Panc02.03(KRas G12D), A427(KRas G12D), HPAC(KRas G12D), TCCPAN2(KRas G12R), PSN1(KRas G12R), KP2(KRas G12R), LS123(KRas G12S), SW620(KRas G12V), H727(KRas The target cells may be any of the following: G12V), CFPAC1 (KRas G12V), CAPAN1 (KRas G12V), CAPAN2 (KRas G12V), RKN (KRas G12V), H441 (KRas G12V), SW480 (KRas G12V), PACADD159 (KRas G12V / G12S), HS766T (KRas Q61H), H460 (KRas Q61H), PANC0213 (KRas Q61R), or A3735 (KRas WT). The day after seeding, the compounds provided herein, or pharmaceutically acceptable salts thereof, were dispensed into treatment plates (e.g., using a Tecan D300e compound printer, in 9-point DRC format (1:3 dilution), in 3-packs at a maximum concentration of 10-μM). Next, the processing plate is returned to a standard 37°C, 5% CO2 humidified incubator for a predetermined processing time.After compound treatment, remove all culture medium from the treatment plate, then lyse the cells (e.g., using 1× lysis buffer according to the manufacturer's protocol). Next, add the Acceptor Mix (prepared according to the manufacturer's protocol) to each well of the assay plate and incubate on an orbital shaker at room temperature for 2 hours. After incubation with the acceptor mix, add the donor mix (prepared according to the manufacturer's protocol) to each well of the assay plate, cover to protect from light, and incubate overnight on an orbital shaker at room temperature. The next day, read the assay plate (e.g., with a BMG Labtech PHERAstar FSX microplate reader). Then, for each individual well, analyze the data by calculating the ratio of ERK1 / 2 phosphorylation to total ERK1 / 2. TIFF2026534205000208.tif12128

[0237] The repeat ratios for each concentration are averaged and normalized to the DMSO control or other corresponding co-treatments. Then, a variable-slope (4-parameter) nonlinear regression curve is fitted for each compound of interest. The data is then converted to IC. 50 It can be reported as a value.

[0238] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, induce ERK phosphorylation in cell lines expressing KRas proteins (e.g., dysregulated KRas proteins (e.g., mutant KRas proteins (e.g., KRas G12D mutant protein, KRas G12R mutant protein, or KRas G12V mutant protein))) with an IC2C of less than 1 nM. 50 Inhibits ERK phosphorylation in cell lines expressing KRas proteins (e.g., dysregulated KRas proteins (e.g., mutant KRas proteins (e.g., KRas G12D mutant protein, KRas G12R mutant protein, or KRas G12V mutant protein))) at IC200 nM or less. 50Inhibition occurs at concentrations below 150 nM, 200 nM, 100 nM, 10 nM, and 1 nM. For example, compounds inhibit IC at concentrations 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 Therefore, ERK phosphorylation can be inhibited in cell lines expressing KRas proteins (e.g., dysregulated KRas proteins (e.g., mutant KRas proteins (e.g., KRas G12D mutant protein, KRas G12R mutant protein, or KRas G12V mutant protein))).

[0239] In some cases, the KRas protein can be "locked" into a GTP-bound state (e.g., by inhibiting the protein's GTPase activity) using the KRas A59G mutant protein (e.g., as a single mutant or as a double mutant with another mutant of interest, e.g., KRas G12X). Such assays may be useful for determining the affinity of the compounds provided herein, or their pharmaceutically acceptable salts, and for determining the effect of the compounds on the GTP-bound state and / or on downstream signaling (e.g., interaction with RBD and / or phosphorylation of downstream kinases such as ERK), potentially independently of the GTP cycling of the KRas protein. For example, see Hall, et al. Proceedings of the National Academy of Sciences 99.19(2002):12138-12142, doi:10.1073 / pnas.192453199; Lu, et al. Biochemistry 57.3(2018):324-333, doi:10.1021 / acs.biochem.7b00974; and Lim, Shuhui, et al. Chemical Science 12.48(2021):15975-15987, doi:10.1039 / D1SC05187C.

[0240] In some embodiments, the potency of the compounds provided herein as KRas inhibitors, or pharmaceutically acceptable salts thereof, can be evaluated by their effect on nucleotide exchange of GDP to GTP. For example, nucleotide exchange can be measured by the increase in fluorescence of protein-bound N-methylanthraniloyl (MANT)-GDP upon addition of an excess amount of a non-hydrolyzable GTP analog, such as guanosine-5'-[(β,γ)-imide] triphosphate (GppNHp, sometimes also called GMPPNP), if the exchange is inhibited. See, for example, Kanie and Jackson, Bio Protoc. 2018;8(7):e2795, doi:10.21769 / BioProtoc.2795. As another example, nucleotide exchange can be measured by a decrease in fluorescence of an incubated mixture of KRas protein-bound fluorophore-tagged GDP (e.g., Bodipy-GDP (e.g., EDA-GTP-DY-647P1)) with the compound provided herein, or a pharmaceutically acceptable salt thereof, followed by treatment with unlabeled GTP. In such an assay, exchanging fluorophore-tagged GDP (e.g., Bodipy-GDP) for unlabeled GTP results in a decrease in the TR-FRET signal. As yet another example, nucleotide exchange can be measured by an increase in fluorescence of an incubated mixture of KRas protein-bound GDP with the compound provided herein, or a pharmaceutically acceptable salt thereof, followed by treatment with labeled GTP. In such an assay, exchanging GDP for labeled GTP results in an increase in the FRET signal. See, for example, International Publication No. 2020 / 085493 and U.S. Patent Application Publication Nos. 2021 / 0122764, 2021 / 0269434, and 2018 / 0334454. In some embodiments of the nucleotide exchange assay, a guanine nucleotide exchange factor (e.g., SOS1) may be added to accelerate nucleotide exchange.

[0241] The inhibition of SOS1 catalytic exchange of GDP to GTP on the KRas protein by the compounds provided herein, or pharmaceutically acceptable salts thereof, can be measured using methods known in the art (e.g., using 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 to determine the inhibition of GTPase activity of the KRas protein. In some embodiments, the potency of the compounds provided herein, or pharmaceutically acceptable salts thereof, can be evaluated by their effect on GTPase activity (or, since a decrease in GTPase activity is generally considered to be associated with abnormal signaling, its absence). For example, the GTPase activity of the KRas protein can be measured using a phosphate assay system that continuously measures phosphate release. In some embodiments, the GTPase activity of the 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, doi:10.1158 / 1541-7786.MCR-15-0203. In some embodiments, the effect of the compounds provided herein, or pharmaceutically acceptable salts thereof, on the GTPase activity of KRas proteins (e.g., dysregulated KRas proteins, e.g., mutant KRas proteins (e.g., KRas G12D mutant protein, KRas G12R mutant protein, or KRas G12V mutant protein)) can be measured by using an enzyme-linked immunosorbent assay (ELISA) to detect, for example, the change in the amount of GST-Ras-RBD bound to the KRas protein after complex pull-down and antibody detection. See, for example, U.S. Patent 2021 / 0179633.

[0242] An exemplary SOS1-catalyzed nucleotide exchange assay protocol is as follows: GST-KRas G12R(1-169) loaded with GDP nucleotides 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 prepare a 1.5× solution. 10 μL of the 1.5× KRas-Ab solution is added to the wells of a black, low-volume 384-well assay plate. The compounds provided herein, or their pharmaceutically acceptable salts, are added to the wells using acoustic transfer techniques. Ten dose-response tests are performed for each compound at the highest dose of 30 μM. The KRas / Ab-compound mixtures are incubated at room temperature for 1 hour. A 3× solution of SOS1 (564-1049) and EDA-GTP-DY-647P1 (Jena Bioscience) is prepared in assay buffer. 5 μL 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 using a PHERAstar plate reader equipped with a filter module with excitation = 337 nm and emission 1 = 620 nm and emission 2 = 665 nm. The HTRF signal is calculated as the ratio of fluorescence intensity [emission 665 nm] / [emission 620 nm]. IC 50 The values ​​are calculated using a 4-parameter variable response sigmoid dose-response curve fit in Graphpad Prism software.

[0243] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, have an IC content of less than 1 μM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). 50 This inhibits the SOS1 catalytic exchange of GDP to GTP on the KRas protein. In some embodiments, the compound has an IC50 of less than 200 nM. 50This compound inhibits the SOS1 catalytic exchange of GDP to GTP on the KRas protein (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, this compound inhibits the SOS1 catalytic exchange of GDP to GTP on the KRas protein in the IC50 range 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 It can be inhibited by this.

[0244] Further assays for evaluating the potency of the compounds provided herein, or pharmaceutically acceptable salts thereof, may include, for example, RAF kinase interaction assays. Such assays can be used to measure the affinity of a KRas:nucleotide complex to the Ras-binding domain (RBD) of RAF protein kinase (e.g., when affected by the compounds provided herein or their pharmaceutically acceptable salts). For example, a FLAG-tagged KRas protein can be pre-loaded with the GTP analog GppNHp and then incubated with biotinylated Raf-RBD to form a complex. A competitive assay can then be performed by adding untagged KRas proteins pre-loaded with GppNHp pre-loaded with various test molecules over a certain concentration range. The affinity of the KRas protein to Raf kinase can be determined by measuring proximity-dependent signals after the addition of streptavidin donors and anti-flag acceptor beads (e.g., ALPHASCREEN® beads). For example, see Hunter et al. Mol Cancer Res. 2015;13(9):1325-35,doi:10.1158 / 1541-7786.MCR-15-0203; Lim et al. Angew Chem Int Ed Engl. 2014, 53(1):199-204,doi:10.1002 / anie.201307387; and Durrant, et al. Molecular Cancer Therapeutics 20.9(2021):1743-1754,doi:10.1158 / 1535-7163.MCT-21-0175. As another example, with respect to a compound provided herein that can selectively bind to a GTP-bound state, or a pharmaceutically acceptable salt thereof, a His-tagged KRas protein may be pre-loaded with the GTP analog GppNHp and then incubated with the compound provided herein, or a pharmaceutically acceptable salt thereof, to form a complex. A competitive assay can then be performed by adding Raf-RBD.IC was compared using proximity-dependent signals after the addition of alpha detection reagent, compared with signals from the same experiment using GDP instead of GppNHP. 50The values ​​can be determined. For example, see International Publication No. 2021 / 085653. It is understood that in many cases, tagging techniques (e.g., FLAG tags, His tags, biotinylation) can be modified in the assay by those skilled in the art. In some embodiments, the RAF kinase interaction assay can be combined with a nucleotide exchange assay. For example, the compounds provided herein, or pharmaceutically acceptable salts thereof, may be incubated with KRas protein (e.g., dysregulated KRas protein, e.g., mutant KRas protein (e.g., KRas G12D mutant protein, KRas G12R mutant protein, or KRas G12V mutant protein)) and GDP, and then GTP (and optionally, a GEF such as SOS1) may be introduced. Then, RAF (e.g., cRAF) acceptor beads (e.g., GST-tagged acceptor beads) may be incubated with the KRas mixture, followed by the introduction of donor beads (e.g., glutathione donor beads), and measurement may be performed using ALPHASCREEN® technology. As an alternative to ALPHASCREEN® technology, uniform time-resolved fluorescence can be performed using any suitable FRET pair. See, for example, U.S. Patent Application Publication 2018 / 0334454 and U.S. Patent Application Publication 2021 / 0230142. Another exemplary assay for measuring the affinity of the KRas:nucleotide complex to RBD involves incubating cells with the compound provided herein or a pharmaceutically acceptable salt thereof, lysing the cells, and then pulling down non-RBD-bound KRas using immobilized RBD. See, for example, U.S. Patent Application Publication 2019 / 0233440. As another example, the effect of the compound provided herein or a pharmaceutically acceptable salt thereof on the interaction between KRas and Raf-RBD can be evaluated using HiBiT and / or NANOBIT® technology, in which two portions of the enzyme are fused or inserted into the two proteins of interest (e.g., KRas and Raf-RBD).When the two target proteins are in close proximity, the two parts of the enzyme are complementary to each other, completing an enzyme that has signaling activity (e.g., produces fluorescence). In some such assays, the affinity of the two parts of the enzyme can be adjusted to reduce or eliminate the signal based on proximity driven by the two parts of the enzyme, for example. See, for example, Schwinn, et al. ACS Chemical Biology 13.2(2018):467-474, doi:10.1021 / acschembio.7b00549. Similarly, the effect of the compounds provided herein, or their pharmaceutically acceptable salts, on the interaction between KRas and Raf-RBD can be evaluated using NANOBRET® technology, where the two parts of the signaling pathway (e.g., protein and ligand) are fused or inserted into the two target proteins (e.g., KRas and Raf-RBD). When the two target proteins are in close proximity, the two parts of the signaling pathway have signaling activity (e.g., produce fluorescence). For example, see Durrant, et al. Molecular Cancer Therapeutics 20.9(2021):1743-1754, doi:10.1158 / 1535-7163.MCT-21-0175. In some embodiments, an RAF kinase interaction assay can be used to determine whether the compounds provided herein, or pharmaceutically acceptable salts thereof, are selective for GDP-bound or GTP-bound KRas proteins (e.g., dysregulated KRas proteins, e.g., mutant KRas proteins (e.g., KRas G12D mutant protein, KRas G12R mutant protein, or KRas G12V mutant protein)).

