Macrocyclic ras inhibitors

Abstract

The present disclosure provides macrocyclic compounds and pharmaceutical compositions and protein complexes thereof capable of inhibiting Ras proteins, and their use in treating cancer.

Description

Background Technology

[0001] Most small molecule drugs act by binding to functionally important pockets on target proteins, thereby modulating the activity of those proteins. For example, cholesterol-lowering drugs called statins bind to the active site of HMG-CoA reductase, thereby preventing the enzyme from binding to its substrate. The fact that many such drug / target interaction pairs are known may mislead some into believing that small molecule regulators targeting most (if not all) proteins can be discovered with a reasonable amount of time, effort, and resources. This is far from the case. It is currently estimated that only about 10% of all human proteins are targetable by small molecules. (Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019)). The remaining 90% are currently considered unattainable or intractable for small molecule drug discovery. These targets are often referred to as “undruggable.” These undruggable targets include a large number of unexplored, medically important human proteins. Therefore, there is great interest in discovering novel molecular modalities that can modulate the function of such undruggable targets.

[0002] The literature has well established that Ras proteins (K-Ras, H-Ras, and N-Ras) play crucial roles in a variety of human cancers and are therefore suitable targets for anticancer therapies. In fact, approximately 30% of all human cancers in the United States are caused by Ras protein mutations, many of which are fatal. Dysregulation of Ras proteins due to activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations of Ras are frequently found in human cancers. For example, an activating mutation at codon 12 in the Ras protein significantly biases the Ras mutant protein population towards the "on" (GTP-binding) state (RAS(ON)) by inhibiting GTPase-activated protein (GAP) dependence and intrinsic GTP hydrolysis rate, leading to oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, enabling activation even in the presence of low concentrations of this nucleotide. Mutations at Ras codons 13 (e.g., G13C) and 61 (e.g., Q61K) also induce oncogenic activity in some cancers.

[0003] Despite extensive drug discovery efforts targeting Ras over the past decades, only two agents targeting the K-Ras G12C mutant (sotorasib and adagrasib) have been approved in the United States. Further efforts are needed to discover other medicines for cancers caused by various Ras mutations. Summary of the Invention

[0004] This document provides Ras inhibitors and compounds that can be used to study Ras inhibition. The methods described herein require the formation of a high-affinity ternary complex or conjugate between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a cytosolic chaperone protein (presenting protein) (e.g., cyclophilin A) that is widely expressed in the cell. More specifically, in some embodiments, the Ras inhibitors described herein induce a new binding pocket in Ras by driving the formation of a high-affinity ternary complex or conjugate between the Ras protein and the widely expressed cytosolic chaperone protein cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way the compounds of the present invention and the complexes or conjugates thereto exert an inhibitory effect on Ras is by spatially blocking the interaction sites between Ras and downstream effector molecules (e.g., RAF and PI3K) required for the propagation of oncogenic signals.

[0005] Therefore, in some embodiments, this disclosure provides compounds having structural formula I or pharmaceutically acceptable salts or stereoisomers thereof: Formula I Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2 The substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; Or R 2 and R 3Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 10 For -OR 11 or -NR 12 R 13 ;and R 11 R 12 and R 13 Each is independently a optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, or R 12 With R 13 Combining them to form optionally substituted 3- to 10-membered heterocyclic alkyl groups.

[0006] In some embodiments, this disclosure provides compounds having structural formula I' or pharmaceutically acceptable salts or stereoisomers thereof: Formula I' in: A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. L represents a bond or -CH(R) 20 )-N(R 21 )-C(O)-, where R 20 and R 21 Each independently represents the C that can be arbitrarily replaced. 1-6 Alkyl; or R 20 and R 21 Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic alkyl groups; W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X4 It is CH2 or NH; R 1 The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; Or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl group; Or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 5 and R 5aTogether with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 6 and R 6a Together with the atoms to which they are attached, they form optionally substituted cycloalkyl or optionally substituted heteroalkyl groups; Or R 7 and R 7a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 5 With R 6 Together they form bonds; R 10 For H, -OR 11 or -NR 12 R 13 ; R 11 R 12 and R 13 Each of the following is independently a optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 4- to 14-membered heterocyclic alkyl group, or an optionally substituted C3-C... 10 cycloalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; and When R 10 When H is present, ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl, and R 2 Hydrogen, substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Or its pharmaceutically acceptable salts or stereoisomers.

[0007] In some embodiments, this disclosure provides compounds having the structural formula I'-a or pharmaceutically acceptable salts or stereoisomers thereof: Formula I'-a in: A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. L represents a bond or -CH(R) 20 )-N(R 21 )-C(O)-, where R 20 and R 21 Each independently represents the C that can be arbitrarily replaced. 1-6 Alkyl; or R 20 and R 21 Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic alkyl groups; W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; Or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 10 For H, -OR 11 or -NR 12 R 13 ; R 11 R 12 and R 13 Each of the following is independently a optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 4- to 14-membered heterocyclic alkyl group, or an optionally substituted C3-C... 10 cycloalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; and When R 10 When H is present, ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl, and R 2 Hydrogen, substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Or its pharmaceutically acceptable salts or stereoisomers.

[0008] In some embodiments, one or more compounds of WO 2022 / 060836 are not included. In some embodiments, any embodiment herein may not include one or more compounds of Table 3.

[0009] Pharmaceutical compositions comprising compounds of formula I or I', or pharmaceutically acceptable salts or stereoisomers thereof, and pharmaceutically acceptable excipients are also provided. Pharmaceutical compositions comprising compounds of Table 1, or pharmaceutically acceptable salts or stereoisomers thereof, and pharmaceutically acceptable excipients are also provided. Pharmaceutical compositions comprising compounds of Table 2, or pharmaceutically acceptable salts or stereoisomers thereof, and pharmaceutically acceptable excipients are also provided.

[0010] A method for treating cancer in a subject in need is also provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof.

[0011] In some embodiments, a method is provided for treating a subject with Ras protein-related conditions, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof.

[0012] Furthermore, a method for inhibiting Ras protein in cells is provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof.

[0013] In particular, any limitations set forth with respect to one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or utilize any compound or composition of the invention.

[0014] Definitions and chemical terms In this application, unless clearly indicated from the context, (i) the term “a” means “one or more”; (ii) the term “or” is used to mean “and / or” unless explicitly indicated to refer only to alternatives or alternatives are mutually exclusive, but this disclosure supports only the definition of alternatives and “and / or”; (iii) the terms “comprising” and “including” should be understood to encompass the listed components or steps, whether they are presented alone or together with one or more additional components or steps; and (iv) where scope is provided, endpoints are included.

[0015] As used herein, the term "about" is used to indicate a value that includes the standard deviation of the error of the apparatus or method used to determine the value. In some embodiments, unless otherwise stated or clearly apparent from the context (e.g., the value would exceed 100% of the possible value), the term "about" refers to a range of values ​​in either direction (greater or less) within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of the value.

[0016] As used in this article, in the context of describing adjacent atoms, the term "adjacent" refers to divalent atoms that are directly linked by covalent bonds.

[0017] As used herein, “compounds of the present invention” and similar terms, whether expressly stated or not, refer to the Ras inhibitors described herein, including compounds of formula I or I' and their sub-formulas, such as the compounds in Table 1 or Table 2, as well as their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including transisomers) and tautomers.

[0018] The term "wildtype" refers to an entity that possesses the structure or activity found in nature in a "normal" state or condition (as opposed to mutants, diseases, alterations, etc.). Those skilled in the art will understand that wild-type genes and polypeptides typically exist in many different forms (e.g., alleles).

[0019] Those skilled in the art will understand that some of the compounds described herein may exist in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, transisomers, tautomers) or isotopic forms (e.g., one or more atoms are substituted with different isotopes of said atoms, such as hydrogen replacing deuterium). Unless otherwise indicated or clearly apparent from the context, the illustrated structures are to be understood as individually or in combination representing any such isomeric or isotopic forms.

[0020] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of this disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are considered in this disclosure. Cis and trans geometric isomers of the compounds of this disclosure have been described and can be isolated in mixtures of isomers or in separate isomeric forms.

[0021] In some embodiments, one or more compounds illustrated herein may exist in different tautomer forms. As will be clear from the context, unless explicitly excluded, references to such compounds encompass all such tautomer forms. In some embodiments, the tautomer form is obtained by the exchange of a single bond with an adjacent double bond and accompanied by proton migration. In some embodiments, the tautomer form may be a proton-shift tautomer, which is an isomer protonated state having the same empirical formula and total charge as the reference form. Examples of portions having a proton-shift tautomer form are keto-enol pairs, amide-imine pairs, lactam-lactamimide pairs, amide-imine pairs, enamine-imine pairs, and cyclic forms in which the proton may occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. In some embodiments, the tautomer form may be in equilibrium or spatially locked into one form through appropriate substitution. In some embodiments, the tautomer form is obtained by interconversion of acetals.

[0022] Unless otherwise stated, the structures illustrated herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P, 33 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Isotopically labeled compounds (e.g., those labeled with...) 3 H and 14 C-labeled compounds can be used in the determination of compound or substrate tissue distribution. Tritiumization (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are available because they are easy to prepare and detect. Additionally, heavier isotopes such as deuterium (i.e., 2 H) substitution can provide certain therapeutic advantages due to increased metabolic stability (e.g., prolonged half-life in vivo or reduced dose requirement). In some embodiments, one or more hydrogen atoms are... 2 H or 3 H is replaced, or one or more carbon atoms are replaced. 13 C or 14 Carbon enrichment is replaced by C-enriched carbon. Positron-emitting isotopes (e.g.) 15 O、 13 N、 11 C and 18 F) It can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can typically be prepared by replacing unlabeled reagents with isotopically labeled reagents by following procedures similar to those disclosed for the compounds of the invention set forth herein.

[0023] Non-limiting examples of compounds of the present invention containing one or more deuterium-substituted moieties (wherein "R" at any position may be deuterium (D)) include: and .

[0024] Other examples include, for example , Deuteration of parts and similar parts, for example, in compounds of formula I and its sub-formulas). Furthermore, deuteration of any available position in part A of the various compounds described herein is also considered, for example... and Furthermore, deuterium substitution can also occur at the junction sites of the compounds of the present invention, for example... Furthermore, deuterium substitution can also occur at the junction sites of the compounds of the present invention, for example... .

[0025] Furthermore, deuterium substitution can also occur at the linker sites of the compounds of the present invention, for example... and .

[0026] In another embodiment, silylation substitution is also considered, for example in the following connectors: .

[0027] As is known in the art, many chemical entities can exist in a variety of different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be used in any such form, including any solid form. In some embodiments, the compounds set forth or illustrated herein may be provided or used in hydrate or solvate form.

[0028] Throughout this specification, substituents of the disclosed compounds are disclosed by group or by range. This disclosure is expressly intended to include every individual combination of members of such groups and ranges. For example, the term "C1-C6 alkyl" is expressly intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, when a compound includes multiple positions of substituents disclosed by group or range, unless otherwise indicated, this disclosure is intended to cover both the individual compound and the group (e.g., class and subclass) of compounds containing each individual combination of members at each position.

[0029] The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein the alkyl is optionally substituted”). It is not intended to imply that the characteristic “X” (e.g., alkyl) itself is optional. As illustrated herein, some compounds of interest may contain one or more “optionally substituted” moieties. Generally, the term “substituted”, whether or not preceded by the term “optionally”, means that one or more hydrogens of the specified moiety are replaced by a suitable substituent (e.g., any of the substituents or groups illustrated herein). Unless otherwise indicated, the “optionally substituted” group may have a suitable substituent at each substituted position of said group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. For example, in the term “optionally substituted C1-C6 alkyl-C2-C9 heteroaryl,” the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. The substituent combinations contemplated in this disclosure are preferably those that form stable or chemically viable compounds. As used herein, the term "stable" means that, for one or more purposes disclosed herein, the compound does not undergo substantial changes when subjected to conditions that permit its generation, detection, and, in some embodiments, its recovery, purification, and use.