[0245] The inhibition of the interaction between the KRas protein and Raf-RBD by the compounds provided herein, or pharmaceutically acceptable salts thereof, can be measured using methods known in the art (for example, using one or more of the methods described herein (for example, using the methods described in Example B3 or Example B4 herein)).

[0246] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, modulate the interaction between the KRas protein and one or more Raf proteins. In some embodiments, the compounds are expressed in an IC50 of less than 1 μM. 50 This inhibits the interaction between the KRas protein and Raf-RBD (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compound has an IC50 of less than 200 nM. 50 This inhibits the interaction between the KRas protein and Raf-RBD (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 in IC50s 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 It inhibits it.

[0247] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, exhibit an IC50 of less than 1 μM in the absence of cyclophylline A. 50 This inhibits the interaction between the KRas protein and Raf-RBD (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compound inhibits IC200 nM in the absence of cyclophylline A. 50 This inhibits the interaction between the KRas protein and Raf-RBD (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 in the absence of cyclophyllin A in IC50s 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 It inhibits it.

[0248] Another exemplary assay for evaluating the potency of the compounds provided herein, or pharmaceutically acceptable salts thereof, includes measuring the phosphorylation of downstream kinases such as ERK (e.g., ERK1 and / or ERK2) or MEK. Using such assays, the inhibition of KRas signaling activity can be measured in cell lines (e.g., A375, A427, A549, AGS, ASPC1, CAL62, CALU1, CAPAN1, CAPAN2, CFPAC1, GP2D, H358, H441, H460, H727, HCT116, HKA1, HPAC, HPAFII, HTK, HUPT3, KMS20, KP2, LS123, LS180, MIAPaCa-2, MKN1, NCI-H1993, NCI-H211, NCI-H424, NCI-H526, Panc02.03, Panc04.03, PATC50, PC9, PK8, PSN1, RKN, SW480, SW620, and / or TCCPAN2). For example, the compounds provided herein, or pharmaceutically acceptable salts thereof, can be brought into contact with cells for a certain period of time, followed by lysis or permeabilization to determine the total ERK or MEK and phosphoERK or phosphoMEK content (e.g., using an antibody or a kit such as Invitrogen InstantOne ERK1 / ERK2(phospho)[pT202 / pY204] / [pT185 / pY187]ELISA or MesoScale Discovery p / t ERK1 / 2). In some embodiments, dose-response curves can be constructed using multiple concentrations of the compounds provided herein, or pharmaceutically acceptable salts thereof.

[0249] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, induce ERK phosphorylation in cell lines expressing KRas proteins (e.g., mutant KRas proteins (e.g., KRas G12D mutant protein, KRas G12R mutant protein, or KRas G12V mutant protein)) at IC250m (e.g., less than 1 nM, less than 750 nM, less than 500 nM, less than 200 nM) 50It inhibits ERK phosphorylation in cell lines expressing KRas proteins (e.g., mutant KRas proteins (e.g., KRas G12D mutant protein, KRas G12R mutant protein, or KRas G12V mutant protein)) at IC250m (e.g., less than 150nM, less than 200nM, less than 100nM, less than 10nM, less than 1nM) 50 This inhibits IC at concentrations of 0.1nM to 100nM, 0.1nM to 50nM, 1nM to 50nM, or 1nM to 20nM. 50 Therefore, ERK phosphorylation can be inhibited in cell lines expressing KRas proteins (e.g., mutant KRas proteins (e.g., KRas G12D mutant protein, KRas G12R mutant protein, or KRas G12V mutant protein)).

[0250] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can selectively inhibit one or more mutant KRas proteins than wild-type KRas proteins. The selectivity between wild-type KRas proteins and mutant KRas proteins described herein can be measured using a cell growth assay in which cell growth depends on signaling activity. For example, HEK293 cells transfected with an appropriate version of wild-type KRas, or HEK293 cells transfected with KRas containing one or more mutations described herein (e.g., G12D mutation, G12R mutation, or G12V mutation) can be used. The growth assay can be performed at a range of inhibitor concentrations (e.g., 10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM), and EC 50 Calculate.

[0251] See also the assays described in International Publication No. 2021 / 120890, International Publication No. 2021 / 041671, and U.S. Patent Application Publication Nos. 2021 / 0130369, 2021 / 0179633, 2018 / 0334454, and 2021 / 0122764.

[0252] The pharmacokinetic parameters of the compounds provided herein, or their pharmaceutically acceptable salts, can be evaluated in animal models, such as mouse models, rat models, dog models, or non-human primate models (e.g., cynomolgus monkey models). These parameters include clearance (CL) and volume of distribution (V). d ), maximum plasma concentration (C max ), maximum plasma concentration time (t max ), half-life (t 1 / 2 Pharmacokinetic parameters, including pharmacokinetics, 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)) may be used as a comparator. See, for example, Example 3 of International Publication No. 2023 / 098425 ("Pharmacokinetic Experiments in Mice").

[0253] The specific pharmacokinetic parameters of the compounds provided herein, or pharmaceutically acceptable salts thereof, can be evaluated in mice, rats, dogs, non-human primates (e.g., cynomolgus monkeys), or hepatocytes such as human hepatocytes. These parameters include clearance (CL) and half-life (t 1 / 2 Pharmacokinetic parameters including ) 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 ("Hepatic Microsomal Metabolic Stability") of International Publication No. 2023 / 284881.

[0254] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can be evaluated in animal models for their pharmacokinetic parameters and / or their ability to induce toxicity (e.g., cutaneous toxicity). For example, the compounds provided herein, or pharmaceutically acceptable salts thereof, may be administered to an animal (e.g., a rat), and bodily fluid (e.g., blood) samples may be taken at various points in time and analyzed for the amount of the remaining compound or pharmaceutically acceptable salt provided herein. In another example, the compounds provided herein, or pharmaceutically acceptable salts thereof, may be administered to an animal (e.g., a rat), and the animal's skin may be evaluated for redness, scaling, and / or thickness. An exemplary protocol is as follows:

[0255] Rats (e.g., male RNU nude rats or Sprague-Dolly IGS rats, 6-8 weeks old) are administered orally once daily for several days (e.g., 14 days) with the compounds provided herein, or pharmaceutically acceptable salts thereof. The compounds provided herein, or pharmaceutically acceptable salts thereof, are administered to rats at a given dose level (e.g., 1, 3, 5, 10, 25, 30, 50, or 100 mg / kg) in a solution or suspension formulation (e.g., 10% DMSO / 90% hydroxypropyl methylcellulose). The rats are given free access to food and water.

[0256] Blood samples from rats (e.g., 200 μL per sample) are collected at predetermined intervals, such as 4, 8, or 24 hours, after the initial dose has been administered. Blood samples are obtained via jugular vein puncture, and then the blood samples (e.g., concomitantly with K2EDTA as an anticoagulant) are temporarily placed on ice and then centrifuged within 30 minutes (e.g., 5 minutes at 4°C and 4600 RPM). Plasma samples can be diluted 1:1 v / v with acidified phosphate buffer and placed on dry ice. After the completion of the final sample collection, all samples are stored at -80°C or analyzed shortly after collection. The concentrations of the compounds provided herein, or their pharmaceutically acceptable salts, measured in acidified plasma samples (e.g., diluted 1:1 v / v with pH 3 phosphate buffer) can be determined (e.g., via LC / MS / MS). For example, acidified plasma samples are prepared for analysis using protein precipitation (e.g., by adding acetonitrile), and internal standards are spiked at known concentrations. The spiked sample is mixed, centrifuged, and the supernatant is used for LC / MS / MS. The LC / MS / MS method uses ACQUITY UPLC BEH C18 1.7μm (2.1) with a first mobile phase of 5mM NH4OAc (0.05% formic acid (FA) or 0.1% FA) and a second mobile phase of acetonitrile (0.1% FA). * Use a 50 mm column. Measure the target analyte using multiple reaction monitoring. Use the concentration of the compound provided herein or its pharmaceutically acceptable salt in the plasma sample, t 1 / 2 (hr), t max (hr), C max (ng / mL), AUC last (hr * ng / mL), AUC Inf (hr * ng / mL), AUC Extr (%), MRT Inf (hr), AUC Inf / D(hr * kg * Determine the pharmacokinetic parameters (ng / mL / mg) and F(%).

[0257] During drug administration, the rats' clinical signs, body weight, and food consumption will be tracked. The likelihood of skin rash will be intermittently tracked before and during drug administration using one or more methodologies. Skin redness (erythema) or scaling will be assessed using a skin scoring system on a scale of 0 to 4. The thickness of the skin on the back will be measured using a micrometer (MITUTOYO ABSOLUTE Digimatic Micrometer Series 227-211). For the skin on the back, thickness will be measured by folding the skin of the applicable area between the thumb and index finger, followed by measurement with the micrometer. The rats will then be sacrificed and evaluated for abnormalities.

[0258] In some embodiments, compounds provided herein, or pharmaceutically acceptable salts thereof, can be tested for their potency in inhibiting hERG potassium channels. Cardiac potassium channels hERGs are responsible for the rapid delayed rectification current (I) in the human ventricle. Kr ) is the cause, I Kr Inhibition of hERG is the most common cause of prolonged cardiac action potentials (HERGs) due to noncardiac drugs. Increased action potential duration leads to QT interval prolongation, which is associated with dangerous ventricular arrhythmias, torsades de pointes. Several methods exist to test hERG inhibitory efficacy, including SyncroPatch hERG and manual patch-clamp experiments.

[0259] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are tested for their potency in inhibiting hERG potassium channels using the SyncroPatch hERG assay. For example, in some embodiments, solutions or suspensions of the compounds provided herein, or pharmaceutically acceptable salts thereof, can be exposed to a single CHO or HEK293 cell at several concentrations (0.30 μM, 1.00 μM, 3.00 μM, 10.00 μM, and 30.00 μM). The effect of the compounds provided herein, or pharmaceutically acceptable salts thereof, on inhibiting hERG potassium channels is measured by electrical pulse patterns, plotted data, and calculated ICs for hERG inhibition by the compounds provided herein, or pharmaceutically acceptable salts thereof. 50 The values ​​can be used to measure this system. An example protocol is as follows:

[0260] hERG potassium channels are endogenous I KrIt is expressed in Chinese hamster ovary (CHO (Sophian Biosciences)) cell lines that lack it. See, for example, the following. Brown,Arthur M.,and David Rampe.Pharmaceutical News 7.4(2000):15-20;Weirich,Jorg,and H.Antoni,Basic Research in Cardiology 93(1998):s125-s132,doi:10.1007 / s003950050236;Yap,Yee Guan,and AJCamm.Clinical & Experimental Allergy 29(1999):174-181,doi:10.1046 / j.1365-2222.1999.0290s3174.x;Haraguchi,Yuji,et al.BMC Pharmacology and Toxicology 16(2015):1-6,doi:10.1186 / s40360-015-0042-9;and Walker, BD, et al.British Journal of Pharmacology 127.1(1999):243-251,10.1038 / sj.bjp.0702502.