[0030] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group can be independently deuterium; oxo group; halogen; -(CH2)0-4R°; -(CH2)0-4OR°; -O(CH2)0-4R°; -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph, which can be substituted with R°; -(CH2)0-4O(CH2)0-1Ph, which can be substituted with R°; -CH=CHPh, which can be substituted with R°; -(CH2)0-4O(CH2)0-1-pyridyl, which can be substituted with R°; 4- to 8-membered saturated or unsaturated heterocyclic alkyl groups (e.g., pyridyl); 3- to 8-membered saturated or unsaturated cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)0-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; -C(S)R°; -(CH2)0-4C(O)OR° °; -(CH2)0-4-C(O)-N(R°)2; -(CH2)0-4-C(O)-N(R°)-S(O)2-R°; -C(NCN)NR°2; -(CH2)0-4C(O)SR°; -(CH2)0-4C(O)oSiR°3; -(CH2)0-4OC(O)R°; -OC( -C(O)N(OR°)R°; -C(O)C(O)R°; -C (O)CH2C(O)R°; -C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R°; -S(O)2NR°2; -(CH2)0-4S(O)R°; -N(R°) S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NOR°)NR°2; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -P(O)(OR°)2; -OP(O)R°2; -OP(O)(OR°)2; -OP(O)(OR°)R°;-SiR°3; -(C1-4 straight-chain or branched alkylene)ON(R°)2; or -(C1-4 straight-chain or branched alkylene)C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen; C; 1-6 Alkyl; C 2-6 alkenyl; C 2-6 Alkyne group; -C1-6 aliphatic; C 3-10 cycloalkyl; C 6-10 Aryl; a 5- to 14-membered heteroaryl group having 1 to 4 cyclic heteroatoms selected from O, N, and S; a 4- to 14-membered heterocycloalkyl group having 1 to 4 cyclic heteroatoms selected from O, N, S, SO, and SO2, wherein the nitrogen is optionally oxidized; C 3-10 cycloalkyl-C 1-6 Alkyl-; C 6-10 Aryl-C 1-6 Alkyl-; (5- to 14-membered heteroaryl)-C 1-6 Alkyl; (4- to 14-membered heterocyclic alkyl)-C 1-6 Alkyl-; -CH2Ph; -O(CH2)0-1Ph; -CH2- (5- to 6-membered heteroaryl ring); -CH2- (5- to 10-membered heteroaryl ring); a 3- to 15-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, sulfur, SO, or SO2, wherein the nitrogen is optionally oxidized; or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the nitrogen is optionally oxidized; or, notwithstanding the foregoing definition, two independently occurring R° together with their intervening atom form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0031] R° (or a ring formed by two independently occurring R° and their intercalary atoms) may be substituted by 1, 2, 3, 4 or 5 independently selected substituents from the following: halogen, oxo, CN, N3, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -(CH2)O-2R ● -(halogenated R) ● -(CH2)O-2OH, -(CH2)O-2OR ● -(CH2)0-2CH(OR) ● )2;-O(halogenated R ● ), -CN, -N3, -(CH2)0-2C(O)R ● , -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR ●, -(CH2)0-2SR ● , -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR ● , -(CH2)0-2NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● , -(C1-4 linear or branched alkylene)C(O)OR ● , -SSR ● , -(CH2)0-4N(R')2; -(CH2)0-4N(R')C(O)R'; -N(R')C(S)R'; -(CH2)0-4N(R')C(O)NR'2; -N(R')C(S)NR'2; -(CH2)0-4N(R')C(O)OR'; -N(R')N(R')C(O)R'; -N(R')N(R')C(O)NR'2; -N(R')N(R')C(O)OR'; -(CH2)0-4C(O)R'; -C(S)R'; -(CH2)0-4C(O)OR'; -(CH2)0-4-C(O)-N(R')2; -(CH2)0-4-C(O)-N(R°)-S(O)2-R'; -C(NCN)NR'2; -(CH2)0-4C(O)SR'; -(CH2)0-4C(O)OSiR'3; -(CH2)0-4OC(O)R'; -OC(O)(CH2)0-4SR'; -SC(S)SR'; -(CH2)0-4SC(O)R'; -(CH2)0-4C(O)NR'2; -C(S)NR'2; -C(S)SR°; -(CH2)0-4OC(O)NR'2; -C(O)N(OR')R'; -C(O)C(O)R'; -C(O)CH2C(O)R'; -C(NOR')R'; -(CH2)0-4SSR'; -(CH2)0-4S(O)2R'; -(CH2)0-4S(O)2OR'; -(CH2)0-4OS(O)2R'; -S(O)2NR'2; -(CH2)0-4S(O)R'; -N(R')S(O)2NR'2; -N(R')S(O)2R'; -N(OR')R'; -C(NOR')NR'2; -C(NH)NR'2; -P(O)2R'; -P(O)R'2; -P(O)(OR')2; -OP(O)R'2; -OP(O)(OR')2; -OP(O)(OR')R'; where R ●Each of the R' and R' may be optionally replaced by 1, 2, 3, 4, or 5 R'', or, in the case of a "halogen group" prefix, by only one or more halogens, and each may be independently selected from C. 1-6 Alkyl; C 2-6 alkenyl; C 2-6 alkynyl group; C 3-10 cycloalkyl; C 6-10 Aryl; a 5- to 14-membered heteroaryl group having 1 to 4 cyclic heteroatoms selected from O, N, and S; a 4- to 14-membered heterocycloalkyl group having 1 to 4 cyclic heteroatoms selected from O, N, S, SO, and SO2, wherein the nitrogen is optionally oxidized; C 3-10 cycloalkyl-C 1-6 Alkyl-; C 6-10 Aryl-C 1-6 Alkyl-; (5- to 14-membered heteroaryl)-C 1-6 Alkyl; (4- to 14-membered heterocyclic alkyl)-C 1-6 Alkyl-C1-4 aliphatic group; -CH2Ph; -O(CH2)0-1Ph; a 3- to 8-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0032] R'' is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 14-membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl-, C 3-10 cycloalkyl-C 1-4 Alkyl-, (5- to 10-membered heteroaryl)-C 1-4 Alkyl-, (4- to 14-membered heterocyclic alkyl)-C 1-4 Alkyl groups, each optionally substituted with one, two, or three independently selected R''' substituents.

[0033] Each R''' is independently selected from 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)-C1-4 alkyl, 4- to 14-membered heterocyclic alkyl, (4- to 14-membered heterocyclic alkyl)-C 1-4 Alkyl, phenyl, phenyl-C 1-4 Alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 Alkyne, halogen, CN, OR a SR a NHOR a C(O)R a C(O)NR a R a C(O)OR a C(O)NR a S(O)2R a OC(O)R a OC(O)NR a R a NHR a NR a R a NR a C(O)R a NR a C(=NR a )R a NR a C(O)OR a NR a C(O)NR a R a C(=NR) a )R a C(=NOH)R a C(=NOH)NR a C(=NCN)NR a R a NR a C(=NCN)NR a R a C(=NR) a )NR a R a NR a C(=NR a )NR a R a NR a S(O)R a NR a S(O)2R a NR a S(O)2NR a R a S(O)R a S(O)NR a R a S(O)2R aS(O)2NR a C(O)R a , -P(O)R a R a -P(O)(OR) a (OR) a -B(OH)2, -B(OR) a )2 and S(O)2NR a R a R''' is the 5- to 10-membered heteroaryl group, the (5- to 6-membered heteroaryl)-C1-4 alkyl group, the 4- to 14-membered heterocyclic alkyl group, and the (4- to 14-membered heterocyclic alkyl)-C1-4 alkyl group. 1-4 Alkyl group, phenyl group, phenyl-C group 1-4 Alkyl, the C 3-10 cycloalkyl, the C 3-10 cycloalkyl-C 1-4 Alkyl, the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 2-6 alkenyl and the C 2-6 The alkynyl groups are each optionally represented by one, two, or three independently selected R groups. b Substituent substitution.

[0034] Each R a Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-14 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 14-membered heterocycloalkyl, phenyl-C 1-4 Alkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, (5- to 10-membered heteroaryl)-C 1-4 Alkyl and (4- to 14-membered heterocyclic alkyl)-C 1-4 Alkyl groups, each optionally composed of one, two, or three independently selected R groups. d Substituent substitution.

[0035] Each R b Independently selected from oxo groups, CN, halogens, NH2, OH, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-14 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 14-membered heterocycloalkyl, phenyl-C1-4 Alkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, (5- to 10-membered heteroaryl)-C 1-4 Alkyl and (4- to 14-membered heterocyclic alkyl)-C 1-4 Alkyl, NHOR c OR c SR c C(O)R c C(O)NR c R c C(O)OR c C(O)NR c S(O)2R c OC(O)R c OC(O)NR c R c C(=NOH)R c C(=NOH)NR c C(=NCN)NR c R c NR c C(=NCN)NR c R c C(=NR) c )NR c R c NR c C(=NR c )NR c R c NHR c NR c R c NR c C(O)R c NR c C(=NR c )R c NR c C(O)OR c NR c C(O)NR c R c NR c S(O)R c NR c S(O)2R c NR c S(O)2NR c R c S(O)R c S(O)NR c R c S(O)2R c S(O)2NR cC(O)R c -P(O)R c R c -P(O)(OR) c (OR) c -B(OH)2, -B(OR) c )2 and S(O)2NR c R c ; Each R c Independently selected from H and C 1-6 Alkyl, C 1-4 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, phenyl-C 1-4 Alkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, (5- to 10-membered heteroaryl)-C 1-4 Alkyl and (4- to 10-membered heterocyclic alkyl)-C 1-4 alkyl; Each R d Independently selected from H and C 1-6 Alkyl, C 1-4 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, phenyl-C 1-4 Alkyl, C 3-10 cycloalkyl-C 1-4 Alkyl, (5- to 10-membered heteroaryl)-C 1-4 Alkyl and (4- to 10-membered heterocyclic alkyl)-C 1-4 alkyl; The two R' substituents, together with the nitrogen atom to which they are attached, can form 4-, 5-, 6-, 6-, 8-, 9-, or 10-membered heterocyclic alkyl groups, which are optionally substituted by one, two, or three independently selected R' groups. e Substituent substitution; Any two of the R a The substituent, together with the nitrogen atom to which it is attached, can form 4-, 5-, 6-, 8-, 9-, or 10-membered heterocyclic alkyl groups, optionally separated by one, two, or three independently chosen R groups. e Substituent substitution; Two of the R c The substituent, together with the nitrogen atom to which it is attached, can form 4-, 5-, 6-, 8-, 9-, or 10-membered heterocyclic alkyl groups, optionally separated by one, two, or three independently chosen R groups. eSubstituent substitution; Each R e Selected independently from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 2-6 alkenyl, C 2-6 Alkyne, CN, OH, -COOH, -COOR f NH2, -NHR f -N(R) f )2、-C(O)NHR f -SO2R f -NHC(O)R f -C(O)R f NR' f S(O)2R' f NR' f S(O)2NR' f R' f 、S(O)2NR' f C(O)R' f 、S(O)2NR' f R f , phenyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl; Each R f Independently selected from H and C 1-6 Alkyl, phenyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl; or Two of the R f The substituent, together with the nitrogen atom to which it is attached, can form 4-, 5-, 6-, 8-, 9-, or 10-membered heterocyclic alkyl groups, optionally separated by one, two, or three independently chosen R groups. g Substituent substitution.

[0036] In some implementation schemes, R g It can be halogen, CN, OH, -COOH, -NH2, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups, -C(O)NH2, -C(O)NH-C 1-6 Alkyl, phenyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl.

[0037] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR. * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R) * 2))2-3O-or-S(C(R) * 2))2-3S-, where each independently occurring R * The substituent is selected from hydrogen, a C1-6 aliphatic group that may be substituted as defined below, a 3- to 8-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the ortho-substituted carbon of the "optionally substituted" group include: -O(CR * 2)2-3O-, where each independently occurring R * It is selected from hydrogen, C1-6 aliphatic groups that may be substituted as defined below, or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] R * Suitable substituents on aliphatic groups include halogens, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a prefix "halogen group", substituted only by one or more halogens, and is independently a C1-4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph, a 3- to 8-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0039] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R † -NR † 2. -C(O)R †-C(O)OR † -C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R) † )S(O)2R † ; where each R † Independently hydrogen, a substituted C1-6 aliphatic group as defined below, an unsubstituted -oPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, or, despite the above definitions, two independently occurring R groups. † Together with its intercalary atoms, it forms an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring with 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0040] R † Suitable substituents on the aliphatic group are independently halogens, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a prefix "halogen," substituted only with one or more halogens, and is independently a C1-4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph, a 3- to 8-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R † Suitable divalent substituents on saturated carbon atoms include =O and =S.

[0041] As used in this article, the term "acetyl" refers to the group -C(O)CH3.

[0042] As used herein, the term "alkoxy" refers to -O-Cl-C 20 Alkyl group, wherein the alkoxy group is attached to the remainder of the compound via an oxygen atom.

[0043] As used herein, the term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms (e.g., 1 to 10 or 1 to 6). In some embodiments, the alkyl group is unbranched (i.e., linear); in other embodiments, the alkyl group is branched. Examples of alkyl groups are (but not limited to) methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and neopentyl.

[0044] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group derived from a straight-chain or branched saturated hydrocarbon by removing two hydrogen atoms, and examples include methylene, ethylene, isopropylene, etc. The term "C" x -C y "alkylene" refers to an alkylene group having x to y carbons. Exemplary values ​​for x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C...). 10 C2-C 20 C2-C6, C2-C 10 Or C2-C 20 Alkylene). In some embodiments, the alkylene may be further substituted with 1, 2, 3 or 4 substituents as defined herein.