[0261] All chemicals used in the solution preparations are purchased from commercial suppliers (e.g., Sigma-Aldrich) and are of ACS reagent grade purity or higher. Stock solutions of the compounds provided herein, or their pharmaceutically acceptable salts, positive control compounds, and reference substances, are prepared in dimethyl sulfoxide (DMSO) and stored cryopreserved. Solutions of each test compound, or its pharmaceutically acceptable salt, positive control compounds, and reference substances provided herein are freshly prepared daily by diluting the stock solution in HEPES-buffered saline (HB-PS; 140 mM NaCl, 4 mM KCl, 2.0 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 5 mM glucose, pH 7.4). Since previous results have shown that ≤0.3% DMSO does not affect the channel current, all test and control solutions may contain up to 0.3% DMSO.

[0262] In some embodiments, a positive control compound may be included in the experiment. In some such embodiments, the positive control compound may be, for example, amitriptyline (Sigma-Aldrich) in a solution of HB-PS and 0.3% DMSO.

[0263] In some embodiments, a positive control compound may be included in the experiment. In some such embodiments, the positive control compound may be, for example, E-4031(4'-[[1-[2-(6-methyl-2-pyridinyl)ethyl-4-piperidinyl]carbonyl]methanesulfonanilide,2HCl)(Sigma-Aldrich) in HB-PS and 0.3% DMSO solution.

[0264] If necessary, the solution should be sonicated to facilitate dissolution. Any visible precipitates observed during the preparation of the formulation or exposure to the test system should be noted for reference.

[0265] The effects of the compounds provided herein, or their pharmaceutically acceptable salts, are first evaluated at 1 μM. Subsequent concentrations are evaluated based on the inhibition observed at this initial concentration.

[0266] CHO cells that are at least two days after plating and more than 75% confluent should be used in the experiment. Before testing, harvest the cells using TrypLE and resuspend them in HB-PBS at room temperature. Prepare HB-PBS and an external solution (80 mM NaCl, 4 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 60 mM M-methyl-D-glucamine (NMDG), 10 mM HEPES, and 5 mM glucose, pH 7.4) and store for up to one month.

[0267] Voltage command protocol: Starting from a holding potential of -80mV, the voltage is first reduced to -50mV for 80ms for leakage subtraction, then to +20mV for 4800ms to open the hERG channel. The voltage is then reduced to -50mV for 5000ms to induce a "rebound" or tail current, which is measured and collected for data analysis. Finally, the voltage is returned to the holding potential (-80mV, 1000ms). This voltage command protocol is repeated every 20,000 milliseconds. This command protocol is performed continuously during the experiment.

[0268] The hERG SyncroPatch assay is performed at room temperature. Setup, prime tip, catch and seal cells, amplifier settings, voltage, and application protocol are established in Biomek Software (Nanion). One cell per well is clamped to form a gigaseal. On one side of the seal, the cells are immersed in an external solution. On the opposite side, 40 μL of vehicle (e.g., HB-PBS) is added, followed by a 300-second pause to establish a baseline period. Then, a dose (40 μL) of the compound provided herein, or a pharmaceutically acceptable salt thereof, is added, and this process is repeated for different concentrations. Exposure to the compound provided herein, or a pharmaceutically acceptable salt thereof, is for at least 300 seconds at each concentration. Records of the entire process must pass quality control criteria (e.g., seal quality, rundown attributes), or the well is abandoned, the compound is retested, and all are automatically set according to exclusion criteria determined before the start of the experiment. Five concentrations (0.30 μM, 1.00 μM, 3.00 μM, 10.00 μM, and 30.00 μM) are tested for each test compound provided herein, or its pharmaceutically acceptable salt. A minimum of two replicates are obtained for each concentration.

[0269] Data analysis will be performed using DataControl, Excel 2013 (Microsoft), and GraphPad Prism 5.0.

[0270] Within the records for each well, the percentage of the control value is calculated for each concentration of the compound provided herein, or its pharmaceutically acceptable salt, as 100% of the current response (current response / peak current) based on the peak current in the presence of the reference compound (e.g., E-4031). The dose-response curve is fitted to the standard Hill equation as shown below. In formula TIFF2026534205000209.tif12128, X is the logarithm of the concentration, and I 後化合物 / I 前化合物 This represents the normalized peak current amplitude, with a maximum value of 1 and a base value of 0.

[0271] Curve fitting and IC 50 The calculation is performed by GraphPad Prism 5.0. If the inhibition obtained at the lowest concentration tested is greater than 50%, or if the inhibition at the highest concentration tested is less than 50%, then IC is calculated. 50 These are reported to be below the minimum concentration or above the maximum concentration, respectively. In some embodiments, a positive control may be included in the experiment. In some such embodiments, the positive control compound may be, for example, cisapride (Tocris Bioscience) in a 0.3% DMSO solution.

[0272] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are not hERG inhibitors. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are IC250+ (e.g., 100nM, 300nM, 500nM, 1μM, 3μM, 5μM, 10μM, 20μM, or 30μM) 50 This inhibits hERG. For example, the compounds provided herein, or their pharmaceutically acceptable salts, inhibit IC50 above 500 nM (e.g., 1 μM, 3 μM, 5 μM, 10 μM, 20 μM, or 30 μM). 50 This inhibits hERG. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are present in an IC50 greater than 1 μM (e.g., 3 μM, 5 μM, 10 μM, 20 μM, or 30 μM). 50This inhibits hERG. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, are present in greater than 10 μM (e.g., greater than 20 μM or 30 μM) IC50. 50 This inhibits hERG. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, have an IC50 greater than 30 μM. 50 This inhibits hERG.

[0273] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can be evaluated for their stability in hepatocytes (e.g., human hepatocytes). In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can be evaluated for their stability in human hepatocytes and for endogenous hepatocyte clearance (CL). int (hep)) values ​​are obtained from which endogenous hepatic clearance (CL) is determined. int The half-life (t) can be estimated. For example, human liver cells can be incubated with the compound provided herein or a pharmaceutically acceptable salt thereof, and aliquots can be taken at various time points and analyzed for the amount of the remaining compound or pharmaceutically acceptable salt thereof. The half-life (t) can then be estimated using a first-order rate equation. 1 / 2 ) and CL int (hep) can be determined. 。 An example protocol is as follows:

[0274] Prepare a 1000× stock solution of the compound provided herein to its final concentration (e.g., 1 mM in DMSO). Similarly, prepare a 1000× stock solution of a positive control compound (e.g., 7-ethoxycoumarin and / or 7-hydroxycoumarin) to its final concentration (e.g., 3 mM in DMSO). Then, prepare a 100× stock solution by dilution with acetonitrile.

[0275] Cell suspension (e.g., 0.5 × 10) 6To prepare cells / mL, cryopreserved hepatocytes (e.g., human hepatocytes) are thawed (e.g., in Williams medium E containing 5% fetal bovine serum and 30% Percoll solution and other supplements), isolated, suspended in Williams medium E (without phenol red) containing incubation medium (e.g., 2 mM L-glutamine and 25 mM HEPES), and then incubated in pre-warmed incubation medium for 0.5 × 10⁶ cells / mL. 6 Dilute to cells / mL. Add the pre-warmed cell suspension (e.g., 198 μL) to the wells of a test plate (e.g., a 96-well plate).

[0276] Quench plates are prepared by transferring a stop solution (e.g., acetonitrile containing tolbutamide and labetalol as internal standards) (e.g., 125 μL) to a set of pre-labeled 96-well plates, one quench plate for T0 and one plate per time point being tested.

[0277] To begin the experiment, add 2 μL of a 100× dose solution of the compound provided herein, or a pharmaceutically acceptable salt thereof, or 2 μL of a 100× dose solution of the control compound, to the wells of the test plate. This is done twice.

[0278] For T0 samples, the plates are mixed to obtain a homogeneous suspension (e.g., by mixing for about 1 minute), and then aliquots (e.g., 25 μL) of each sample on the test plate are immediately transferred to the wells of a quench plate containing ice-cooled stop solution (e.g., 125 μL), and then mixed.

[0279] The test plate is incubated (e.g., in a 95% humidified incubator with 5% CO2 at 37°C, with constant shaking) to initiate the reaction. At 15, 30, 60, and 90 minutes, the plate is mixed, and then an aliquot (e.g., 25 μL) of each sample is transferred to a well in a quench plate containing ice-cooled stop solution (e.g., 125 μL), and then mixed.

[0280] Medium control (MC) sample plates (at least one for the first and last time points, with additional time points being optional) are prepared in the same manner as the test plates, except that incubation medium is used instead of cell suspension. At each corresponding time point as a test plate, the corresponding MC plate is removed from the incubator and the reaction is stopped by mixing it with ice-cooled stop solution (e.g., 125 μL).

[0281] Immediately after adding stop solution to each plate, vortex the plate (e.g., on a plate shaker at 600 RPM for 10 minutes). Then, centrifuge the plate (e.g., at 3220 × g for 20 minutes at 4°C).

[0282] After centrifugation, transfer the supernatant from the plate (e.g., 80 μL / well) to another plate containing ultrapure water (240 μL per well) according to the plate map (e.g., a corresponding 96-well plate). Seal this analytical plate and store it at 4°C until LC-MS / MS analysis.

[0283] The remaining percentage of the compound provided herein, or its pharmaceutically acceptable salt, after incubation is calculated by the following formula: Using a first-order rate equation, t 1 / 2 and CL int Calculate.

[0284] First-order reaction rate equation: C t =C0×e -k×t TIFF2026534205000210.tif10128CL int (hep)=k / million cells / mL CL int (liver) = CL int (hep) * Liver weight (g / kg body weight) × hepatocyte density

[0285] Table 2 shows reference values ​​for various liver weights, hepatic blood flow, and hepatocyte solidity. For example, see: Sohlenius-Sternbeck, Anna-Karin Toxicology in vitro 20.8(2006):1582-1586,doi:10.1016 / j.tiv.2006.06.003; Davies, Brian, and Tim Morris Pharmaceutical Research 10.7(1993):1093-1095; and Obach, R. Scott, et al. Journal of Pharmacology and Experimental Therapeutics 283.1(1997):46-58.

[0286] [Table 2]

[0287] Table 3 shows the lower and upper limits for the assays described. For example, CL int (hep) 6.4 μL / min / 10 6 If the values ​​fall below the cell level, it may be difficult to accurately determine experimental values.

[0288] [Table 3]

[0289] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can be evaluated for their stability in simulated human bodily fluids (e.g., simulated gastric juice or simulated intestinal juice). For example, the compounds provided herein, or pharmaceutically acceptable salts thereof, can be incubated in simulated human bodily fluids (e.g., simulated gastric juice (e.g., feeding or fasting) or simulated intestinal juice (e.g., feeding or fasting)), and aliquots can be taken at various points in time and analyzed for the amount of the remaining compound or pharmaceutically acceptable salt provided herein. An exemplary protocol is as follows:

[0290] Prepare a fasting-like gastric juice (FaSSGF) (0.02 mM lecithin, 0.08 mM sodium taurocholate, 0.1 mg / mL pepsin, 34.2 mM sodium chloride, 25.1 mM hydrochloric acid, and deionized water, pH 1.6 ± 0.05).

[0291] Prepare a working solution of the compound provided herein, or a pharmaceutically acceptable salt thereof (e.g., 2 μM in DMSO). Similarly, prepare a working solution of the control compound (e.g., omeprazole) (e.g., 2 μM in DMSO). Transfer an aliquot (e.g., 2 μL) of either working solution to a deep-well plate, one plate per time condition to be tested (e.g., 0 min, 60 min, 120 min, 360 min, and 1440 min). Transfer to a later time point (e.g., T 60 , T 120 , T 360 , and T 1440 Add an aliquot (e.g., 198 μL) of FaSSGF to the plate corresponding to the ), and adjust the sample to have a final DMSO concentration of 1%. Incubate the plate at 37°C for the specified time while shaking at 600 RPM. At the end of the specified time, stop the reaction by adding a stop solution (e.g., 400 μL) and mix the resulting solution. Take out a portion of this mixture (e.g., 200 μL) and mix with the addition of a further stop solution (e.g., 400 μL). Similarly, the T0 sample is prepared by adding a stop solution (e.g., 400 μL), mixing, then adding FaSSGF (e.g., 200 μL), and mixing again. The T0 sample is further prepared by removing a portion (e.g., 200 μL) of this mixture and mixing with a further addition of a stop solution (e.g., 400 μL). After the second addition of the stop solution at each time point, centrifuge the sample (e.g., 4000 RPM, 4°C for 20 minutes). Take a portion of the supernatant (e.g., 60 μL) and mix it with purified water (e.g., 180 μL) for LC-MS / MS analysis. LC-MS / MS analysis is performed on ACQUITY UPLC BEH C18 1.7 μm 2.1 *The analysis is performed using a 50 mm column (part number 186002350) with mobile phase A (0.1% formic acid in water) and mobile phase B (0.1% formic acid in acetonitrile). The remaining percentage of the compound provided herein, or its pharmaceutically acceptable salt, at each incubation time is calculated based on the peak area ratio of the analyte to the internal standard from the LC-MS / MS analysis using the following formula. TIFF2026534205000213.tif12128 PAR is the peak area ratio, which is the ratio of the peak area of ​​the target analyte to the peak area of ​​the internal standard. T is the peak area ratio at the specified time, and PAR0 is the peak area ratio at T0.

[0292] Prepare a feeding-simulating intestinal fluid (FeSSIF) (0.282% (w / v) lecithin, 0.806% (w / v) sodium taurocholate, 0.865% (w / v) acetic acid, 1.52% (w / v) potassium chloride, and deionized water, pH 5.0 ± 0.05).

[0293] Prepare a working solution of the compound provided herein, or a pharmaceutically acceptable salt thereof (e.g., 2 μM in DMSO). Similarly, prepare a working solution of the control compound (e.g., chlorambucil) (e.g., 2 μM in DMSO). Transfer an aliquot (e.g., 2 μL) of either working solution to a deep-well plate, one plate per time condition to be tested (e.g., 0 min, 60 min, 120 min, 360 min, and 1440 min). Transfer to a later time point (e.g., T 60 , T 120 , T 360 , and T 1440Add an aliquot of FeSSIF (e.g., 198 μL) to the plate corresponding to the ), and adjust the sample to have a final DMSO concentration of 1%. Incubate the plate at 37°C for the specified time while shaking at 600 RPM. At the end of the specified time, stop the reaction by adding a stop solution (e.g., 400 μL) and mix the resulting solution. Take out a portion of this mixture (e.g., 200 μL) and mix with the addition of a further stop solution (e.g., 400 μL). Similarly, the T0 sample is prepared by adding a stop solution (e.g., 400 μL), mixing, then adding FeSSIF (e.g., 200 μL) and mixing again. The T0 sample is further prepared by removing a portion of this mixture (e.g., 200 μL) and mixing with the addition of a further stop solution (e.g., 400 μL). After the second addition of the stop solution at each time point, centrifuge the sample (e.g., 4000 RPM, 4°C for 20 minutes). Take a portion of the supernatant (e.g., 60 μL) and mix it with purified water (e.g., 180 μL) for LC-MS / MS analysis. LC-MS / MS analysis is performed using ACQUITY UPLC HSS T3 1.8 μm 2.1. * The analysis is performed using a 50 mm column (part number 186003538) with mobile phase A (0.1% formic acid in water) and mobile phase B (0.1% formic acid in acetonitrile). The remaining percentage of the compound provided herein, or its pharmaceutically acceptable salt, at each incubation time is calculated based on the peak area ratio of the analyte to the internal standard from the LC-MS / MS analysis using the following formula. TIFF2026534205000214.tif12128 PAR is the peak area ratio, which is the ratio of the peak area of ​​the target analyte to the peak area of ​​the internal standard. T is the peak area ratio at the specified time, and PAR0 is the peak area ratio at T0.

[0294] Prepare a fasting-like intestinal fluid (FaSSIF) (0.056% (w / v) lecithin, 0.161% (w / v) sodium taurocholate, 0.39% (w / v) monobasic potassium phosphate, 0.77% (w / v) potassium chloride, and deionized water, pH 6.5 ± 0.05).

[0295] Prepare a working solution of the compound provided herein, or a pharmaceutically acceptable salt thereof (e.g., 2 μM in DMSO). Similarly, prepare a working solution of the control compound (e.g., chlorambucil) (e.g., 2 μM in DMSO). Transfer an aliquot (e.g., 2 μL) of either working solution to a deep-well plate, one plate per time condition to be tested (e.g., 0 min, 60 min, 120 min, 360 min, and 1440 min). Transfer to a later time point (e.g., T 60 , T 120 , T 360 , and T 1440 Add an aliquot (e.g., 198 μL) of FaSSIF to the plate corresponding to the ), and adjust the sample to have a final DMSO concentration of 1%. Incubate the plate at 37°C for the specified time while shaking at 600 RPM. At the end of the specified time, stop the reaction by adding a stop solution (e.g., 400 μL) and mix the resulting solution. Take out a portion of this mixture (e.g., 200 μL) and mix with the addition of a further stop solution (e.g., 400 μL). Similarly, the T0 sample is prepared by adding a stop solution (e.g., 400 μL), mixing, then adding FaSSIF (e.g., 200 μL) and mixing again. The T0 sample is further prepared by removing a portion (e.g., 200 μL) of this mixture and mixing with a further addition of a stop solution (e.g., 400 μL). After the second addition of the stop solution at each time point, centrifuge the sample (e.g., 4000 RPM, 4°C for 20 minutes). Take a portion of the supernatant (e.g., 60 μL) and mix it with purified water (e.g., 180 μL) for LC-MS / MS analysis. LC-MS / MS analysis is performed using ACQUITY UPLC HSS T3 1.8 μm 2.1. * The analysis is performed using a 50 mm column (part number 186003538) with mobile phase A (0.1% formic acid in water) and mobile phase B (0.1% formic acid in acetonitrile). The remaining percentage of the compound provided herein, or its pharmaceutically acceptable salt, at each incubation time is calculated based on the peak area ratio of the analyte to the internal standard from the LC-MS / MS analysis using the following formula. TIFF2026534205000215.tif12128 PAR is the peak area ratio, which is the ratio of the peak area of ​​the target analyte to the peak area of ​​the internal standard. T is the peak area ratio at the specified time, and PAR0 is the peak area ratio at T0.

[0296] In some embodiments, the compounds provided herein, or their pharmaceutically acceptable salts, can be evaluated for their solubility in simulated human bodily fluids (e.g., simulated gastric juice or simulated intestinal juice) or aqueous solutions (e.g., water or citrate buffer at pH 3.0). For example, the compounds provided herein, or their pharmaceutically acceptable salts, can be incubated in simulated human bodily fluids (e.g., simulated gastric juice or simulated intestinal juice) or aqueous solutions (e.g., water or citrate buffer at pH 3.0). For example, the compounds provided herein, or their pharmaceutically acceptable salts, can be incubated in simulated human bodily fluids (e.g., simulated gastric juice (e.g., feeding or fasting) or simulated intestinal juice (e.g., feeding or fasting)) or aqueous solutions (e.g., water or citrate buffer at pH 3.0), and aliquots can be taken at various time points and analyzed for the amount of the remaining compound or pharmaceutically acceptable salt provided herein. An exemplary protocol is as follows:

[0297] Prepare a fasting-like gastric juice (FaSSGF) (0.02 mM lecithin, 0.08 mM sodium taurocholate, 0.1 mg / mL pepsin, 34.2 mM sodium chloride, 25.1 mM hydrochloric acid, and deionized water, pH 1.6 ± 0.05). Equilibrate the FaSSGF at 37°C.

[0298] Prepare a feeding-simulating intestinal fluid (FeSSIF) (0.282% (w / v) lecithin, 0.806% (w / v) sodium taurocholate, 0.865% (w / v) acetic acid, 1.52% (w / v) potassium chloride, and deionized water, pH 5.0 ± 0.05). Equilibrate the FeSSIF at 37°C.

[0299] Prepare a fasting-simulating intestinal fluid (FaSSIF) (0.056% (w / v) lecithin, 0.161% (w / v) sodium taurocholate, 0.39% (w / v) monobasic potassium phosphate, 0.77% (w / v) potassium chloride, and deionized water, pH 6.5 ± 0.05). Equilibrate the FaSSIF at 37°C.

[0300] Prepare a citrate buffer solution (100 mM sodium citrate, pH 3.07). The solubility of the citrate buffer solution and the solution in water is determined at room temperature.

[0301] Combine the compound provided herein, or a pharmaceutically acceptable salt thereof (e.g., 6 mg), with FaSSGF, FeSSIF, FaSSIF, citrate buffer, or water (e.g., 3 mL). Stir the vial (at 37°C for simulated human body fluids, or at room temperature for citrate buffer and water), and at 30 minutes, 3 hours, and 24 hours, take aliquots, filter them (e.g., using a 0.2 μm syringe filter), and then analyze by HPLC (e.g., HPLC is performed using an Agilent 1290 Infinity LC System with a VWD (Variable Wavelength Detector) and an Agilent 1260 ELSD (Evaporative Light Scattering Detector)). The instrument has a flow rate range of 0.2 to 5.0 mL / min, an operating pressure range of 0 to 1300 bar, a temperature range of 5°C above ambient temperature to 60°C, and a wavelength range of 190 to 600 nm. Using mobile phase A of 0.1% trifluoroacetic acid (TFA) in distilled water, mobile phase B of 0.1% TFA in acetonitrile, and a Waters Acuity UPLC CSH C-18 column, 2.1 × 150 mm, 1.7 μm, the solubility concentration of the compounds provided herein, or their pharmaceutically acceptable salts, can be determined.

[0302] In some embodiments, the kinetic solubility of the compounds provided herein, or their pharmaceutically acceptable salts, can be determined. In some embodiments, the kinetic solubility of the compounds provided herein, or their pharmaceutically acceptable salts, is determined at a physiologically relevant pH (e.g., 7.4). For example, a stock solution of the compounds provided herein, or their pharmaceutically acceptable salts, can be prepared and any solids separated (e.g., by centrifugation). The resulting mixture (e.g., supernatant) can then be filtered, and the solubility of the compounds provided herein, or their pharmaceutically acceptable salts, can be determined via liquid chromatography. An exemplary protocol is as follows:

[0303] A stock solution (e.g., 200 μM stock solution) of the compound provided herein, or a pharmaceutically acceptable salt thereof, is diluted with a buffer (e.g., phosphate buffer, pH 7.4) (e.g., 10 μL stock solution in 490 μL buffer). The diluted sample is vortexed for at least 2 minutes, then shaken on a shaker at room temperature for 24 hours (e.g., at 800 RPM). The sample is then centrifuged (e.g., at 4000 RPM for 10 minutes at 25°C). The supernatant is filtered (e.g., in plate format by centrifugation for 5 minutes), and the concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof, is determined by an LC-UV system (e.g., using mobile phase A of 0.1% TFA and 5 mM NH4OAc in water / MeCN(v:v,95:5), and mobile phase B of 0.1% TFA and 5 mM NH4OAc in water / MeCN(v:v,5:95)).

[0304] In some embodiments, the chemical stability of the compounds provided herein, or their pharmaceutically acceptable salts, can be determined. For example, an aliquot of a solution of the compounds provided herein, or their pharmaceutically acceptable salts, is added to an acidic solution (e.g., pH 1.5 or pH 5) and incubated for a certain period of time. A sample of the incubation mixture can be taken, and the remaining amount of the compounds provided herein, or their pharmaceutically acceptable salts, can be determined by liquid chromatography-mass spectrometry (LCMS) and / or nuclear magnetic resonance (NMR). An exemplary protocol is as follows:

[0305] To prepare an HCl solution with a pH of 1.5, add 1 mL of 1 N hydrogen chloride solution to 99 mL of deionized water and stir for 5 minutes. While stirring and monitoring with a pH meter, adjust the pH to the desired pH using concentrated hydrochloric acid. To prepare an HCl solution with a pH of 5, add 1 mL of 1 N hydrogen chloride solution to 99 mL of deionized water and stir for 5 minutes. While stirring and monitoring with a pH meter, adjust the pH to the desired pH using 1 N sodium hydroxide.