[0045] Unless otherwise specified, as used herein, the term "alkenyl" refers to a monovalent straight-chain or branched group having 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds, and examples include vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl groups include both cis and trans isomers. Unless otherwise specified, as used herein, the term "alkenylene" refers to a divalent straight-chain or branched group having 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0046] As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched group containing a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons), and examples of such groups include ethynyl and 1-propynyl.

[0047] As used herein, the term "alkynyl sulfone" indicates a structure containing The group, wherein R is any chemically feasible substituent described herein.

[0048] As used herein, the term "amino" signifies -N(R) † )2, for example -NH2 and -N(CH3)2.

[0049] As used herein, the term "aminoalkyl" refers to an alkyl moiety on one or more carbon atoms that is replaced by one or more amino moieties.

[0050] As described herein, the term "amino acid" refers to a molecule having a side chain, an amino group, and an acid group (e.g., -CO2H or -SO3H), wherein the amino acid is linked to a parent molecule group via the side chain, amino group, or acid group (e.g., side chain). As used herein, the term "amino acid" in its broadest sense refers to any compound or substance that can be incorporated into a polypeptide chain, for example, by forming one or more peptide bonds. In some embodiments, the amino acid has the universal structure H2N-C(H)(R)-COOH. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a synthetic amino acid; in some embodiments, the amino acid is a D-amino acid; in some embodiments, the amino acid is an L-amino acid. "Standard amino acid" refers to any one of the twenty standard L-amino acids commonly found in naturally occurring peptides. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxyvaline, isoleucine, leucine, lysine, methionine, valine, ornithine, phenylalanine, proline, pyrrolidone, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0051] As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or polycyclic system formed of carbon atoms, wherein the ring attached to a side group is aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthryl, and anthracene. The aryl ring may be attached to its side group at any heteroatom or carbon ring atom that produces a stable structure, and either of the ring atoms may optionally be substituted unless otherwise specified.

[0052] As used herein, the term “C0” indicates a bond. For example, a portion of the term -N(C(O)-(C0-C5 alkylene-H)- includes -N(C(O)-(C0 alkylene-H)-, which is also represented as -N(C(O)-H)-.

[0053] As used herein, the terms "carbocyclic" and "carbocyclic group" refer to a monovalent, optionally substituted C3-C group. 12 A monocyclic, bicyclic, or tricyclic structure, which may be a bridging ring, a fused ring, or a spirocyclic ring, wherein all rings are formed of carbon atoms and at least one ring is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of carbocyclic groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, dihydroindenyl, decahydronaphthyl, etc. The carbocyclic ring may be attached to its side groups at any ring atom that produces a stable structure, and unless otherwise specified, any of the ring atoms may optionally be substituted.

[0054] As used herein, the term "carbonyl" refers to a C(O) group, which can also be represented as C=O.

[0055] As used herein, the term "carboxyl" refers to -CO2H, (C=O)(OH), COOH, or C(O)OH or its unprotonated counterpart.

[0056] As used herein, the term "cyano" refers to the -CN group.

[0057] As used herein, the term "cycloalkyl" means a monovalent saturated cyclic hydrocarbon group, which, unless otherwise specified, can be a bridging ring, fused ring, or spiro ring having three to eight cyclic carbons, and examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0058] As used herein, the term "cycloalkenyl" means a monovalent, non-aromatic saturated cyclic hydrocarbon group, which, unless otherwise specified, can be a bridging ring, fused ring, or spiro ring having three to eight cyclic carbons and containing one or more carbon-carbon double bonds.

[0059] As used in this article, the term "diastereomer" refers to stereoisomers that are not mirror images of each other and cannot be superimposed on each other.

[0060] As used herein, the term “enantiomer” means each individual optically active form of the compounds of the present invention having an optical purity of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90%, and more preferably at least 98%, or an enantiomer excess (as determined by standard methods in the art).

[0061] The term "guanidinyl" refers to a group having the following structure: , where each R is independently any chemically feasible substituent described herein.

[0062] As used herein, the term "guanidinyl alkyl" refers to an alkyl moiety on one or more carbon atoms that is substituted by one or more guanidinyl moieties.

[0063] As used herein, the term "haloacetyl" refers to an acetyl group in which at least one hydrogen atom is replaced by a halogen.

[0064] As used herein, the term "haloalkyl" refers to an alkyl moiety on one or more carbon atoms that is replaced by one or more identical or different halogen moieties.

[0065] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0066] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein in which at least one carbon atom is replaced by a heteroatom (e.g., an O, N, or S atom). The heteroatom may appear in the middle or at the end of the group.

[0067] As used herein, the term "heteroaryl" refers to a monovalent, monocyclic, or polycyclic structure containing at least one fully aromatic ring: that is, it contains 4-hydroxyl groups within a monocyclic or polycyclic system. n +2 π electrons and containing at least one cyclic heteroatom selected from N, O, or S in the aromatic ring. Exemplary unsubstituted heteroaryl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbon atoms. The term "heteroaryl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the aforementioned heteroaryl rings is fused with one or more aryl rings or carbocyclic rings (e.g., benzene or cyclohexane rings). Examples of heteroaryl groups include (but are not limited to) pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl. The heteroaryl ring may be attached to its side groups at any ring atom that produces a stable structure, and any of the ring atoms may optionally be substituted unless otherwise specified. In some implementations, the heteroaryl group is substituted by 1, 2, 3 or 4 substituents.

[0068] As used herein, the term "heterocyclic alkyl" refers to a monovalent monocyclic, bicyclic, or polycyclic system in which at least one ring is a non-aromatic ring and said non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. It may be a bridging ring, a fused ring, or a spirocyclic ring. The 5-membered ring has zero to two double bonds, and the 6-membered and 7-membered rings have zero to three double bonds. Exemplary unsubstituted heterocyclic alkyl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heterocyclic alkyl" also refers to a heterocyclic compound having a bridging polycyclic structure, wherein one or more carbons or heteroatoms bridge two non-adjacent members in a monocyclic ring, such as a quinine cycloyl group. The term "heterocyclic alkyl" includes bicyclic, tricyclic, and tetracyclic groups fused with any of the aforementioned heterocycles to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings (e.g., aryl, cyclohexane, cyclohexene, cyclopentane, cyclopentene, pyridine, or pyrrolidine rings). Examples of heterocyclic alkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphthidyl. The heterocyclic alkyl ring may be attached to its side group at any ring atom that produces a stable structure, and unless otherwise specified, any of the ring atoms may optionally be substituted.

[0069] As used in this article, the term "hydroxyl group" refers to the -OH group.

[0070] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety that is substituted on one or more carbon atoms by one or more -OH moieties.

[0071] As used herein, the term "isomer" means any tautomer, stereoisomer, transisomer, enantiomer, or diastereomer of any compound of the present invention. It should be understood that the compounds of the present invention may have one or more chiral centers or double bonds, and thus exist in stereoisomeric form, such as double-bonded isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the present invention, the chemical structures illustrated herein, and therefore the compounds of the present invention, encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms, as well as mixtures of enantiomers and stereoisomers, such as racemates. The enantiomers and stereoisomers of the compounds of this invention can generally be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0072] As used herein, the term "connector" refers to a divalent organic moiety that links a first part (e.g., a portion of a macrocycle) to a second part (e.g., a second part of the same macrocycle). In some embodiments, the connector enables the compound to achieve an IC50 of 1 μM or less in the Ras-RAF destruction assay provided herein. The purpose of this biochemical assay is to measure the ability of the test compound to promote the formation of a ternary complex between a nucleotide-loaded Ras isoform and cyclophilin A; the resulting disruption of the ternary complex and BRAF RBD The binding of the constructs inhibits Ras signal transduction via the RAF effector.

[0073] In an assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween 20, 0.1% BSA, 100 mM NaCl, and 5 mM MgCl2, label-free cyclophilin A, His6-K-Ras-GMPPNP (or other Ras variants), and GST-BRAF were added. RBDCompounds were combined in 384-well assay plates at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. Compounds were initially present in the wells at a final concentration of 30 μM, in a 10-point 3-fold dilution series. After incubation at 25 °C for 3 hours, a mixture of anti-HisEu-W1024 and anti-GST allophycocyanin was added to the assay wells at final concentrations of 10 nM and 50 nM, respectively, and the reactants were incubated for another 1.5 hours. The TR-FRET signal was read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that promoted the disruption of the Ras:RAF complex were identified as those that reduced the TR-FRET ratio relative to the DMSO control wells.

[0074] This assay can also be used to assess selectivity. In some embodiments, the compounds of the present invention exhibit higher selectivity for one or more specific Ras mutants than for other Ras mutants or wild-type compounds compared to compounds known in the art. For example, the compounds of the present invention may exhibit higher selectivity for KRASG12V than for wild-type KRAS.

[0075] In some embodiments, the linker contains 20 or fewer linear atoms. In some embodiments, the linker contains 15 or fewer linear atoms. In some embodiments, the linker contains 10 or fewer linear atoms. In some embodiments, the molecular weight of the linker is less than 500 g / mol. In some embodiments, the molecular weight of the linker is less than 400 g / mol. In some embodiments, the molecular weight of the linker is less than 300 g / mol. In some embodiments, the molecular weight of the linker is less than 200 g / mol. In some embodiments, the molecular weight of the linker is less than 100 g / mol. In some embodiments, the molecular weight of the linker is less than 50 g / mol.

[0076] As used herein, the term "stereoisomer" refers to all possible different isomers and conformations that a compound (e.g., any compound of the formula described herein) may have, particularly all possible stereochemical and conformational isomers of the basic molecular structure, all diastereomers, enantiomers, or conformational isomers, including transisomers. Some compounds of the present invention may exist in different tautomer forms, all of which are included within the scope of the present invention.

[0077] As used herein, the term "sulfonyl" refers to the -S(O)2- group.

[0078] As used in this article, the term "thiocarbonyl" refers to the -C(S)- group.

[0079] As used herein, the term "vinyl ketone" refers to a group containing a carbonyl group directly linked to a carbon-carbon double bond.

[0080] As used herein, the term "vinyl sulfone" refers to a group containing a sulfonyl group directly linked to a carbon-carbon double bond.

[0081] As used herein, the term "acetylenoid" refers to a structure containing The group, wherein R is any chemically feasible substituent described herein.

[0082] Those skilled in the art will understand from this disclosure that certain compounds described herein may be provided or used in any of a variety of forms, such as salt forms, protected forms, prodrug forms, ester forms, isomer forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may refer to a specific form of the compound. In some embodiments, reference to a particular compound may refer to the compound in any form. In some embodiments, for example, a formulation of a single stereoisomer of the compound may be considered a different form of the compound rather than a racemic mixture of the compound; a specific salt of the compound may be considered a different form from another salt form of the compound; a formulation containing one conformational isomer ((Z) or (E)) of the double bond may be considered a different form from a formulation containing another conformational isomer ((E) or (Z)) of the double bond; a formulation in which one or more atoms have isotopes different from those present in a reference formulation may be considered a different form. Detailed Implementation

[0083] compound This document provides Ras inhibitors. The methods described herein require the formation of a high-affinity ternary complex or conjugate between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a cytosolic chaperone protein (presenting protein) (e.g., cyclophilin A) that is widely expressed in the cell. More specifically, in some embodiments, the Ras inhibitors described herein induce a new binding pocket in Ras by driving the formation of a high-affinity ternary complex or conjugate between the Ras protein and the widely expressed cytosolic chaperone protein cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way the compounds of the present invention and the complexes or conjugates thereto exert an inhibitory effect on Ras is by spatially blocking the interaction sites between Ras and downstream effector molecules (e.g., RAF) required for the propagation of oncogenic signals.

[0084] Without being bound by theory, the inventors hypothesize that the non-covalent interactions between the compounds of the present invention and Ras and chaperone proteins (e.g., cyclophilin A) contribute to the inhibition of Ras activity. For example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, as well as combinations thereof, may contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors.

[0085] The compounds of this invention can inhibit a variety of Ras proteins (e.g., K-Ras, N-Ras, H-Ras and their mutants at positions 12, 13, and 61, such as G12C, G12D, G12V, G12S, G12R, G13C, G13D, Q61H, Q61K, Q61R, and Q61L, as well as other mutants described herein, or combinations thereof). In some embodiments, the compounds of this invention inhibit G12C, G12D, G12R, or G12S mutants of RAS, or combinations thereof. In some embodiments, the compounds of this invention selectively interact with K-RasG12V relative to the wild type and relative to other mutants.