[0306] A portion (e.g., 10 μL) of a stock solution (e.g., 10 mM) of the compound provided herein, or a pharmaceutically acceptable salt thereof, is taken at each time point (e.g., T0, T0). 30m , T 60m , T 90m , T 240m , and T 3d The sample is added to an HCl solution (e.g., 90 μL) at pH 1.5 or pH 5 in separate vials as indicated. The sample is incubated at 37°C for the desired time frame, and then immediately neutralized to pH 7 with 10 μL of HEPES buffer. Time point T0 is neutralized immediately after the preparation of the sample. The sample is then analyzed by LC-MS to determine the amount of the remaining compound provided herein, or its pharmaceutically acceptable salt.

[0307] To prepare DCl solutions at pH 1.5 and pH 5, use 20% DCl in D2O and, while monitoring with a pH meter, adjust the pH of deuterium oxide (5 mL) to the desired pH of 1.5 or 5, then stir at room temperature for 5 minutes.

[0308] The compounds provided herein, or their pharmaceutically acceptable salts, are dissolved in a DCl solution at pH 1.5 or pH 5 to obtain a 3 mg / mL solution. The obtained solution is incubated at 37°C at the desired time (T0, T0). 90m , T 240m , T 5d Incubate until ) and then take an aliquot (e.g., 0.3 mL), 1 Analysis by 1H NMR was performed to determine the remaining amount of the compounds provided herein or their pharmaceutically acceptable salts, and / or the presence of compounds other than those provided herein. At the same time, 30 μL of the solution was neutralized to pH 7 with HEPES buffer and analyzed by LC-MS to determine the remaining amount of the compounds provided herein or their pharmaceutically acceptable salts, and / or the presence of compounds other than those provided herein.

[0309] In some embodiments, the compounds provided herein, or their pharmaceutically acceptable salts, can be evaluated as potential substrates for efflux (e.g., as potential substrates for p-glycoprotein (P-gp)). In some embodiments, the compounds provided herein, or their pharmaceutically acceptable salts, are evaluated as substrates for efflux using efflux pump-expressing cells, e.g., MDCKII cells. For example, the compounds provided herein, or their pharmaceutically acceptable salts, can be applied to one side of a cell monolayer, incubated, and then the recovery rate of the compound on the opposite side of the cell monolayer can be measured to determine the permeability of the compound to the cell monolayer in that direction. An exemplary protocol is as follows:

[0310] For confluent cell monolayer formation, MDCKII cells (e.g., obtained from the Netherlands Cancer Institute) are placed on a polycarbonate membrane (PC) in a 96-well insertion system at a density of 2.33 × 10⁶ 5 cells / cm 2 Sow the seeds for 4 to 7 days.

[0311] A solution of the compound provided herein, or a pharmaceutically acceptable salt thereof, is diluted from a DMSO stock solution with transport buffer (e.g., Hanks equilibrium salt solution (HBSS) containing 10 mM HEPES, pH 7.4) to a final concentration (e.g., 2.00 μM (DMSO < 1%)) and applied to the apical or basolateral side of a cell monolayer. The permeation of the compound provided herein, or a pharmaceutically acceptable salt thereof, in the A-to-B and B-to-A directions is determined twice. For control data, digoxin is tested at 10.0 μM in the A-to-B or B-to-A direction, and nadolol and metoprolol are tested twice in the A-to-B direction (e.g., at 2.00 μM). The plate is incubated (e.g., in an incubator at 37.0°C for 2.5 hours using 5% CO2 at saturated humidity without shaking). The efflux ratio of each compound is then determined. The compounds provided herein, or their pharmaceutically acceptable salts, and control compounds are quantified by LC-MS / MS analysis based on the analyte / internal standard (IS) peak area ratio.

[0312] Apparent transmittance coefficient P app (cm / s) is calculated using the following formula. P app =(dC r / dt)xV r / (AxC0) In the formula, dC r / dt is the cumulative concentration of the compound in the receiver chamber as a function of time. r is the volume of solution in the receiver chamber (0.075 mL at the top and 0.25 mL at the bottom). A is the surface area for transport (e.g., 0.143 cm² for the area of ​​a single layer). 2 ) and C0 is the initial concentration in the donor chamber.

[0313] The outflow ratio was calculated using the following formula. Outflow ratio=P app (BA) / P app (AB) While not bound by any particular theory, the efflux ratio is thought to indicate how efficiently the test compound is removed from the test cells.

[0314] The recovery rate was calculated using the following formula. % Solution recovery rate = 100 x [(V r xC r )+(V d xC d )] / (V d xC0) Here, V d This represents the volume in the donor chamber (0.075 mL at the apical end and 0.25 mL at the lateral base). d and C r These represent the final concentrations of the transport compound in the donor chamber and receiver chamber, respectively.

[0315] While not bound by any particular theory, recovery rates are thought to provide information about whether the test compound may have solubility issues, is attached to cell membranes, is metabolized, or is a combination of these.

[0316] After the transport assay, the integrity of the cell monolayer is determined using the Lucifer yellow rejection assay (e.g., to determine whether the cell monolayer from the efflux study is intact). The buffer is removed from both the apical and basal chambers, and then Lucifer yellow dye (e.g., 75 μL of 100 μM solution in transport buffer) and transport buffer (e.g., 250 μL) are added to the apical and basal chambers, respectively. The plate is incubated (e.g., without shaking, at 37°C in 5% CO2 and 95% relative humidity for 30 minutes). After incubation, a sample of Lucifer yellow (e.g., 20 μL) is taken from the apical side and transport buffer (e.g., 60 μL) is added. A sample of Lucifer yellow (e.g., 80 μL) is taken from the basal side. The relative fluorescence units (RFU) of Lucifer yellow are measured at 425 / 528 nm (excitation / emission) using an Envision plate reader.

[0317] The percentage of Lucifer Yellow in the bottom well is calculated using the following formula. TIFF2026534205000216.tif13128 Here, RFU 頂端 and RFU 側底 These are the relative fluorescence units of Lucifer Yellow in the apical and lateral wells, respectively. 頂端 and V 側底 These are the volumes of the apical and basal wells, respectively (0.075 mL and 0.25 mL). % Lucifer Yellow should be less than 2.0 to indicate an intact cell monolayer.

[0318] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, can be evaluated for metabolite formation. For example, the compounds provided herein, or pharmaceutically acceptable salts thereof, may be incubated with hepatocytes (e.g., rat hepatocytes, canine hepatocytes, or human hepatocytes), and at the end of incubation, the sample may be analyzed for the amount of the remaining compounds provided herein, or pharmaceutically acceptable salts thereof, as well as for the amount of any metabolites from phase 1 metabolism, phase 2 metabolism, or a combination thereof. An exemplary protocol is as follows:

[0319] Prepare a working solution of the compound provided herein, or a pharmaceutically acceptable salt thereof (e.g., 10 μM in DMSO). Similarly, prepare a working solution of a control compound (e.g., 7-ethoxycoumarin) (e.g., 30 μM in DMSO). Aliquots of each working solution of the compounds provided herein, or the working solution of the control compounds, are incubated in a medium (e.g., Williams medium E containing HEPES (e.g., 5.958 g / L) and glutamine (e.g., 0.292 g / L)) in hepatocytes (e.g., 1.0 × 10⁶ cells). 6 Incubate the cells (e.g., rat hepatocytes, canine hepatocytes, or human hepatocytes) together with 5% CO2 / saturated moisture in a total volume of 200 μL at 37°C for 0 or 120 minutes. After incubation, add MeCN (800 μL) to each sample and centrifuge the samples. Dry the supernatant under N2 gas and reconstitute the residue (e.g., with 200 μL of 10% MeCN containing 0.1% FA). Reconstituted residues of the compounds provided herein or their pharmaceutically acceptable salts are subjected to LC-UV-MS (for example, LC with mobile phase A of 0.1% FA and 2 mM NH4FA in H2O / MeCN (v:v=95:5) and mobile phase B of 0.1% FA and 2 mM NH4FA in H2O / MeCN (v:v=5:95) using an ACQUITY UPLC® HSS T3 2.1 × 100 mm, 1.8 μm column; UV detector with λ:190~500 nm, ESI) + Using the Xevo G2 QTOF instrument in MS mode,E / MS 2 MS using the scanning mode). The reconstituted residue of the control compound is subjected to LC-UV-MS (for example, LC using ACQUITY UPLC® HSS T3 2.1×100 mm, 1.8 μm column with mobile phase A of 0.1% FA in H2O and mobile phase B of 0.1% FA in MeCN, UV detector with λ: 190~500 nm, MS using Xevo G2 Q-TOF instrument, ESI + MS in mode E (Use the scanning mode.) Then, analyze the data to identify and, if desired, quantify the metabolites.

[0320] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may exhibit potent and selective inhibition of dysregulated KRas proteins (e.g., wild-type KRas protein and / or 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))). In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may selectively inhibit dysregulated KRas proteins (e.g., wild-type KRas protein and / or 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))) more selectively than other GTPase or non-GTPase targets. In some embodiments, the compounds provided herein can exhibit nanomolar potency against KRas proteins (e.g., wild-type KRas protein and / or 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))) and have minimal activity against related GTPases (e.g., wild-type NRas protein and / or wild-type HRas protein).

[0321] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate greater inhibition of KRas proteins (e.g., wild-type KRas protein and / or 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 related GTPases (e.g., wild-type NRas protein and / or wild-type HRas protein). In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate that inhibition of KRas proteins (e.g., wild-type KRas protein and / or 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))) is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than inhibition of related GTPases (e.g., wild-type NRas protein and / or wild-type HRas protein). In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate up to 10,000-fold greater inhibition of KRas proteins (e.g., wild-type KRas protein and / or 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 related GTPases (e.g., wild-type NRas protein and / or wild-type HRas protein).

[0322] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may exhibit inhibition of KRas proteins (e.g., wild-type KRas protein and / or 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))) about 2 to 10 times greater than inhibition of related GTPases (e.g., wild-type NRas protein and / or wild-type HRas protein). In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may exhibit inhibition of KRas proteins (e.g., wild-type KRas protein and / or 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))) about 10 to 100 times greater than inhibition of related GTPases (e.g., wild-type NRas protein and / or wild-type HRas protein). In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate that inhibition of KRas proteins (e.g., wild-type KRas protein and / or 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))) is about 100 to 1000 times greater than inhibition of related GTPases (e.g., wild-type NRas protein and / or wild-type HRas protein).In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may exhibit inhibition of KRas proteins (e.g., wild-type KRas protein and / or 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))) about 1,000 to 10,000 times greater than inhibition of related GTPases (e.g., wild-type NRas protein and / or wild-type HRas protein).

[0323] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may exhibit potent and selective inhibition of dysregulated KRas proteins (e.g., 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))). In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may selectively inhibit dysregulated KRas proteins (e.g., 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))) more selectively than other GTPase or non-GTPase targets. In some embodiments, the compounds provided herein can exhibit nanomolar potency against 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)) and have minimal activity against the relevant GTPases (e.g., wild-type KRas protein, wild-type NRas protein, and / or wild-type HRas protein).

[0324] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate greater 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)) than inhibition of wild-type KRas protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate greater 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)) than inhibition of wild-type KRas protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate that 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)) is up to 10,000 times greater than inhibition of wild-type KRas protein.

[0325] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate 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)) about 2 to 10 times greater than the inhibition of wild-type KRas protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate 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)) about 10 to 100 times greater than the inhibition of wild-type KRas protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate 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)) about 100 to 1000 times greater than inhibition of wild-type KRas protein. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate 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)) about 1000 to 10000 times greater than inhibition of wild-type KRas protein.

[0326] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may exhibit nanomolar potency against dysregulated KRas proteins (e.g., 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))) with minimal activity against wild-type NRas proteins and / or wild-type HRas proteins. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may exhibit greater inhibition of dysregulated KRas proteins (e.g., 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))) than inhibition of wild-type NRas proteins and / or wild-type HRas proteins. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate that inhibition of dysregulated KRas proteins (e.g., 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))) is at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or 100-fold greater than inhibition of wild-type NRas proteins and / or wild-type HRas proteins. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate that inhibition of dysregulated KRas proteins (e.g., 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))) is up to 1000 times greater than inhibition of wild-type NRas proteins and / or wild-type HRas proteins.In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate that inhibition of dysregulated KRas proteins (e.g., 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))) is up to 10,000 times greater than inhibition of wild-type NRas proteins and / or wild-type HRas proteins.

[0327] In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate that inhibition of dysregulated KRas proteins (e.g., 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))) is about 2 to 10 times greater than inhibition of wild-type NRas proteins and / or wild-type HRas proteins. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate that inhibition of dysregulated KRas proteins (e.g., 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))) is about 10 to 100 times greater than inhibition of wild-type HRas proteins and / or wild-type NRas proteins. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate that inhibition of dysregulated KRas proteins (e.g., 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))) is about 100 to 1000 times greater than inhibition of wild-type NRas proteins and / or wild-type HRas proteins. In some embodiments, the compounds provided herein, or pharmaceutically acceptable salts thereof, may demonstrate that inhibition of dysregulated KRas proteins (e.g., 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))) is about 1,000 to about 10,000 times greater than inhibition of wild-type NRas proteins and / or wild-type HRas proteins.

[0328] The compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for treating diseases and disorders including cardiovascular diseases (e.g., arteriovenous malformations or Noonan syndrome), endometritis, inflammatory and / or autoimmune diseases (e.g., non-malignant syndromes of autoimmunity and abnormal leukocyte homeostasis), proliferative disorders, cancers including hematological cancers and solid tumors (e.g., advanced solid tumors), and MAPK pathway disorders (e.g., neurofibromatosis type 1). In some embodiments, the diseases and disorders are KRas-related diseases and disorders (e.g., mutant KRas-related diseases or disorders (e.g., KRas G12D-, KRas G12R-, or G12V--related diseases or disorders)).

[0329] In some embodiments, compounds provided herein, or pharmaceutically acceptable salts thereof, are useful for preventing diseases and disorders as defined herein (e.g., cardiovascular diseases, endometriosis, and inflammatory and / or autoimmune diseases, or cancer).

[0330] In some embodiments of any of the methods or uses described herein, the inflammatory disease and / or autoimmune disease is a RAS-associated autoimmune leukoproliferative disorder. See, for example, Niemela et al. Blood. 2011;117(10):2883-6, doi:10.1182 / blood-2010-07-295501.

[0331] In some embodiments, the subject has been identified or diagnosed with cancer having KRas dysregulation (e.g., KRas mutation or amplification) (e.g., as determined using a regulatory-approved assay or kit, e.g., FDA-approved assay or kit). In some embodiments, the subject has cancer (e.g., tumor sample) having KRas dysregulation (e.g., KRas mutation or amplification) (e.g., as determined using a regulatory-approved assay or kit). The subject may have 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-approved assay or kit, e.g., FDA-approved assay or kit). The subject may have cancer (e.g., tumor sample) having KRas dysregulation (e.g., KRas mutation or amplification) (e.g., if the cancer (e.g., tumor sample) is identified as such using a regulatory-approved kit or assay, e.g., FDA-approved assay or kit). In some embodiments, the subject is suspected of having mutant KRas-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has cancer (e.g., a tumor sample) with KRas dysregulation (e.g., KRas mutation or amplification) (optionally, the clinical record indicates that the subject should be treated with any of the compounds and / or compositions provided herein).

[0332] In some such embodiments, the cancer (e.g., tumor specimen) has a KRas mutation selected from the group consisting of KRas G12X mutation, KRas G13X mutation, and KRas Q61X mutation. In some embodiments, the KRas mutation is 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 KRas mutation is selected from the group consisting of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, and KRas G12V mutations. In some embodiments, the cancer (e.g., tumor sample) has a KRas mutation selected from the group consisting of KRas G12A, KRas G12D, KRas G12R, and KRas G12V mutations. In some embodiments, the cancer (e.g., tumor sample) has a KRas G12A mutation. In some embodiments, the cancer (e.g., tumor sample) has a KRas G12C 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 G12S mutation. In some embodiments, the cancer (e.g., tumor sample) has the KRas G12V mutation.

[0333] 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.

[0334] As used herein, the term “KRas-related cancer” refers to cancers related to, or having, dysregulation of the expression, activity, or level of the KRAS gene, KRas protein, or any one thereof (e.g., one or more of the types of dysregulation of the expression, activity, or level of the KRAS gene, KRas protein, or any of them as described herein). Non-exclusive examples of KRas-related cancers are described herein.

[0335] As used herein, the term “mutant KRas-related cancer” refers to cancer associated with or possessing a KRas mutation (e.g., a KRAS gene and / or KRas protein having a mutation corresponding to a mutation in the KRas protein). Non-exclusive examples of mutant KRas-related cancers are described herein.

[0336] As used herein, the term “KRas G12X-related cancer” refers to cancer associated with or possessing a KRas G12X mutation (e.g., the KRAS gene having a mutation corresponding to the G12X mutation in the KRas protein and / or the KRas protein having the G12X mutation). Non-exclusive examples of KRas G12X-related cancers are described herein.

[0337] As used herein, the term “KRas G12A-related cancer” refers to cancer associated with or possessing a KRas G12A mutation (e.g., the KRAS gene having a mutation corresponding to the G12A mutation in the KRas protein and / or the KRas protein having the G12A mutation). Non-exclusive examples of KRas G12A-related cancers are described herein.

[0338] As used herein, the term “KRas G12C-related cancer” refers to cancer associated with or possessing a KRas G12C mutation (e.g., the KRAS gene having a mutation corresponding to the G12C mutation in the KRas protein and / or the KRas protein having the G12C mutation). Non-exclusive examples of KRas G12C-related cancers are described herein.

[0339] As used herein, the term “KRas G12D-related cancer” refers to cancer associated with or possessing a KRas G12D mutation (e.g., the KRAS gene having a mutation corresponding to the G12D mutation in the KRas protein and / or the KRas protein having the G12D mutation). Non-exclusive examples of KRas G12D-related cancers are described herein.

[0340] As used herein, the term “KRas G12R-related cancer” refers to cancer associated with or possessing a KRas G12R mutation (e.g., the KRAS gene having a mutation corresponding to the G12R mutation in the KRas protein and / or the KRas protein having the G12R mutation). Non-exclusive examples of KRas G12R-related cancers are described herein.

[0341] As used herein, the term “KRas G12S-related cancer” refers to cancer associated with or possessing a KRas G12S mutation (e.g., the KRAS gene having a mutation corresponding to the G12S mutation in the KRas protein and / or the KRas protein having the G12S mutation). Non-exclusive examples of KRas G12S-related cancers are described herein.

[0342] As used herein, the term “KRas G12V-related cancer” refers to cancer associated with or possessing a KRas G12V mutation (e.g., the KRAS gene having a mutation corresponding to the G12V mutation in the KRas protein and / or the KRas protein having the G12V mutation). Non-exclusive examples of KRas G12V-related cancers are described herein.

[0343] As used herein, the term “KRas G13X-related cancer” refers to cancer associated with or possessing a KRas G13X mutation (e.g., the KRAS gene having a mutation corresponding to the G13X mutation in the KRas protein and / or the KRas protein having the G13X mutation). Non-exclusive examples of KRas G13X-related cancers are described herein.

[0344] As used herein, the term “KRas G13C-related cancer” refers to cancer associated with or possessing a KRas G13C mutation (e.g., the KRAS gene having a mutation corresponding to the G13C mutation in the KRas protein and / or the KRas protein having the G13C mutation). Non-exclusive examples of KRas G13C-related cancers are described herein.

[0345] As used herein, the term “KRas G13D-related cancer” refers to cancer associated with or possessing a KRas G13D mutation (e.g., the KRAS gene having a mutation corresponding to the G13D mutation in the KRas protein and / or the KRas protein having the G13D mutation). Non-exclusive examples of KRas G13D-related cancers are described herein.

[0346] As used herein, the term “KRas G13V-related cancer” refers to cancer associated with or possessing a KRas G13V mutation (e.g., the KRAS gene having a mutation corresponding to the G13V mutation in the KRas protein and / or the KRas protein having the G13V mutation). Non-exclusive examples of KRas G13V-related cancers are described herein.

[0347] As used herein, the term “KRas Q61X-related cancer” refers to cancer associated with or possessing a KRas Q61X mutation (e.g., the KRAS gene having a mutation corresponding to the Q61X mutation in the KRas protein and / or the KRas protein having the Q61X mutation). Non-exclusive examples of KRas Q61X-related cancers are described herein.

[0348] As used herein, the term “KRas Q61E-related cancer” refers to cancer associated with or possessing a KRas Q61E mutation (e.g., the KRAS gene having a mutation corresponding to the Q61E mutation in the KRas protein and / or the KRas protein having the Q61E mutation). Non-limiting examples of KRas Q61E-related cancers are described herein.

[0349] As used herein, the term “KRas Q61H-related cancer” refers to cancer associated with or possessing a KRas Q61H mutation (e.g., the KRAS gene having a mutation corresponding to the Q61H mutation in the KRas protein and / or the KRas protein having the Q61H mutation). Non-exclusive examples of KRas Q61H-related cancers are described herein.

[0350] As used herein, the term “KRas Q61K-related cancer” refers to cancer associated with or possessing a KRas Q61K mutation (e.g., the KRAS gene having a mutation corresponding to the Q61K mutation in the KRas protein and / or the KRas protein having the Q61K mutation). Non-exclusive examples of KRas Q61K-related cancers are described herein.

[0351] As used herein, the term “KRas Q61L-related cancer” refers to cancer associated with or possessing a KRas Q61L mutation (e.g., the KRAS gene having a mutation corresponding to the Q61L mutation in the KRas protein and / or the KRas protein having the Q61L mutation). Non-exclusive examples of KRas Q61L-related cancers are described herein.

[0352] As used herein, the term “KRas Q61P-related cancer” refers to cancer associated with or possessing a KRas Q61P mutation (e.g., the KRAS gene having a mutation corresponding to the Q61P mutation in the KRas protein and / or the KRas protein having the Q61P mutation). Non-exclusive examples of KRas Q61P-related cancers are described herein.

[0353] As used herein, the term “KRas Q61R-related cancer” refers to cancer associated with, or possessing, a KRas Q61R mutation (e.g., the KRAS gene having a mutation corresponding to the Q61R mutation in the KRas protein and / or the KRas protein having the Q61R mutation). Non-exclusive examples of KRas Q61R-related cancers are described herein.

[0354] Such mutations may be associated with the development of various cancers. For example, see Hunter et al. Mol Cancer Res. 2015;13(9):1325-35, doi:10.1158 / 1541-7786. MCR-15-0203.

[0355] This specification provides a method for treating cancer in a subject requiring treatment for cancer, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is treatment-naive with respect to cancer. In some embodiments, the subject has received one or more lines of prior therapy for cancer.

[0356] Furthermore, this specification also provides a method for treating cancer in a subject requiring treatment for cancer, the method comprising administering to the subject, as monotherapy, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is treatment-naive with respect to cancer. In some embodiments, the subject has received one or more lines of prior therapy for cancer.

[0357] In some embodiments, the subject has received one or more lines of prior therapy for cancer prior to administration of the compound provided herein. In some such embodiments, the subject has received prior chemotherapy for cancer prior to administration of the compound provided herein. In some embodiments, the subject has received first-line or second-line chemotherapy prior to administration of the compound provided herein. In some embodiments, the subject has received standard therapeutic chemotherapy prior to administration of the compound provided herein.