[0086] Therefore, this paper provides compounds having the structure of formula I': Formula I' in: A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. L represents a bond or -CH(R) 20 )-N(R 21 )-C(O)-, where R 20 and R 21 Each independently represents the C that can be arbitrarily replaced. 1-6 Alkyl; or R 20 and R 21 Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic alkyl groups; W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; Or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl group; Or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 5 and R 5a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 6and R 6a Together with the atoms to which they are attached, they form optionally substituted cycloalkyl or optionally substituted heteroalkyl groups; Or R 7 and R 7a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 5 With R 6 Together they form bonds; R 10 For H, -OR 11 or -NR 12 R 13 ; R 11 R 12 and R 13 Each of the following is independently a optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 4- to 14-membered heterocyclic alkyl group, or an optionally substituted C3-C... 10 cycloalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; and When R 10 When H is present, ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl, and R 2 Hydrogen, substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Or its pharmaceutically acceptable salts or stereoisomers.

[0087] In some implementation schemes, R 4 R 5 R 6 and R 7 Each of them is hydrogen. In some implementations, R 4 and R 6 It is hydrogen, and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups. In some embodiments, R 5 and R 7 It is hydrogen, and R 4 and R 6Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups.

[0088] In some implementation schemes, R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl.

[0089] In some implementation schemes, R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; In some implementation schemes, R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups.

[0090] In some implementation schemes, R 5 and R 5a Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; In some implementation schemes, R 6 and R 6a Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; In some implementation schemes, R 7 and R 7a Together with the atoms to which it is attached, it can optionally form a 4-membered cycloalkyl group.

[0091] In some embodiments, compounds of formula I' are provided herein: Formula I' in: A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. L represents a bond or -CH(R) 20 )-N(R 21 )-C(O)-, where R 20 and R 21 Each independently represents the C that can be arbitrarily replaced. 1-6 Alkyl; or R 20 and R 21 Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic alkyl groups; W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4It is CH2 or NH; R 1 The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; Or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl group; Or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 5 and R 5aTogether with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 6 and R 6a Together with the atoms to which they are attached, they form optionally substituted cycloalkyl or optionally substituted heteroalkyl groups; Or R 7 and R 7a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 5 With R 6 Together they form bonds; R 10 For H, -OR 11 or -NR 12 R 13 ; R 11 R 12 and R 13 Each of the following is independently a optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted 4- to 14-membered heterocyclic alkyl group, or an optionally substituted C3-C... 10 cycloalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; and When R 10 When H is present, ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl, and R 2 Hydrogen, substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Or its pharmaceutically acceptable salt.

[0092] In some implementations, part of formula I' Selected from: , , , , , , , , , , , , , , , , , and ;in: R 5a H, halogen or C 1-6 alkyl; R 6a H, halogen or C 1-6 alkyl; Each R 23 Independently halogen or C 1-6 Alkyl; and Each p is an independent integer of 0, 1, or 2.

[0093] In some embodiments, compounds of formula I'-a are provided herein: Formula I'-a in: A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. L represents a bond or -CH(R) 20 )-N(R 21 )-C(O)-, where R 20 and R 21 Each independently represents the C that can be arbitrarily replaced. 1-6 Alkyl; or R 20 and R 21 Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic alkyl groups; W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; Or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 10 For H, -OR 11 or -NR 12 R 13 ; R 11 R 12 and R 13 Each of the following is independently a optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 4- to 14-membered heterocyclic alkyl group, or an optionally substituted C3-C... 10 cycloalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; and When R 10 When H is present, ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl, and R 2 Hydrogen, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Or its pharmaceutically acceptable salts or stereoisomers.

[0094] This article also provides compounds having the structure of Formula I: Formula I Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2 The substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; Or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 10 For -OR 11 or -NR12 R 13 ;and R 11 R 12 and R 13 Each is independently a optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups Or its pharmaceutically acceptable salts or stereoisomers.

[0095] In some embodiments, the compound has the structure of Formula I. Formula I in: A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; Or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 10 For H, -OR 11 or -NR 12 R 13 ; R 11 R 12 and R 13 Each of the following is independently a optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 4- to 14-membered heterocyclic alkyl group, or an optionally substituted C3-C... 10 cycloalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; and When R 10 When H is present, ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl, and R 2 Hydrogen, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Or its pharmaceutically acceptable salts or stereoisomers.

[0096] In some embodiments, ring A is optionally substituted 2,4-oxazole-diyl or optionally substituted 2,5-oxazole-diyl; R 2 Hydrogen, substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 10 For H.

[0097] In some embodiments, ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl; R2 Hydrogen, substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 10 For H.

[0098] In some embodiments, the compound has a structure of formula I'-b. Formula I'-b Where R 22 H, CN, OH, or optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Alkoxy groups, optionally substituted C groups 3-6 Cycloalkyl or optionally substituted 4- to 6-membered heterocycloalkyl; and R 2 The substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl.

[0099] In some embodiments of the compounds disclosed herein, R 2 Optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl.

[0100] In some embodiments, compounds having the structure of Formula I are provided herein: Formula I Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2 The substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; Or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 10 For -OR 11 or -NR 12 R 13 ;and R 11 R 12 and R 13 Each is independently a optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; Or its pharmaceutically acceptable salt.

[0101] In some embodiments, the compound is not one of the compounds listed in Table 3.

[0102] In some implementation schemes, X 4 For NH. In some implementations, X 4 It is CH2.

[0103] In some embodiments, the compounds disclosed herein have a structure of formula Ia, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Ia In some embodiments, the compounds disclosed herein have a structure of formula Ib, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Ib In some embodiments of the compounds disclosed herein, R 4 R 5 R 6 and R 7 Each of them is hydrogen.

[0104] In some embodiments, the compounds disclosed herein have a structure of formula Ic, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Ic In some embodiments, the compounds disclosed herein have a structure of formula Id, or a pharmaceutically acceptable salt or stereoisomer thereof: FormulaId In some embodiments, the compounds disclosed herein have a structure of formula Ie, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Ie In some embodiments of the compounds disclosed herein, A is an optionally substituted 5- to 6-membered heteroaryl group. In some embodiments of the compounds disclosed herein, A is an oxazole-diyl or thiazole-diyl group.

[0105] In some embodiments, the compounds disclosed herein have a structure of formula Ic-1, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Ic-1 In some embodiments, the compounds disclosed herein have a structure of formula Id-1, or a pharmaceutically acceptable salt or stereoisomer thereof: FormulaId-1 In some embodiments, the compounds disclosed herein have a structure of formula Ie-1, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Ie-1 In some embodiments, the compounds disclosed herein have a structure of formula Ic-2, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Ic-2 In some embodiments, the compounds disclosed herein have a structure of formula Id-2, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Id-2 In some embodiments, the compounds disclosed herein have a structure of formula Ie-2, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Ie-2 In some embodiments of the compounds disclosed herein, R 3 It is hydrogen. In some implementations, R 2 With R 3 Combining them forms optionally substituted 8- to 14-membered heterocyclic alkyl groups. In some embodiments, R 2 It is an optionally substituted C1-C6 heteroalkyl or an optionally substituted 3- to 7-membered heterocyclic alkyl. In some embodiments, R 2 The substituted C1-C6 heteroalkyl group is used. In some embodiments, R 2 It is a 3- to 7-membered heterocyclic alkyl group that is optionally substituted.

[0106] In some embodiments, the compounds disclosed herein have a structure of formula Ic-3, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Ic-3 Each R 14 Independently, it is a C1-C3 alkyl group; and n can be 0, 1, 2, or 3.

[0107] In some embodiments, the compounds disclosed herein have a structure of formula Id-3, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Id-3 Each R 14 Independently, it is a C1-C3 alkyl group; and n can be 0, 1, 2, or 3.

[0108] In some embodiments, the compounds disclosed herein have a structure of formula Ie-3, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Ie-3 Each R 14 Independently, it is a C1-C3 alkyl group; and n can be 0, 1, 2, or 3.

[0109] In some embodiments, the compounds disclosed herein have a structure of formula Ic-4, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Ic-4 Each R 14 Independently, it is a C1-C3 alkyl group; and n can be 0, 1, 2, or 3.

[0110] In some embodiments, the compounds disclosed herein have a structure of formula Id-4, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula ID-4 Each R 14 Independently, it is a C1-C3 alkyl group; and n can be 0, 1, 2, or 3.

[0111] In some embodiments, the compounds disclosed herein have a structure of formula Ie-4, or a pharmaceutically acceptable salt or stereoisomer thereof: Formula Ie-4 Each R 14 Independently, it is a C1-C3 alkyl group; and n can be 0, 1, 2, or 3.

[0112] In some implementations, each R 14 The methyl group is methyl. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 0.

[0113] In some embodiments, the compounds disclosed herein have the structure of formula Ic-5: Formula Ic-5 Or its pharmaceutically acceptable salt or stereoisomer, wherein R 15 It is a C1-C3 alkyl or a C3-C6 cycloalkyl.

[0114] In some embodiments, the compounds disclosed herein have the structure of formula Id-5: Formula Id-5 Or its pharmaceutically acceptable salt or stereoisomer, wherein R 15 It is a C1-C3 alkyl or a C3-C6 cycloalkyl.

[0115] In some embodiments, the compounds disclosed herein have the structure of formula Ie-5: Formula Ie-5 Or its pharmaceutically acceptable salt or stereoisomer, wherein R 15 It is a C1-C3 alkyl or a C3-C6 cycloalkyl.

[0116] In some embodiments, the compounds disclosed herein have the structure of formula Ic-6: Formula Ic-6 Or its pharmaceutically acceptable salt or stereoisomer, wherein R 15 It is a C1-C3 alkyl or a C3-C6 cycloalkyl.

[0117] In some embodiments, the compounds disclosed herein have the structure of formula Id-6: Formula Id-6 Or its pharmaceutically acceptable salt or stereoisomer, wherein R 15 It is a C1-C3 alkyl or a C3-C6 cycloalkyl.

[0118] In some embodiments, the compounds disclosed herein have the structure of formula Ie-6: Formula Ie-6 Or its pharmaceutically acceptable salt or stereoisomer, wherein R 15 It is a C1-C3 alkyl or a C3-C6 cycloalkyl.

[0119] In some implementation schemes, R 15 It is a C3-C6 cycloalkyl group. In some embodiments, R 15 It is cyclopropyl.

[0120] In some embodiments of the compounds disclosed herein, R 1 for: Where X 3 For N or CH; m is 1 or 2; R 15 R 16 R 17 and R 18 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R 16 and R 17 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 17 and R 18 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 17 and R 15 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

[0121] In some implementation schemes, R 1 for: .

[0122] In some implementation schemes, R 1 for .

[0123] In some implementation schemes, R 16 It is methyl. In some embodiments, R 16 It is cyclopropyl.

[0124] In some embodiments of the compounds disclosed herein, W is an optionally substituted 3- to 10-membered heterocyclic alkyl group. In some embodiments, W is an optionally substituted 4- to 6-membered heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group contains an oxygen atom. In some embodiments, the heterocyclic alkyl group contains a nitrogen atom.

[0125] In some embodiments of the compounds disclosed herein, W is a optionally substituted 3- to 10-membered heterocyclic alkyl group. In some embodiments, W is a optionally substituted 3- to 6-membered heterocyclic alkyl group. In some embodiments, W is an optionally substituted cyclopropyl group.

[0126] In some embodiments of the compounds disclosed herein, R 10 For -OR 11 In some implementations, R 11The alkyl group is optionally substituted with a C1-C6 alkyl group. In some embodiments, R 11 The substituted C1-C6 heteroalkyl group is used. In some embodiments, R 10 It is -OCH2CH3.

[0127] In some embodiments of the compounds disclosed herein, R 10 For -NR 12 R 13 In some implementations, R 12 With R 13 Combining them forms optionally substituted 3- to 10-membered heterocyclic alkyl groups. In some embodiments, R 12 With R 13 The combination forms optionally substituted pyrrolidines. In some embodiments, R 12 With R 13 Combining them forms optional substituted nitrogen-containing heterocyclic butanes.

[0128] In some implementation schemes, R 10 for In some implementations, R 10 for In some implementations, R 10 for .

[0129] In some implementation schemes, R 10 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , -OCH3, -N(CH3)2, -OCH2CH(CH3)2 or -OCH2SO2CH3, each of which may be optionally substituted.

[0130] In some embodiments, the compounds of the present invention are selected from Table 1, or pharmaceutically acceptable salts or stereoisomers thereof.

[0131] Table 1. Certain compounds of the present invention

[0132] In some embodiments, the compound of the present invention is: Or, or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the compounds of the present invention are selected from Table 2, or their pharmaceutically acceptable salts or stereoisomers.

[0134] Table 2. Certain compounds of the present invention In some embodiments, the compounds of the present invention are selected from the compounds in Table 3, or pharmaceutically acceptable salts or stereoisomers thereof.

[0135] In some embodiments, the compounds of the present invention are not selected from the compounds in Table 3. In some embodiments, the compounds of the present invention are not selected from the compounds in Table 3 or their pharmaceutically acceptable salts or stereoisomers. In some embodiments, the compounds of the present invention are not selected from the compounds in Table 3 or their pharmaceutically acceptable salts or transisomers.

[0136] Table 3: Some Compounds In some embodiments, the compounds of the present invention have improved oral bioavailability (F%) compared to compounds known in the art. Methods for measuring oral bioavailability are known in the art, and one such method is provided below: Oral bioavailability could be determined in BALB / c mice. Following intravenous (IV) concentration and oral-gastric (PO) administration of the test compound, approximately 30 μL of whole blood samples were collected at specified time points into tubes containing K₂EDTA. Blood samples were centrifuged at 4600 rpm for approximately 5 minutes at 4°C, and plasma samples were stored at -80°C for bioanalysis. Plasma samples were extracted by protein precipitation and analyzed by tandem mass spectrometry (LC MS / MS) on a system such as the API 5500 using electrospray ionization with positive ionization.

[0137] All PK parameters were obtained from time-varying plasma concentration data using non-compartmental analysis with WinNonlin. Bioavailability (F%, also %F) was estimated using the following equation: AUC inf,PO The plasma concentration area under time from zero to infinity after PO administration.

[0138] AUC inf,IV The plasma concentration area under time from zero to infinity after IV administration.

[0139] dose IV Total dose administered for IV dose PO Total dose administered to PO Generally speaking, an F% (or %F) value of more than 30% is preferred, and a value of more than 50% is even more preferred.

[0140] In some embodiments, the compounds of the present invention exhibit higher selectivity for one or more specific Ras mutants than for other Ras mutants or wild-type compounds compared to compounds known in the art. Methods for measuring such selectivity are known in the art, such as Ras-Raf binding assays, the procedures for which are provided above. Therefore, in some embodiments, the compounds of the present invention exhibit higher selectivity for KRAS. G12V The selectivity is higher than other Ras mutants or higher than wild-type or combinations thereof. In some embodiments, the compounds of the present invention exhibit less than 1 μM of KRAS in the above Ras-Raf binding assay. G12V The IC50 value. In some embodiments, as measured using Ras-Raf binding assays, the compounds of the present invention exhibit at least 10-fold KRAS affinity relative to wild-type KRAS. G12V The selectivity.

[0141] In some embodiments, the compounds of the present invention are more potent against one or more specific Ras mutants than against other Ras mutants or wild-types, compared to compounds known in the art. Methods for measuring such potency are known in the art, such as pERK assays, the protocols of which are provided in the examples below. In some embodiments, the compounds of the present invention exhibit greater potency against KRAS compared to compounds known in the art. G12V The compounds of this invention may also exhibit greater efficacy against other RAS mutants or combinations thereof disclosed herein. In some embodiments, pERK assays are used to determine efficacy relative to KRAS. G12DThe compounds of this invention exhibit at least 1.5 times the activity against KRAS. G12V Its effectiveness.

[0142] In some embodiments, the compounds of the present invention exhibit a greater detrimental effect on cell viability against one or more specific Ras mutants compared to other Ras mutants or wild-types, compared to compounds known in the art. Methods for measuring cell viability are known in the art, such as the CellTiter-Glo® cell viability assay, the protocol of which is provided in the examples below. Therefore, in some embodiments, the compounds of the present invention exhibit a greater detrimental effect on KRAS cells compared to compounds known in the art. G12V The compounds of this invention also exhibit a greater reduction in cell viability against other RAS mutants or combinations thereof disclosed herein. In some embodiments, the compounds of this invention show a greater reduction in cell viability against KRAS compared to wild-type KRAS. G12V Cell viability showed a greater decrease.

[0143] In some embodiments, the compounds of the present invention may exhibit higher metabolic stability, permeability, or solubility, or combinations thereof, compared to compounds known in the art. Methods for measuring such properties are known in the art. In some embodiments, the compounds of the present invention may exhibit improvements in any or a combination of the following properties compared to compounds known in the art: selectivity, potency, cell viability, metabolic stability, permeability, oral bioavailability, or solubility.

[0144] In some embodiments, the compounds of the present invention are prodrugs or are used as prodrugs, for example, in relation to administration to cells or to a subject in need.

[0145] Pharmaceutical compositions are also provided, the pharmaceutical compositions comprising the compounds of the present invention or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

[0146] The compounds of this invention are also applicable to antibody-drug conjugates and degradation agents.

[0147] Furthermore, a method for treating cancer in a subject in need is provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. The cancer may be, for example, pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or squamous cell lung cancer. In some embodiments, the cancer comprises a Ras mutation, such as K-Ras G12V. Other Ras mutations are described herein.

[0148] Furthermore, a method for treating Ras protein-related conditions in a subject in need is provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0149] Furthermore, a method for inhibiting Ras protein in cells is provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12V. Other Ras proteins are described herein. The cells may be cancer cells, such as pancreatic cancer cells, colorectal cancer cells, lung cancer (e.g., non-small cell lung cancer cells), acute myeloid leukemia cells, multiple myeloma cells, thyroid adenocarcinoma cells, myelodysplastic syndrome cells, melanoma cells, or squamous cell lung cancer cells. Other cancer types are described herein. The cells may be in vivo or in vitro.

[0150] Regarding the compounds of the present invention, one stereoisomer may exhibit superior inhibition compared to another stereoisomer. For example, one transisomer may exhibit inhibition, while another transisomer may exhibit very little or no inhibition.

[0151] In some embodiments, the methods or uses described herein also include the administration of additional anticancer therapies. In some embodiments, the additional anticancer therapy is a HER2 inhibitor, EGFR inhibitor, second Ras inhibitor, SHP2 inhibitor, SOS1 inhibitor, Raf inhibitor, MEK inhibitor, ERK inhibitor, PI3K inhibitor, PTEN inhibitor, AKT inhibitor, mTORC1 inhibitor, BRAF inhibitor, PD-L1 inhibitor, PD-1 inhibitor, CDK4 / 6 inhibitor, or a combination thereof. In some embodiments, the additional anticancer therapy is an SHP2 inhibitor. In other embodiments, the additional anticancer agent or therapy is a pan-KRAS inhibitor (e.g., pan-KRAS-IN-1, BI-286, YL-17231). Other additional anticancer therapies are described herein.

[0152] In some implementations, this document provides compounds of formula V: (V) in: R 4 R 5 R 6 R 7 R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl group; Or R 5 With R 7Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; Or R 4 With R 6 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 5 R 5a R 6a R 7 and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; Or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 5 and R 5a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 6 and R 6a Together with the atoms to which they are attached, they form optionally substituted cycloalkyl or optionally substituted heteroalkyl groups; Or R 7 and R 7a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; Or R 5 With R 6 Together they form bonds; X 4 It can be NH or CH2; Z 1 For O or S; PG is an amino protecting group; R 24 For H or C 1-6 alkyl; R 25 It is a halogen; and R 12 and R 13Each is independently a optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, or R 12 and R 13 Together with the nitrogen atom to which it is attached, it forms optionally substituted 3- to 11-membered heterocyclic alkyl groups.

[0153] In some implementation schemes, X 4 It is NH.

[0154] In some implementation schemes, R 24 C 1-6 alkyl.

[0155] In some implementations, PG is Boc or Cbz.

[0156] In some implementation schemes, R 25 It can be Br or I.

[0157] In some implementation schemes, R 12 and R 13 Together with the nitrogen atom to which it is attached, it forms an optionally substituted 7- to 11-membered spirochetal alkyl group.

[0158] In some implementation schemes, R 5 With R 7 Together they form methylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl.

[0159] In some implementations, part of formula (V) for , or In some implementations, part of equation (V) for In some implementations, part of equation (V) for In some implementations, part of equation (V) for .

[0160] In some implementation schemes, R 5 With R 7 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 4 R 5 R 5a R 6 R 6aR 7 and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl.

[0161] In some implementation schemes, Z 1 For O. In some implementations, Z 1 Let it be S.

[0162] In some implementations, compounds of formula (VI) are provided herein: (VI) in: Z 1 For O or S; PG is an amino protecting group; R 24 For H or C 1-6 Alkyl; and R 25 It is a halogen.

[0163] In some implementation schemes, Z 1 For O. In some implementations, Z 1 Let it be S.

[0164] In some implementations, PG is Boc or Cbz.

[0165] In some implementation schemes, R 24 C 1-6 alkyl.

[0166] In some implementation schemes, R 25 It can be Br or I.

[0167] In some implementation schemes, Z 1 For O, R 25 For I, PG is Boc and R 14 For Et.

[0168] In some embodiments, compounds of formula VII are provided herein: (VII) in: R 1It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 ynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl, -B(OH)2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl; R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl; R 26 It is a halogen, toluenesulfonyloxy group, CH3SO3-, CF3SO3-, or -B(OH)2; and R 27 -CH2-OH, -CH2O-PG 1 -COOH or -COOR 28 ; R 28 C 1-6 Alkyl or NR 29 R 29 ; R 29 For H or independently for C 1-6 Alkyl; and PG 1 It is a hydroxyl protecting group.

[0169] In some implementation schemes, R 1 It is H, 4-methylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, -B(OH)2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl.

[0170] In some implementation schemes, R 1 It is -B(OH)2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl, and R 26 It can be Br or I.

[0171] In some implementation schemes, R 2 For H, C 1-6 Alkyl, 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl or 3-cyanocyclobutyl.

[0172] In some implementation schemes, R 26 It can be Br or I.

[0173] In some implementation schemes, PG 1 For TBDPS.

[0174] In some implementation schemes, R 27 It is -CH2OH.

[0175] In some embodiments, the compound of formula (VII) is selected from: , , , and .

[0176] In some embodiments, compounds of formula (VIII) are provided herein: (VIII) in: Z 1 For O or S; PG is protected by H or an amino group; R 30 and R 31 Each is H; or R 30 and R 31 Together with the nitrogen atom to which it is attached, it forms optionally substituted 7- to 11-membered spirochetal alkyl groups; R 24 For H or C 1-6 Alkyl; and R 25 It can be Br or I.

[0177] In some implementation schemes, R 24 For H.

[0178] In some implementations, PG stands for Boc.

[0179] In some implementation schemes, R 30 and R 31 Each is represented by H.

[0180] In some implementation schemes, R 30 and R 31 Together with the nitrogen atom to which it is attached, it forms an optionally substituted 7- to 11-membered spirochetal alkyl group.

[0181] In some implementation schemes, Z 1 For O. In some implementations, Z 1 Let it be S.

[0182] In some embodiments, the compound of formula (VIII) is: or .

[0183] In some implementations, compounds of formula (IX) are provided herein: (IX) in: Z 1 For O or S; PG is an amino protecting group; PG 2 It is a hydroxyl protecting group; and R 25 It can be Br or I.

[0184] In some implementations, PG stands for Boc.

[0185] In some implementation schemes, PG 2 It is -C(O)CH3.

[0186] In some implementation schemes, Z 1 For O. In some implementations, Z 1 Let it be S.

[0187] In some implementation schemes, R 25 It is Br.

[0188] In some implementations, this document provides compounds of formula (X): (X) in: PG is protected by H or an amino group; Z 1 For O or S; R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl; R 32 It is a halogen, -B(OH)2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane-2-yl; R 4 R 5 R 6 R7 R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl group; Or R 5 With R 7 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; Or R 4 With R 6 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 5 R 5a R 6a R 7 and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; Or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 5 and R 5a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 6 and R 6a Together with the atoms to which they are attached, they form optionally substituted cycloalkyl or optionally substituted heteroalkyl groups; Or R 7 and R 7a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 5 With R 6 They form bonds together.

[0189] In some implementations, PG stands for Boc.

[0190] In some implementation schemes, R 2 H or C that is optionally substituted1-6 alkyl.

[0191] In some implementation schemes, R 32 It is 4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl, Br, or I.

[0192] In some implementation schemes, Z 1 For O. In some implementations, Z 1 Let it be S.

[0193] In some implementation schemes, R 4 R 5 R 6 R 7 R 5a R 6a and R 7a Each is hydrogen.

[0194] In some implementation schemes, R 5 With R 7 Together they form methylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is hydrogen.

[0195] In some implementations, compounds of formula (XI) are provided herein: (XI) in: PG is protected by H or an amino group; Z 1 For O or S; R 1 The substituted C1-C6 alkyl, substituted C2-6 alkenyl, substituted C2-6 ynyl, substituted C1-C6 heteroalkyl, substituted 3- to 10-membered cycloalkyl, substituted 3- to 6-membered cycloalkenyl, substituted 3- to 15-membered heterocycloalkyl, substituted 6- to 10-membered aryl or substituted 5- to 10-membered heteroaryl. R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl; R4 R 5 R 6 R 7 R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl group; Or R 5 With R 7 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; Or R 4 With R 6 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 5 R 5a R 6a R 7 and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; Or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 5 and R 5a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 6 and R 6a Together with the atoms to which they are attached, they form optionally substituted cycloalkyl or optionally substituted heteroalkyl groups; Or R 7 and R 7a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 5 With R 6 They form bonds together.