[0358] In some embodiments, subjects with colorectal cancer have previously received one or more of the following: capecitabine, fluorouracil (5-FU), leucovorin, and oxaliplatin. In some embodiments, subjects with colorectal cancer have previously received FOLFOX (fluorouracil, leucovorin, and oxaliplatin). In some embodiments, subjects with colorectal cancer have previously received FOLFIRI (fluorouracil, leucovorin, and irinotecan). In some embodiments, subjects with colorectal cancer have previously received FOLFIRINOX (fluorouracil, leucovorin (e.g., leucovorin calcium), irinotecan (e.g., irinotecan hydrochloride), and oxaliplatin). In some embodiments, subjects with colorectal cancer have previously received CAPEOX (capecitabine and oxaliplatin). In some embodiments, subjects with colorectal cancer have previously received FOLFIRI and one or more of bevacizumab, ziv-aflibercept, and ramucirumab. In some embodiments, subjects with colorectal cancer have previously received FOLFIRI and one or more of cetuximab or panitumumab. In some embodiments, subjects with colorectal cancer have previously received FOLFOX and one or more of bevacizumab, ziv-aflibercept, and ramucirumab. In some embodiments, subjects with colorectal cancer have previously received FOLFOX and one or more of cetuximab or panitumumab. In some embodiments, subjects with colorectal cancer have previously received FOLFIRINOX and one or more of bevacizumab, ziv-aflibercept, and ramucirumab. In some embodiments, subjects with colorectal cancer have previously received FOLFIRINOX and one or more of cetuximab or panitumumab. In some embodiments, subjects with colorectal cancer have previously received CAPEOX and one or more of bevacizumab, ziv-aflibercept, and ramucirumab.In some embodiments, subjects with colorectal cancer have previously received CAPEOX and one or more of cetuximab or panitumumab.

[0359] In some embodiments, subjects with endometrial cancer have previously received one or more of the following: cisplatin, carboplatin, paclitaxel, capecitabine, mitomycin, and gemcitabine. In some embodiments, subjects with endometrial cancer have previously received cisplatin and radiotherapy. In some embodiments, subjects with endometrial cancer have previously received cisplatin and radiotherapy, followed by carboplatin and paclitaxel. In some embodiments, subjects with endometrial cancer have previously received capecitabine and mitomycin. In some embodiments, subjects with endometrial cancer have previously received gemcitabine. In some embodiments, subjects with endometrial cancer have previously received paclitaxel. In some embodiments, subjects with endometrial cancer have previously received carboplatin and paclitaxel. In some embodiments, subjects with endometrial cancer have previously received carboplatin, paclitaxel, and pembrolizumab. In some embodiments, subjects with endometrial cancer have previously received carboplatin, paclitaxel, and dolsterimab (e.g., dolsterimab-gxly). In some embodiments, subjects with endometrial cancer have previously received carboplatin, paclitaxel, and trastuzumab. In some embodiments, subjects with endometrial cancer have previously received carboplatin, paclitaxel, and bevacizumab. In some embodiments, subjects with endometrial cancer have previously received megestrol acetate and tamoxifen. In some embodiments, subjects with endometrial cancer have previously received everolimus and letrozole.

[0360] In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received one or more of the following: pembrolizumab, atezolizumab, cemiprimab (e.g., cemiprimab-rwlc), durvalumab, nivolumab, ipilimumab, tremelimumab (e.g., tremelimumab-actl), carboplatin, cisplatin, pemetrexed, paclitaxel (e.g., albumin-bound paclitaxel), and bevacizumab. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received pembrolizumab. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received carboplatin, pemetrexed, and pembrolizumab. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received cisplatin, pemetrexed, and pembrolizumab. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received cemiplumab. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received cemiplumab, pemetrexed, and carboplatin. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received cemiplumab, pemetrexed, and cisplatin. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received carboplatin, paclitaxel, bevacizumab, and atezolizumab. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received carboplatin, paclitaxel (e.g., albumin-bound paclitaxel), and atezolizumab. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received cemiprimab, paclitaxel, and carboplatin.In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received tremelimumab, durvalumab, carboplatin, and paclitaxel (e.g., albumin-conjugated paclitaxel). In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received tremelimumab, durvalumab, carboplatin, and pemetrexed. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received tremelimumab, durvalumab, cisplatin, and pemetrexed. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received tremelimumab, durvalumab, carboplatin, and paclitaxel (e.g., albumin-conjugated paclitaxel). In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received tremelimumab, durvalumab, carboplatin, and gemcitabine. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received tremelimumab, durvalumab, cisplatin, and gemcitabine. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received nivolumab and ipilimumab. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received carboplatin, paclitaxel (e.g., albumin-bound paclitaxel), and pembrolizumab. In some embodiments, subjects with lung cancer (e.g., NSCLC) have previously received nivolumab, ipilimumab, paclitaxel, and carboplatin.

[0361] In some embodiments, subjects with ovarian cancer have previously received one or more of the following: paclitaxel, carboplatin, fluorouracil, leucovorin, oxaliplatin, capecitabine, docetaxel, and doxorubicin (e.g., liposomal doxorubicin). In some embodiments, subjects with ovarian cancer have previously received paclitaxel and carboplatin. In some embodiments, subjects with ovarian cancer have previously received fluorouracil, leucovorin, and oxaliplatin. In some embodiments, subjects with ovarian cancer have previously received hormone therapy (e.g., aromatase inhibitors, e.g., anastrozole, letrozole, or exemestane). In some embodiments, subjects with ovarian cancer have previously received docetaxel and carboplatin. In some embodiments, subjects with ovarian cancer have previously received carboplatin and doxorubicin (e.g., liposomal doxorubicin). In some embodiments, subjects with ovarian cancer have previously received paclitaxel, carboplatin, and bevacizumab. In some embodiments, subjects with ovarian cancer have previously received fluorouracil, leucovorin, oxaliplatin, and bevacizumab. In some embodiments, subjects with ovarian cancer have previously received capecitabine, oxaliplatin, and bevacizumab.

[0362] In some embodiments, subjects with pancreatic cancer have previously received one or more of the following: capecitabine, fluorouracil, gemcitabine, irinotecan, leucovorin, paclitaxel (e.g., albumin-conjugated paclitaxel), and oxaliplatin. In some embodiments, subjects with pancreatic cancer have previously received FOLFIRINOX. In some embodiments, subjects with pancreatic cancer have previously received GEMOX (gemcitabine and oxaliplatin). In some embodiments, subjects with pancreatic cancer have previously received gemcitabine. In some embodiments, subjects with pancreatic cancer have previously received gemcitabine and paclitaxel (e.g., albumin-conjugated paclitaxel). In some embodiments, subjects with pancreatic cancer have previously received NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, and oxaliplatin).

[0363] This specification provides for the use of compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of cancer, for example, any of the cancers provided herein.

[0364] This specification provides for the use of compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as pharmaceuticals for the treatment of cancer, for example, any of the cancers provided herein.

[0365] This specification provides for the use of compounds provided herein, or pharmaceutically acceptable salts thereof, in the manufacture of pharmaceuticals for the treatment of cancer, for example, any of the cancers provided herein.

[0366] This specification provides compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as pharmaceuticals. Furthermore, this specification also provides compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use as pharmaceuticals for the treatment of cancer, for example, any of the cancers provided herein.

[0367] This specification provides compounds provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of cancer, for example, any of the cancers provided herein.

[0368] As used herein, “monotherapy” means, when referring to the compounds provided herein or their pharmaceutically acceptable salts, that the compounds provided herein or their pharmaceutically acceptable salts are the only therapeutic agent or therapy (e.g., an anticancer agent or therapy) administered to the subject during a treatment cycle (e.g., no additional targeted therapeutic agents, anticancer agents, chemotherapeutic agents, or checkpoint inhibitors are administered to the subject during a treatment cycle). As those skilled in the art will understand, monotherapy does not exclude the concurrent administration of pharmaceuticals for the treatment of cancer or adverse or common symptoms associated with the treatment, such as pain, rash, edema, photosensitivity, itching, skin discoloration, hair fragility, alopecia, brittle nails, cracked nails, discolored nails, swollen keratin, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms including nausea, diarrhea, and loss of appetite.

[0369] As used herein, “the subject has received one or more lines of prior therapy” means that the subject has previously received one or more therapeutic agents or therapies for cancer other than the compound provided herein or its pharmaceutically acceptable salts, during a treatment cycle prior to administration of the compound provided herein (e.g., therapies such as anticancer drugs or chemotherapy, radiation, or surgery). In some embodiments, the subject is intolerant to one or more therapeutic agents or therapies previously administered for cancer. In some embodiments, the subject did not respond to one or more therapeutic agents or therapies previously administered for cancer. In some embodiments, the subject did not respond adequately to one or more therapeutic agents or therapies previously administered for cancer. In some embodiments, the subject has ceased responding to one or more therapeutic agents or therapies previously administered for cancer. In some embodiments, a lack of response, an insufficient response, or a discontinued response can be determined by objective criteria (e.g., tumor volume, or criteria such as RECIST 1.1). In some embodiments, a lack of response, an insufficient response, or a discontinued response can be determined by the subject's physician.

[0370] As used herein, “subject is treatment-naive with respect to cancer” means that the subject has not previously received one or more therapeutic agents or therapies for cancer.

[0371] For any solid tumor described herein, the solid tumor may be a primary tumor or a metastatic (or secondary) tumor. As used herein, a “primary” tumor is a tumor located at the site where it 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.

[0372] This specification provides a method for treating cancer in a subject requiring cancer treatment, the method comprising: a) detecting KRas dysregulation (e.g., KRas mutations (e.g., KRas G12A mutation, KRas G12C mutation, KRas G12D mutation, KRas G12R mutation, KRas G12S mutation, or KRas G12V mutation (e.g., KRas G12D mutation or KRas G12V mutation)) or amplification in a sample derived from the subject (e.g., detecting a KRAS gene having a mutation corresponding to a mutation in the KRas protein, and / or detecting a KRas protein having a mutation, an increase in KRAS gene copy number, and / or an increase in KRas mRNA or protein expression); and b) administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. This specification provides a method for treating cancer in a subject requiring cancer treatment, the method comprising: a) detecting KRas dysregulation (e.g., KRas mutation (e.g., KRas G12X mutation)) or amplification in a sample derived from the subject (e.g., detecting a KRAS gene having a mutation corresponding to a mutation in the KRas protein, and / or detecting a KRas protein having a mutation, an increase in KRAS gene copy number, and / or an increase in KRas mRNA or protein expression); and b) administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. Furthermore, this specification also provides a method for treating KRas-related cancers (e.g., mutant KRas-related cancers (e.g., KRas G12A-related cancer, KRas G12C-related cancer, KRas G12D-related cancer, KRas G12R-related cancer, KRas G12S-related cancer, or KRas G12V-related cancers (e.g., KRas G12D-related cancer or KRas G12V-related cancer))) in subjects requiring such treatment, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.Furthermore, this specification also provides a method for treating KRas-related cancers in subjects requiring treatment for KRas-related cancers (e.g., mutant KRas-related cancers (e.g., KRas G12X-related cancers)), comprising administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein to the subject. For example, this specification describes a method for treating KRas-related cancer in a subject requiring treatment for KRas-related cancer (e.g., mutant KRas-related cancer (e.g., KRas G12A-related cancer, KRas G12C-related cancer, KRas G12D-related cancer, KRas G12R-related cancer, or KRas G12V-related cancer (e.g., KRas G12D-related cancer or KRas G12V-related cancer)), the method comprising: a) KRas dysregulation (e.g., KRas mutation (e.g., KRas G12A mutation, KRas G12C mutation, KRas G12D mutation, KRas G12R mutation, KRas G12S mutation, or KRas G12V mutation (e.g., KRas G12D mutation or KRas G12V mutation)) in a sample derived from the subject A method is provided comprising: a) detecting a G12V mutation)) or amplification) (for example, detecting a KRAS gene having a mutation corresponding to a mutation in the KRas protein, and / or detecting a KRas protein having a mutation, an increase in KRAS gene copy number, and / or an increase in KRas mRNA or protein expression); and b) administering a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt thereof.For example, this specification provides a method for treating KRas-related cancer in a subject requiring treatment for such KRas-related cancer (e.g., mutant KRas-related cancer (e.g., KRas G12X-related cancer)), the method comprising: a) detecting KRas dysregulation (e.g., KRas mutation (e.g., KRas G12X mutation) or amplification) in a sample derived from the subject (e.g., detecting a KRAS gene having a mutation corresponding to a mutation in the KRas protein, and / or detecting a KRas protein having a mutation, an increase in KRAS gene copy number, and / or an increase in KRas mRNA or protein expression); and b) administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0373] Some embodiments of any method or use described herein include cancer (e.g., KRas-related cancer (e.g., mutated KRas-related cancer (e.g., KRas G12A-related cancer, KRas G12C-related cancer, KRas G12D-related cancer, KRas G12R-related cancer, KRas G12S-related cancer, or KRas G12V-related cancer (e.g., KRas G12D-related cancer or KRas G12V-related cancers include 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 cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), multiple neuroendocrine type I and II tumors, 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., colonic adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma), 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 cancer)), genitourinary cancer (e.g., bladder cancer (e.g., urothelial carcinoma of the bladder), kidney cancer (e.g., clear cell renal cell carcinoma, renal papillary cell carcinoma, kidney pigmented macules) Chromophobe cancer, prostate cancer (e.g., prostate adenocarcinoma), testicular cancer (e.g., testicular germ cell tumor, seminocarcinoma), or ureteral cancer), gynecological cancer (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinosarcoma, uterine endometrioid adenocarcinoma, uterine serous carcinoma, papillary serous carcinoma, uterine corpus endometrial cancer)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)), hematological cancer (e.g., leukemia (e.g., chronic lymphocytic leukemia...