[0196] In some implementations, PG is H or Boc.

[0197] In some implementation schemes, R 1 H or optionally substituted heterocyclic alkyl.

[0198] In some implementation schemes, R 2 H or C that is optionally substituted 1-6 alkyl.

[0199] In some implementation schemes, Z 1 For O. In some implementations, Z 1 Let it be S.

[0200] In some implementation schemes, R 4 R 5 R 6 R 7 R 5a R 6a and R 7a Each is hydrogen.

[0201] In some implementation schemes, R 5 With R 7 Together they form methylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is hydrogen.

[0202] Synthesis method The compounds described in this article can be obtained from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic methods.

[0203] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described in the following embodiments, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof known to those skilled in the art. As another example, synthetic methods described in WO2020 / 132597, WO 2021 / 091982, WO 2021 / 091967, WO 2021 / 091956, WO 2022 / 060836 (e.g., Examples A225 and A387), WO 2022 / 235864, WO 2022 / 235870, WO 2023 / 060253, and WO 2023 / 133543 (the disclosures of each of these documents are incorporated herein by reference) can be used to prepare the compounds of the present invention. These methods include (but are not limited to) those described in the following embodiments.

[0204] Scheme 1. General Synthesis of Macrocyclic Esters Scheme 1 outlines the general synthesis of macrocyclic esters. Appropriately substituted indolyl boronic acid esters (1) can be prepared in four steps starting from protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylprop-1-ol and appropriately substituted boronic acid, including palladium-mediated coupling, alkylation, deprotection and palladium-mediated borylation.

[0205] ( S )-hexahydropyridazine-3-carboxylic acid methyl ester analogues (3) can be prepared by a variety of methods highlighted below.

[0206] Methyl amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (4) can be obtained by reacting (S)-2-amino-3-(4-bromothiazol-2-yl)propionic acid (2) with ( S It is prepared by coupling with a methyl 3-carboxylic acid derivative (3) of hexahydropyridazine-3-carboxylic acid.

[0207] The final macrocyclic ester can be obtained by coupling methyl amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (4) with a suitably substituted indoleboronic ester (1) in the presence of a Pd catalyst, followed by hydrolysis and macrocyclic lactone formation to produce a suitably protected macrocyclic intermediate (5). Deprotection and coupling with a suitably substituted carboxylic acid (or other coupling partner) yield the macrocyclic product. Additional deprotection or functionalization steps may be required to produce the final compound (6).

[0208] Furthermore, regarding Scheme 1, the thiazole can be replaced by alternatively substituted 5- to 6-membered heterocyclic alkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered heterocyclic alkyl groups (e.g., morpholino), or optionally substituted 6-membered aryl groups (e.g., phenyl). PNG is a hydroxyl protecting group when attached to the oxygen atom of the molecule and an amino protecting group when attached to the nitrogen atom (e.g., in compound 4). The substituent R in Scheme 1... 1 and R 2 And a portion of A as defined in this specification and the claims. The subscript n is 1, 2, or 3. R 3 The variable W corresponds to that defined in this specification and the claims.

[0209] In some embodiments, Scheme 1A outlines the general synthesis of macrocyclic esters.

[0210] Option 1A. As shown in schemes 1 and 1A, PNG is a hydroxyl protecting group when attached to the oxygen atom of the molecule. PNG is an amino protecting group when attached to the nitrogen atom (e.g., in compound 4). Substituent R 1 R 2 R 4 R 4a R 5 R 5a R 6 R 6a R 7 R 7a Part A is defined in this specification and claims. 3 The variable W corresponds to that defined in this specification and the claims.

[0211] Scheme 2. General Synthesis of Macrocyclic Esters Scheme 2 outlines another general synthesis of macrocyclic esters. Appropriately substituted indolyl boronic acid esters (1) can be prepared in four steps starting from protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylprop-1-ol and appropriately substituted boronic acid, including palladium-mediated coupling, alkylation, deprotection and palladium-mediated borylation.

[0212] Methyl amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (3) can be obtained by reacting (S)-2-amino-3-(4-bromothiazol-2-yl)propionic acid (2) with ( S It is prepared by coupling with methyl hexahydropyridazine-3-carboxylate (3).

[0213] The final macrocyclic ester can be obtained by coupling methyl amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (3) with a suitably substituted indoleboronic ester (1) in the presence of a Pd catalyst, followed by hydrolysis and macrocyclic lactone formation to produce a suitably protected macrocyclic intermediate (4). Deprotection and coupling with a suitably substituted carboxylic acid (or other coupling partner) yield the macrocyclic product. Additional deprotection or functionalization steps may be required to produce the final compound (6).

[0214] Furthermore, regarding Scheme 1, the thiazole can be replaced by alternatively substituted 5- to 6-membered heterocyclic alkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, optionally substituted 3- to 6-membered heterocyclic alkyl groups (e.g., morpholino), or optionally substituted 6-membered aryl groups (e.g., phenyl). PNG is a hydroxyl protecting group when attached to the oxygen atom of the molecule, and an amino protecting group when attached to the nitrogen atom of the molecule (e.g., in compound 3). The substituent R in Scheme 2... 1 and R 2As defined in this specification and the claims. The subscript n is 1, 2, or 3. R 3 The variable W corresponds to that defined in this specification and the claims.

[0215] Option 3. Substitution of macrocyclic esters in general synthesis Scheme 3 outlines another general synthesis of macrocyclic esters. Appropriately substituted indoleboronic esters (1) can be prepared as described in Schemes 1 and 2.

[0216] Amino-substituted (S)-2-amino-3-(4-bromothiazol-2-yl)propionic acid can be prepared from 2,4-dibromothiazol as shown in Scheme 3 above.

[0217] Methyl 3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (3) can be obtained by reacting amino-substituted (S)-2-amino-3-(4-bromothiazol-2-yl)propionic acid with ( S It is prepared by coupling with methyl hexahydropyridazine-3-carboxylate.

[0218] The final macrocyclic ester can be prepared as described in Schemes 1 and 2. As shown in Scheme 3, PG is a hydroxyl protecting group when attached to the oxygen atom of the molecule and an amino protecting group when attached to the nitrogen atom of the molecule. PNG is a hydroxyl protecting group when attached to oxygen and an amino protecting group when attached to nitrogen. Substituent R 1 and R 2 As defined in this specification and the claims. The subscript n is 1, 2, or 3. R 3 The variable W corresponds to that defined in this specification and claims. The two R substituents on the nitrogen atom in compounds 3, 4, 5, and 6 correspond to the substituent R also defined in this specification and claims. 12 and R 13 .

[0219] Option 4. Substitution of macrocyclic esters in general synthesis The oxazole-containing compound can be prepared by a method similar to that shown in schemes 1 to 3, but using a diamino-substituted iodo-oxazole (3). This compound can be prepared as shown in scheme 4 above.

[0220] The final macrocyclic ester can be prepared as described in schemes 1 and 2. Compounds with various substitutions on the pyridazine ring as disclosed and claimed herein can be prepared using methods known in the art and described in WO2024067857, which are incorporated herein by reference in their entirety for all purposes.

[0221] As shown in Scheme 4, PG represents an amino protecting group when attached to the nitrogen atom of the molecule. PNG is a hydroxyl protecting group when attached to the oxygen atom of the molecule, and an amino protecting group when attached to nitrogen. Substituent R 1 and R 2 As defined in this specification and the claims. The subscript n is 1, 2, or 3. R 3 The variable W corresponds to that defined in this specification and claims. The two R substituents on the nitrogen atom in compounds 3, 4, 5, and 6 correspond to the substituent R also defined in this specification and claims. 12 and R 13 The substituents R1 and R2 correspond to the substituent R as defined in this specification and claims. 12 and R 13 In some implementation schemes, The R group is hydrogen or an alkyl group that is optionally substituted.

[0222] As detailed in this specification and claims, the synthetic route described in the general scheme is suitable for synthesizing the hexahydropyridazine moiety. quilt Replacement compounds.

[0223] Pharmaceutical Compositions and Methods of Use The compounds of interest in this invention are Ras inhibitors and can be used to treat cancer. Therefore, one embodiment of this invention provides pharmaceutical compositions comprising the compounds of this invention or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients, and methods for preparing such compositions using the compounds of this invention.

[0224] As used herein, the term "pharmaceutical composition" refers to a compound, such as the compound of the present invention, or a pharmaceutically acceptable salt thereof, formulated together with a pharmaceutically acceptable excipient.

[0225] In some embodiments, the compound is present in the pharmaceutical composition in a unit dose suitable for administration in a treatment regimen, the compound showing a statistically significant likelihood of achieving a predetermined therapeutic effect when administered to the relevant population. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for administration by: oral administration, such as enemas (aqueous or non-aqueous solutions or suspensions), tablets (e.g., intended for buccal, sublingual, and systemic absorption), pills, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, such as sterile solutions or suspensions, or sustained-release formulations; topical administration, such as creams, ointments, or controlled-release patches or sprays applied to the skin, lungs, or mouth; intravaginal or rectal administration, such as pessaries, creams, or foams; sublingual; ocular; transdermal; or nasal, pulmonary, and other mucosal surfaces.

[0226] As used herein, “pharmaceuticalally acceptable excipient” means any inactive ingredient (e.g., a medium that suspends or dissolves the active compound) that is non-toxic and non-inflammatory in the body of a subject. Typical excipients include, for example: anti-adhesion agents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, fragrances, flow enhancers, lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydrates. Excipients include (but are not limited to): optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, croscarmellose, croscarmellose, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methyl cellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methyl cellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium glycolate starch, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. A variety of agents and materials are well known to those skilled in the art to be used as excipients. For example, see Ansel et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients.

[0227] Unless explicitly stated otherwise, the compounds described herein may be provided or used in salt form, for example, in pharmaceutically acceptable salt form. As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds described herein that are suitable for use in contact with tissues of humans and other animals to a reasonable medical judgment without excessive toxicity, irritation, anaphylaxis, etc., and that are proportionate to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use (Edited by PH Stahl and CG Wermuth), Wiley-VCH, 2008. The salts may be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free bases with a suitable organic acid.

[0228] The compounds of the present invention may have ionizable groups, thereby enabling their preparation into pharmaceutically acceptable salt forms. These salts may be acid addition salts involving inorganic or organic acids, or, where the compounds of the present invention are in acid form, the salts may be prepared from inorganic or organic bases. In some embodiments, the compounds are prepared or used in pharmaceutically acceptable salt forms, which are prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, or tartaric acid, for forming acid addition salts; and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, etc., for forming base salts. Methods for preparing suitable salts are recognized in the art.

[0229] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, diglucuronate, dodecyl sulfate, ethanesulfonate, fumarate, glucohepanoate, glyceryl phosphate, hemisulfate, heptaate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-optionally substituted hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including (but not limited to) ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.

[0230] As used herein, the term "subject" refers to any member of the animal kingdom. In some embodiments, "subject" refers to a human at any developmental stage. In some embodiments, "subject" refers to a human patient. In some embodiments, "subject" refers to a non-human animal. In some embodiments, a non-human animal is a mammal (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cattle, primates, or pigs). In some embodiments, a subject includes (but is not limited to) mammals, birds, reptiles, amphibians, fish, or insects. In some embodiments, a subject may be a transgenic animal, a genetically engineered animal, or a clone.

[0231] As used herein, the term "dosage form" refers to a physically discrete unit of a compound (e.g., the compound of the present invention) intended for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, this amount is an amount (or a whole portion thereof) of a unit dose suitable for administration according to a dosing regimen, said amount being determined to be associated with a desired or beneficial outcome when administered to the relevant population (i.e., according to a therapeutic dosing regimen). Those skilled in the art will understand that the total amount of a therapeutic composition or compound administered to a particular subject is determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0232] As used herein, the term "dosing regimen" refers to a set of unit doses (usually more than one) individually administered to a subject, said unit doses typically spaced at intervals. In some embodiments, a given therapeutic compound (e.g., the compound of the present invention) has a recommended dosing regimen, which may involve one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each spaced at equal intervals; in some embodiments, the dosing regimen comprises multiple doses and at least two distinct intervals separating the individual doses. In some embodiments, all doses within the dosing regimen have the same unit dose amount. In some embodiments, the different doses within the dosing regimen have different amounts. In some embodiments, the dosing regimen comprises a first dose at a first dose amount, followed by one or more additional doses at a second dose amount different from the first dose amount. In some embodiments, the dosing regimen comprises a first dose at a first dose amount, followed by one or more additional doses at a second dose amount identical to the first dose amount. In some embodiments, when administered in a relevant population, the dosing regimen is associated with a desired or beneficial outcome (i.e., a therapeutic dosing regimen).