Claims

1. Formula (Ic): A compound thereof, or a pharmaceutically acceptable salt thereof, During the ceremony, E １ CH and CR ４ Selected from the group consisting of R ４ is -CN, Halo, C １－３ Alkyl, C １－３ Haloalkyl and C ３－６ Selected from the group consisting of cycloalkyl groups, R １ This includes 1 to 4 R ７ A 4- to 10-membered heterocyclyl which may be substituted with Each R ７ is independently selected from the group consisting of R ａ , R ｂ , and X １ is, -CH ２ - and X ２ is, -CH ２ - and X ３ is, -CH ２ - or - CHR Ｌ - and b4 is 0, R １０ These are -Cl, -F, -CN, and 1 to 3 R ｃ C may be replaced with １－３ Selected from the group consisting of alkyl groups, R Ｌ is, -CH ３ , -CF ３ ,-CHF ２ , and -CH ２ Selected from the group consisting of F, Y ２ is, -CH ２ - and R ３ is -F, C １－３ Alkoxy, and C １－３ They may be substituted with one or two substituents independently selected from the group consisting of haloalkoxys. And, Each R ａ teeth, (a) Hello, (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 these may be substituted in C １－６ Alkyl, C ２－６ Alkenyl, or C ２－６ Alkinyl Independently selected from the group consisting of, Each R ｂ is, -(L ｂ ) ｂ -R ｂ１ and R ｂ１ Independently selected from the group consisting of, b is 1, 2, or 3. Each L ｂ is -O-, -N(H)-, -N(C １－３ Alkyl)-,-S(O) ０－２ -, -C (=O)-, and C １－３ Independently selected from the group consisting of alkylenes, Each R ｂ１ C ３－１０ Cycloalkyl, 4-10 membered heterocyclyl, C ６－１０ They are independently selected from the group consisting of aryls and 5- to 10-membered heteroaryls, each of which has 1 to 3 R ｇ It may also be replaced 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 Independently selected from the group consisting of, Each R ｄ and R ｅ is independently selected from the group consisting of -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 C ｈ alkyl optionally substituted with 1 to 3 R １－６ groups Each R ｆ This consists of -H and 1 to 3 R ｈ C may be replaced with １－６ Independently selected from the group consisting of alkyl and, Each R ｇ R ｈ , C １－３ Alkyl, C １－３ Haloalkyl, C ３－５ Independently selected from the group consisting of cycloalkyl and 4-5 membered heterocyclyl, Each R ｈ These are halo, cyano, -OH, and -C. １－６ Alkoxy, -C １－６ Haloalkoxy, -NH ２ , -N(H)(C １－３ Alkyl), and -N(C １－３ Alkyl) ２ Independently selected from the group consisting of, The aforementioned compound, or a pharmaceutically acceptable salt thereof.

2. R Ｌ However, -CH ３ The compound according to claim 1.

3. E １ The compound according to claim 1 or 2, wherein the compound is CH.

4. R ３ However, it may be substituted with one or two -F values. (For example, R ３ teeth, The compound according to any one of claims 1 to 3.

5. R ３ but, (for example, The compound according to any one of claims 1 to 4.

6. R １ but, A 7- to 10 (e.g., 7) membered heterocycline having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms. The 7-10 member heterocycline has 1-4 R ７ The compound according to any one of claims 1 to 5, which may be substituted with

7. R １ but, A 7- to 10 (e.g., 7) membered monocyclic heterocycline having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms. The 7-10 member monocyclic heterocyclil has 1-4 (for example, 1-2) R ７ The compound according to any one of claims 1 to 6, which may be substituted with

8. R １ However, in one or more ring carbon atoms, there are 1 to 4 R ７ It may be replaced with The compound according to claim 6 or 7.

9. Each R ７ However, -OH, -CN, -F, and 1 to 3 R ｃ C may be replaced with １－３ Independently selected from the group consisting of alkyls, R ７ Each R that exists above ｃ The compound according to any one of claims 6 to 8, which is independently selected from the group consisting of -F, -OH, and -CN.

10. R １ but, The compound according to any one of claims 1 to 9.

11. R １ but, (for example ) and R ７ This is 1 to 3 R ｇ The compound according to any one of claims 1 to 9, which is a five-membered heteroaryl that may be substituted with

12. R ７ However, 1 to 2 R ｇ It is a pyrazolyl which may be substituted with (for example, R ７ is one R ｇ It may be replaced with (is), or R ７ However, one R ｇ It is an oxazolyl which may be substituted with (for example, R ７ is one R ｇ It may be replaced with The compound according to claim 11, which is the compound described above.

13. R ７ but The compound according to claim 11 or 12.

14. R １ but, A 7- to 10 (e.g., 7) membered spirocyclic bicyclic heterocycline having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms. The 7-10 membered spirocyclic bicyclic heterocyclil has 1-4 (for example, 1-2) R ７ The compound according to any one of claims 1 to 6, which may be substituted with

15. R １ but, And ring A1 is, A 4- to 7-membered heterocyclyl ring having one ring oxygen atom and no additional ring heteroatoms. The compound according to any one of claims 1 to 6 or 14, wherein n4 is 0, 1, or 2, and n5 is 0, 1, or 2, provided that n4 + n5 is 0, 1, or 2.

16. R １ However, 1 to 2 R ７ It may be replaced with The compound according to any one of claims 1 to 6 or 14 to 15.

17. R １ but, The compound according to any one of claims 1 to 6 or 14 to 16.

18. R １ but, Each of these has 1 to 2 R ７ The compound according to any one of claims 1 to 6 or 14 to 15, which may be substituted with

19. R １ but, (for example, ) or (for example, The compound according to any one of claims 1 to 6, 14 to 15, or 18.

20. R １ However, 1 to 4 (for example, 1 to 2) R ７ The compound according to any one of claims 1 to 6, which is a four-membered heterocycline that may be substituted with .

21. R １ However, 1 to 4 (for example, 1 to 2) R ７ It may be replaced with The compound according to any one of claims 1 to 6 or 20.

22. R １ but, (for example, ) or The compound according to any one of claims 1 to 6 or 20 to 21.

23. Each R ７ but, (a)-F, (b) Cyano, (c)-OH, (d) 1 to 2 R ｇ R is a 5-6 member heteroaryl which may be substituted with ｂ１ , (e) C which may be substituted with 1 to 3 F １－３ Alkyl, (f) -OH or C １－３ C substituted with alkoxy １－３ Alkyl, and (g)-C(=O)N(R ｆ ) ２ A compound according to any one of claims 20 to 22, independently selected from the group consisting of the above.

24. R １ but, (for example, ) and R ７ is -OH or C １－３ C substituted with alkoxy １－３ Alkyl (for example, C substituted with -OH) １－３ A compound according to any one of claims 1 to 6 or 20 to 22, wherein the compound is alkyl.

25. R １ but, (for example, The compound according to any one of claims 1 to 6, 20 to 22, or 24.

26. R １ but, And each R ７ teeth, (a) C which may be substituted with 1 to 3 -F １－３ Alkyl, and (b) -OH or C １－３ C substituted with alkoxy １－３ Alkyl A compound according to any one of claims 1 to 6 or 20 to 22, independently selected from the group consisting of the above.

27. R １ but, (for example ) and R ７ａ C is a C substituted with -OH. １－３ Alkyl (e.g., -CH ２ OH) and R ７ｂ teeth, (a) C which may be substituted with 1 to 3 -F １－３ Alkyl (e.g., methyl), and (b) -OH or C １－３ C substituted with alkoxy １－３ Alkyl A compound according to any one of claims 1 to 6, 20 to 22, or 26, selected from the group consisting of the above.

28. R １ but, (for example, ) or The compound according to any one of claims 1 to 6, 20 to 22, or 26 to 27.

29. R １ However, at the ring carbon atoms, -CN, -(C １－３ Alkylene)-CN, or -(C ３－６ A 4- to 10-membered heterocycline substituted with cycloalkylene-CN, wherein the heterocycline has 1 to 3 R ７ The compound according to any one of claims 1 to 6, which may be further substituted with

30. R １ However, in the ring carbon atoms, -CN or -(C １－３ It is a 6- to 8-membered heterocycline substituted with alkylene-CN. The heterocycline has one ring nitrogen atom and 0 to 1 ring oxygen atom, The heterocycline has 1 to 3 R ７ It may be further replaced by The compound according to any one of claims 1 to 6 or 29.

31. Each R ７ However, -OH, -CN, -F, and 1 to 3 R ｃ C may be replaced with １－３ Alkyl (for example, C which may be substituted with 1 to 3 -F atoms) １－３ A compound according to claim 29 or 30, independently selected from the group consisting of alkyl.

32. R １ but, (for example, The compound according to any one of claims 1 to 6 or 29 to 31, which is the compound described above.

33. The part is The compound according to any one of claims 1 to 32.

34. The compound of formula (I-c) is formula (I-c3) or (I-c4): A compound of, or a pharmaceutically acceptable salt thereof, During the ceremony, E １ CH is, R ７ C is a C substituted with -OH. １－３ It is alkyl, b4 is 0, R １０ These are -Cl, -F, -CN, and 1 to 3 R ｃ C may be replaced with １－３ Selected from the group consisting of alkyl groups, X １ is, -CH ２ - and X ２ is, -CH ２ - and X ３ is, -CH ２ - or - CHR Ｌ - is, The compound according to claim 1.

35. X ２ However, -CH ２ - and X ３ However, CH ２ - The compound according to claim 34.

36. X ２ However, -CH ２ - and X ３ However, -CHR Ｌ - The compound according to claim 34.

37. X ２ However, -CH ２ - and X ３ The compound according to claim 34 or 36, wherein the compound is -CHMe-.

38. The aforementioned compound is the compound of formula (I-c4), The part, The compound according to any one of claims 34 to 37.

39. R ７ However, -CH ２ The compound according to any one of claims 34 to 38, wherein it is an OH group.

40. Y ２ However, -CH ２ - and R ３ However, it may be substituted with one or two -F values. The compound according to any one of claims 34 to 39.

41. R ３ but, (for example, The compound according to any one of claims 34 to 40, which is:

42. The part is The compound according to any one of claims 34 to 41.

43. The compound according to claim 1, wherein the compound of formula (I-c) is selected from the group consisting of compound numbers 101, 101a, 103, 103a, 107, 107a, 107b, 111, 111a, 121, 121a, 122, 122a, 136, 136a, 137, 137a, 140, 140a, 141, 141a, 142, 142a, 144, 144a, 146, 146a, 146b, 151, 151a, 151b, 151c, 152, 152a, 152b, 153, 153a, 153b, 155, 155a, 155b, 156, and 156a, or pharmaceutically acceptable salts thereof.

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

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

46. A method for treating 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 according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 44.

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

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

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

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

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

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

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

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

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

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

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

58. The method according to claim 57, wherein the additional therapy or therapeutic agent is selected from the group consisting of Ras pathway-targeted therapeutic agents, kinase-targeted therapeutic agents, mTORC1 inhibitors or degrading agents, YAP inhibitors or degrading agents, proteasome inhibitors or degrading agents, HSP90 inhibitors or degrading agents, farnesyltransferase inhibitors or degrading agents, PTEN inhibitors or degrading agents, signaling pathway inhibitors or degrading agents, checkpoint inhibitors, apoptotic pathway modulators, chemotherapeutic agents, angiogenesis-targeted therapies, immunotherapy, radiotherapy, and combinations thereof.

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