[0233] "Treatment regimen" refers to a dosing regimen in a relevant population that is associated with the desired or beneficial treatment outcome.

[0234] The term "treatment" (also "treat" or "treating") in its broadest sense refers to any application of a substance (such as the compounds of this invention) that partially or completely alleviates, improves, reduces, or inhibits one or more symptoms, features, or causes of a particular disease, condition, or disorder; delays its onset; reduces its severity; or reduces its incidence. In some embodiments, such treatment may be administered to a subject who does not exhibit signs of the relevant disease, condition, or disorder, or to a subject who exhibits only early signs of the disease, condition, or disorder. Alternatively, in some embodiments, treatment may be administered to a subject exhibiting one or more definitive signs of the relevant disease, condition, or disorder. In some embodiments, treatment may be directed to a subject diagnosed with the relevant disease, condition, or disorder. In some embodiments, treatment may be directed to a subject known to have one or more sensitivity factors that are statistically associated with an increased risk of developing the relevant disease, condition, or disorder.

[0235] The term "therapeuticly effective amount" means an amount sufficient to treat a disease, condition, or disorder when administered to a population suffering from or susceptible to such a disease, condition, or disorder according to a therapeutic dosing regimen. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence or severity of one or more symptoms of the disease, condition, or disorder, or delays its onset. Those skilled in the art will understand that the term "therapeuticly effective amount" does not actually require achieving successful treatment in a particular individual. Rather, a therapeutically effective amount can be an amount that provides a specific expected pharmacological response in a large number of subjects when administered to a patient requiring this treatment. It should be particularly understood that a particular subject can actually be "therapeuticly effective" and "intractable". In some embodiments, references to a therapeutically effective amount can refer to an amount measured in one or more specific tissues (e.g., tissues affected by the disease, condition, or disorder) or bodily fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will understand that in some embodiments, a therapeutically effective amount may be formulated as a single dose or administered in a single dose. In some implementations, the therapeutically effective amount may be formulated as multiple doses, for example, as part of a dosing regimen, or administered in multiple doses.

[0236] For use as a treatment for subjects, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the desired type of treatment, such as prevention, control, or treatment, the compounds or pharmaceutically acceptable salts thereof are formulated in a manner consistent with these parameters. A summary of such techniques can be found in [link to relevant documentation]. Remington: The Science and Practice of Pharmacy , No. 21 Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceuticals Technology Edited by J. Swarbrick and JC Boylan, 1988–1999, Marcel Dekker, New York, each incorporated herein by reference.

[0237] The compositions can be prepared according to conventional mixing, granulation, or coating methods, and the pharmaceutical compositions of the present invention may contain, by weight or volume, about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the compounds of the present invention or pharmaceutically acceptable salts thereof. In some embodiments, the compounds set forth herein or pharmaceutically acceptable salts thereof may be present in an amount of 1% to 95% by weight of the total weight of the composition (e.g., the pharmaceutical composition).

[0238] The composition may be suitable for delivery in the following dosage forms: intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, transdermal, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, ​​intrathecal, epidural, ocular, or by injection, inhalation, or direct contact with the mucous membranes of the nose, genitourinary tract, genitals, or mouth. Therefore, the pharmaceutical composition may be in the following forms, for example: tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, oral enemas, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, formulations suitable for iontophoresis delivery, or aerosols. The composition may be formulated according to conventional pharmaceutical practice.

[0239] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a formulation comprising a compound as described herein) to a subject or system. Administration to animal subjects (e.g., to humans) may be performed via any suitable route. For example, in some embodiments, administration may be performed via bronchial (including bronchial infusion), buccal, intestinal, intradermal, intra-arterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including tracheal infusion), transdermal, vaginal, or intravitreal administration.

[0240] Formulations may be prepared in a manner suitable for systemic, topical, or local application. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection), or those prepared for transdermal, mucosal, or oral administration. Formulations will typically include diluents, and in some cases, adjuvants, buffers, preservatives, etc. Compounds or pharmaceutically acceptable salts thereof may also be administered in the form of liposome compositions or microemulsions.

[0241] For injection, the formulation can be prepared in conventional forms, such as liquid solutions or suspensions, or in solid forms suitable for preparation as solutions or suspensions in liquids prior to injection, or in emulsion forms. Suitable excipients include, for example, water, saline, dextrose, glycerol, etc. Such compositions may also contain a certain amount of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitol monolaurate, etc.

[0242] Various sustained-release drug delivery systems have also been designed. See, for example, U.S. Patent No. 5,624,677.

[0243] Systemic administration may also include relatively non-invasive methods, such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or their pharmaceutically acceptable salts. As will be understood in the art, suitable forms include syrups, capsules, and tablets.

[0244] Each compound or its pharmaceutically acceptable salt described herein can be formulated in a variety of ways known in the art. For example, the first and second doses in a combination therapy can be formulated together or separately. Other modalities of combination therapy are described herein.

[0245] Individually or separately formulated dosages may be packaged together as a pillbox. Non-limiting examples include (but are not limited to) pillboxes containing, for example, two pills, one pill and powder, suppositories and liquid in a vial, two topical creams, etc. The pillbox may include optional components to facilitate the administration of a unit dose to a subject, such as vials for reconstituted powder form, syringes, custom IV delivery systems, inhalers, etc. Additionally, the unit-dose pillbox may contain instructions for the preparation and administration of the composition. The pillbox may be manufactured as a single-use unit dose for one subject, for multiple uses for a specific subject (at a constant dose, or where the potency of individual compounds or their pharmaceutically acceptable salts may vary with the progression of therapy); or the pillbox may contain multiple doses suitable for administration to multiple subjects (“bulk packaging”). Pillbox components may be assembled in cartons, blister packs, bottles, tubes, etc.

[0246] Oral formulations include tablets containing a mixture of an active ingredient and a non-toxic, pharmaceutically acceptable excipient. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives, including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginate, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, optionally substituted hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow aids, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may include colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0247] Two or more compounds may be mixed together in tablets, capsules, or other media, or they may be separated. In one example, the first compound is contained on the inside of the tablet, and the second compound is on the outside, such that the majority of the second compound is released before the first compound is released.

[0248] Oral formulations may also be provided in chewable tablet form or in hard gelatin capsule form, wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin); or in soft gelatin capsule form, wherein the active ingredient is mixed with an aqueous or oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets may be prepared using the ingredients mentioned above for tablets and capsules, in a conventional manner using equipment such as mixers, fluidized bed apparatus, or spray drying equipment.

[0249] Controlled release through dissolution or diffusion can be achieved by appropriately coating the compound into tablets, capsules, granules, or granules, or by incorporating the compound or a pharmaceutically acceptable salt thereof into a suitable matrix. Controlled release coatings may include one or more of the coating substances mentioned above, or, for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glyceryl palmitate, ethyl cellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethacrylate, methacrylate hydrogels, 1,3-butanediol, ethylene glycol methacrylate, or polyethylene glycol. In controlled-release matrix formulations, matrix materials may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate, methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0250] Liquid forms of compounds or pharmaceutically acceptable salts and compositions thereof that can be incorporated into the present invention for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical mediators.

[0251] Generally, when administered to humans, the oral dose of any compound of the present invention or a pharmaceutically acceptable salt thereof will depend on the nature of the compound and can be readily determined by those skilled in the art. The dose may be, for example, about 0.001 mg to about 2000 mg daily, about 1 mg to about 1000 mg daily, about 5 mg to about 500 mg daily, about 100 mg to about 1500 mg daily, about 500 mg to about 1500 mg daily, about 500 mg to about 2000 mg daily, or any range thereof.

[0252] In some embodiments, the pharmaceutical composition may also contain additional compounds having antiproliferative activity. Depending on the administration regimen, the compounds or pharmaceutically acceptable salts thereof will be formulated into suitable compositions for easy delivery. Each compound of the combination therapy or a pharmaceutically acceptable salt thereof may be formulated in a variety of ways known in the art. For example, the first and second doses of the combination therapy may be formulated together or separately. Ideally, the first and second doses are formulated together for simultaneous or near-simultaneous administration.

[0253] It should be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapies, i.e., the compounds and pharmaceutical compositions can be formulated together with one or more other desired therapeutic agents or medical procedures, or administered concurrently with, before, or after the administration of said one or more other desired therapeutic agents or medical procedures. The specific combination of therapies (therapeutic agents or procedures) employed in the combination regimen should take into account the compatibility of the desired therapeutic agent or procedure with the desired therapeutic effect to be achieved. It will also be understood that the therapies employed may achieve the desired effect for the same condition, or they may achieve different effects (e.g., controlling any adverse effects).

[0254] As described in this article, each drug in a combination therapy can be administered independently from once to four times daily for one day to one year, and even for a subject's entire life. This may indicate chronic, long-term use.

[0255] In some embodiments, compounds set forth herein, or compounds of Formula I' or any of the sub-formulas set forth herein, or compounds listed in any of the claims, or pharmaceutically acceptable salts, solvates, tautomers, or isomers thereof, may promote, enhance, or increase GTP hydrolysis in RAS mutant proteins. Methods for measuring such hydrolysis are known in the art: see, for example, WO 2024206858, which is incorporated herein by reference in its entirety.

[0256] How to use In some embodiments, the present invention discloses a method for treating a disease or condition characterized by abnormal Ras activity caused by a Ras mutant. In some embodiments, the disease or condition is cancer.

[0257] Therefore, a method for treating cancer in a subject of need is also provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendix cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophageal and gastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendix cancer, endometrial cancer, or melanoma. A method for treating Ras protein-related conditions in a subject of need is also provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.

[0258] In some embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and the methods provided herein can be used to treat a wide variety of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compounds of the present invention or salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods include (but are not limited to) tumor types such as: astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral cavity, ovarian, prostate, and thyroid carcinomas and sarcomas. Other cancers include, for example: Heart-related sarcomas, such as: angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung cancer, for example: bronchial protocarcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal tract, such as: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet tumor, glucocorticoid tumor, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor (vipoma)), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Urogenital tract, such as: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminomatous sarcoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma); The liver, for example: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bile duct cancer, such as gallbladder cancer, ampullary cancer, and bile duct cancer; Bone, for example: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondrogenic exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma and giant cell tumor; Nervous system, such as: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord (neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma); Gynecological conditions, such as: uterus (endometrial cancer, uterine cancer, endometrial cancer), cervix (cervical cancer, pretumoral cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)), fallopian tubes (cancer tumors); Hematopoietic system, such as: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders (e.g., myelofibrosis and myeloproliferative neoplasms), multiple myeloma, myelodyplasia syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); Skin conditions, such as: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, developmental nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal glands, for example: neuroblastoma.

[0259] In some implementations, the Ras protein is wild-type (Ras WT Therefore, in some embodiments, the compounds of the present invention are used to treat patients suffering from Ras WT (e.g. K-Ras) WT H-Ras WT or N-Ras WT In methods for treating cancer patients, Ras protein is amplified (e.g., K-Ras) in some implementations. amp Therefore, in some embodiments, the compounds of the present invention are used to treat patients suffering from Ras amp (K-Ras amp H-Ras amp or N-Ras amp In methods for treating patients with cancer. In some embodiments, the cancer contains Ras mutations, such as the Ras mutations described herein. In some embodiments, the mutation is selected from: (a) The following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V and combinations thereof; (b) The following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R and combinations thereof; and (c) The following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T and combinations thereof; Or a combination of any of the foregoing. In some embodiments, the cancer contains a K-RasG12V mutation and is colorectal cancer. In some embodiments, the cancer contains a K-RasG12V mutation and is pancreatic cancer. In some embodiments, the cancer contains a K-RasG12V mutation and is non-small cell lung cancer.

[0260] Methods for detecting Ras mutations are known in the art. Such methods include (but are not limited to) direct sequencing and the use of highly sensitive diagnostic assays (with CE-IVD markers), as described, for example, in Domagala et al., Pol J Pathol 3: 145-164 (2012), which are incorporated herein by reference in their entirety, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro. See also, for example, WO 2020 / 106640.

[0261] A method for inhibiting Ras protein in cells is also provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. A method for inhibiting RAF-Ras binding is also provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. The cells may be cancer cells. Cancer cells may be any type of cancer described herein. The cells may be in vivo or in vitro.

[0262] Combination therapy The methods of the present invention may include the compounds of the present invention used alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). The dose of one or more of the additional therapies (e.g., non-pharmacological treatments or therapeutic agents) may be reduced relative to the standard dose when administered alone. For example, the dose may be determined empirically based on the combination and arrangement of drugs or inferred through isoradiometric analysis (e.g., Black et al.). Neurology 65:S3-S6 (2005)).

[0263] The compounds of the present invention may be administered before, after, or simultaneously with one or more of such additional therapies. When combined, the dosage of the compounds of the present invention and the dosage of the one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) provide a therapeutic effect (e.g., a synergistic or additive therapeutic effect). The compounds of the present invention and additional therapies (e.g., anticancer agents) may be administered together, for example as a single pharmaceutical composition, or separately, and when administered separately, the administration may occur simultaneously or sequentially. Such sequential administration may be close in time or distant in time.

[0264] In some embodiments, the compositions disclosed herein comprise the compound of the present invention and an additional therapeutic agent. In some embodiments, the compositions disclosed herein comprise the compound of the present invention and two additional therapeutic agents. In some embodiments, the compositions disclosed herein comprise the compound of the present invention and three additional therapeutic agents. In some embodiments, the compositions disclosed herein comprise the compound of the present invention and four or more additional therapeutic agents.

[0265] Pharmaceutical compositions comprising the said combination or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient are also provided. Compositions comprising a therapeutic combination can be used in methods of modulating RAS (e.g., in a subject's body or cells) and in methods of treating RAS-related diseases and conditions (e.g., cancer) as described herein. This disclosure particularly provides compositions, methods, and kits for treating or preventing RAS-related diseases or conditions.

[0266] Exemplary agents that can be used in combination with the compounds of the present invention are set forth below. All references herein are incorporated by way of reference for the agents set forth (including the compounds or molecular structures disclosed therein), whether or not so expressly stated.

[0267] a) RAS(ON) inhibitors The compositions and methods disclosed herein may include the compounds of the present invention plus a RAS(ON) inhibitor. In some embodiments, the RAS(ON) inhibitor is compound 6A of RMC-6236, RMC-7977, RMC-6291, RMC-4998, RMC-9805, RMC-044, RMC-5127, GFH547, ERAS-0015, or WO 2024 / 067857. Exemplary RAS(ON) inhibitors that can be used in combinations according to this disclosure can be found in any of the following patent applications: WO 2024206858, WO 2024169914, WO202453208, WO 2024206858, WO 2024149819, WO 2024104364, WO 2024067857, WO2024060966, WO 2024017859, WO 2024102421, WO 2024008834, WO 2024008610, WO2023232776, WO 2023240263, WO 2023086341, WO 2023208005, WO 2023133543, WO2023060253, WO 2023025832, WO 2023015559, WO 2023060253, WO 2022235870, WO2022235864, WO 2022060836, WO 2021091982, WO 2021091967、WO 2021091956、WO2020132597、CN 117903169、CN 117720556、CN 117720555、CN 117720554、CN 117534687、CN 117534685、CN Patent applications 117534684, PCT / US2024 / 030993, PCT / US2024 / 023272 and PCT / US2024 / 023208, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein.

[0268] In some implementations, the RAS(ON) inhibitor is the multiselective inhibitor RMC-6236. .

[0269] In some implementations, the multiselective inhibitor of RAS(ON) is compound 6A of WO 2024 / 067857. .

[0270] Some embodiments comprising combinations of the compounds of the present invention include compositions comprising a RAS(ON) mutant selective inhibitor. In some embodiments, the RAS(ON) mutant selective inhibitor is a RAS(ON) G12C selective inhibitor. In some embodiments, the RAS(ON) mutant selective inhibitor is a RAS(ON) G12D selective inhibitor. In some embodiments, the RAS(ON) mutant selective inhibitor is a RAS(ON) G13C selective inhibitor. In some embodiments, the RAS(ON) mutant selective inhibitor is a RAS(ON) Q61H selective inhibitor. In some embodiments, the RAS(ON) mutant selective inhibitor is a RAS(ON) G13D selective inhibitor.

[0271] In some embodiments, the RAS(ON) mutant selective inhibitor available according to this disclosure is RMC-9805, which is a G12D mutant selective inhibitor. .

[0272] In some implementations, the RAS(ON) mutant selective inhibitor is the RAS(ON) G12C selective ternary complex inhibitor RMC-6291. (Schulze et al., Science. 2023 Aug 18; 381(6659): 794-799).

[0273] In some embodiments, combination therapies comprising the compounds of the present invention may include one or more RAS(ON) inhibitors, such as the compounds of the present invention plus one or more RAS(ON) multiselective inhibitors and / or one or more RAS(ON) mutant selective inhibitors.

[0274] b) RAS / MAPK inhibitors The compositions and methods described herein may include combinations of the compounds of the present invention with one or more RAS / MAPK pathway inhibitors. The RAS / MAPK pathway is a signal transduction cascade downstream of various cell surface growth factor receptors, in which activation of the RAS (and its various isoforms and allotypes) is a central event driving a variety of cellular effector events that determine cell proliferation, activation, differentiation, mobilization, and other functional properties. SHP2 transmits a positive signal from growth factor receptors to the RAS activation / deactivation cycle, which is regulated by guanine nucleotide exchange factors (GEFs, such as SOS1), which load GTP onto the RAS to produce a functionally active GTP-binding RAS and a GTP-promoting protein (GAP, such as NF1), which terminates the signal by converting GTP to GDP. The GTP-binding RAS generated by this cycle transmits the necessary positive signal to a series of serine / threonine kinases (including RAF and MAP kinases), from which additional signals are emitted for various cellular effector functions. In some implementations, the therapeutic agent that can be combined with the RAS(ON) inhibitor is an inhibitor of the MAP kinase (MAPK) pathway (or "MAPK pathway inhibitor"). MAPK pathway inhibitors include (but are not limited to) one or more MAPK pathway inhibitors described in Cancers (Basel) September 2015; 7(3): 1758-1784. For example, MAPK inhibitors may be selected from one or more of the following: trametinib, binimetinib, selumetinib, cobimetinib, LERafAON (NeoPharm), ISIS 5132; vemurafenib, pimaertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA 119 / BAY 86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (Roche, described in PLoS) One. 25 November 2014; 9(11) in; and GSK1120212 (or JTP-74057, described in Clin Cancer Res. 1 March 2011; 17(5):989-1000 in). MAPK pathway inhibitors may be PLX8394, LXH254, GDC-5573 or LY3009120.MAPK pathway inhibitors can be PI3Kα:RAS disruptors, such as BBO-10203.

[0275] i) RAS(OFF) inhibitors and RAS(OFF) degraders The compositions and methods described herein may include combinations of the compounds of the present invention with one or more RAS(OFF) inhibitors. Various mutant-selective and pan-KRAS inhibitors have been disclosed, and these inhibitors are known in the art. RAS(OFF) inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein. RAS(OFF) inhibitors are designed to inhibit RAS activity by targeting different regions of the RAS protein in an inactive (GDP-bound) state, thereby preventing its activation and downstream signaling.

[0276] In some embodiments, the RAS(OFF) inhibitor is a KRAS(OFF) inhibitor with a molecular weight of less than 700 Da. The term "KRAS(OFF) inhibitor" refers to any RAS(OFF) inhibitor that binds to KRAS at the GDP-binding "off" site. In some embodiments, the KRAS(OFF) inhibitor is... KRAS G12C Mutations are specific. KRAS G12C (OFF) Inhibitors use methods that allow the inhibitors to selectively target KRAS. G12C The mutant protein has a covalently binding group, and many such inhibitors contain a pyrimidine core. KRAS G12C (OFF) inhibitors all target KRAS. G12C The same cysteine ​​residues in the mutant protein lead to a conformational change that locks the protein into an inactive state. KRAS G12C(OFF) inhibitors include (but are not limited to) adagrasib (MRTX849), divarasib (RG6330 / GDC-6036), fulzerasib (IBI351 / GFH925), garsorasib (D-1553), glecirasib (JAB-21822), olomorasib (LY3537982), opnurasib (JDQ443), sotorasib (AMG 510), ARS-853, ARS-1620, and BI. The following are listed: 1823911, BPI-421286, D3S-001, GEC255, HBI-2438, HS-10370, JAB-21000, JAB-21822, JMKX001899, JNJ-74699157 (ARS-3248), MK-1084, and YL-15293. In some embodiments, the KRAS(OFF) inhibitor is selected from AMG 510 and MRTX849. In some embodiments, the KRAS(OFF) inhibitor is sotoraraciab (AMG 510). In some embodiments, the KRAS(OFF) inhibitor is adagraciab (MRTX849). In some embodiments, the KRAS(OFF) inhibitor is divaracib (GDC-6036). In some implementations, the KRAS(OFF) inhibitor is selected from BPI-421286, JNJ-74699157 (ARS-3248), LY3537982, MRTX1257, ARS853, ARS1620 or GDC-6036.

[0277] In some implementations, KRAS(OFF) inhibitors are effective against... KRAS G12D Mutations are specific. Using KRAS G12C Starting with (OFF) inhibitors, many KRAS inhibitors have been developed. G12D (OFF) inhibitors, thus sharing the G12C inhibitor backbone when combined with other chemical motifs (e.g., piperazine-based compounds). KRAS G12DNon-limiting examples of (OFF) inhibitors include ASP3082, BPI-501836, ERAS-4693, ERAS-5024, HBW-012-D, HBW-012-E, HRS-4642, JAB-22000, KD-8, TSN1611, LY3962673, MRTX282, MRTX1133, Q2a, SHR1127, TH-Z827, TH-Z835, TSN1611, VRTX153, and DN022150.

[0278] In some implementations, small molecule RAS(OFF) inhibitors... KRAS G12V Mutations (e.g., JAB-23000 or QTX3544) are specific. In some implementations, small molecule RAS(OFF) inhibitors are specific. KRAS G13D The mutation is specific. In some embodiments, the small molecule RAS(OFF) inhibitor is a pan-KRAS(OFF) inhibitor, such as A2A-03, ABREV01, ABT-200, ADT-030, ADT-1004, AN9025, BBP-454, BGB-53038, BI-2865, BI 3706674, ERAS-4, ERAS-254, ERAS-4001, HB-700 (G12X+G13D), JAB-23400, OC211, PF-07934040, QTX3034, RSC-1255, YL-17231, or ZG2001. In some embodiments, the Ras inhibitor is JAB-23400. In some embodiments, the Ras inhibitor is BI-2852. In some implementations, Ras inhibitors target the on and off states of Ras, such as BBO-11818, JAB-23E73, JAB-23425, BBO-8520, FMC-376, GFH375 (VS-7375), INCB161734, QTX3046, TSN1611, or TH-Z835.

[0279] In the current implementation plan, we propose to suppress RAS (OFF) in this category: WO 2024206766, WO 2024206747, WO 2024197503, WO2024193698, WO 2024192424, WO 2024179546, WO 2024178313, WO 2024178304, WO2024173842, WO 2024167922, WO 2024160225, WO 2024159471,WO 2024159470, WO2024158778, WO 2024158242, WO 2024153119, WO 2024153116, WO 2024138486, WO2024138206, WO 2024138052, WO 2024131829, WO 2024125642, WO 2024125600, WO2024123913, WO 2024123102, WO 2024120433, WO 2024120419, WO 2024119277, WO2024118926, WO 2024109233, WO 2024112654, WO 2024104453, WO 2024104425, WO2024107686, WO 2024104453, WO 2024103010, WO 2024097559, WO 2024091409, WO2024088273, WO 2024085661, WO 2024083258, WO 2024083256, WO 2024083246, WO2024083168, WO 2024078555, WO 2024076674, WO 2024076672, WO 2024076670, WO2024067714, WO 2024067575, WO 2024064335, WO 2024063578, WO 2024063576, WO2024061370, WO 2024061333, WO 2024061267, WO 2024056063, WO 2024055112, WO2024054926, WO 2024054647, WO 2024054625, WO 2024051763, WO 2024051721, WO2024050742, WO 2024050640, WO 2024046406, WO 2024046370, WO2024045066, WO2024044667, WO 2024044649, WO 2024044334, WO 2024041621, WO 2024041606, WO2024041589, WO 2024041573, WO 2024040131, WO 2024040109, WO 2024040080, WO2024036270, WO 2024034657, WO 2024034593, WO 2024034591, WO 2024034123, WO2024032747, WO 2024032704, WO 2024032703, WO 2024032702, WO 2024031088, WO2024030647, WO 2024030633, WO 2024029613, WO 2024022507, WO 2024022444, WO2024020159, WO 2024019103, WO 2024017859, WO 2024017392, WO 2024015731, WO2024015262, WO 2024012456, WO 2024009191, WO 2024008179, WO 2024008178, WO2024008068, WO 2024006445, WO 2024006424, WO 2024002373, WO 2023287896, WO2023287730, WO 2023284881, WO 2023284730, WO 2023284537, WO 2023283933, WO2023283213, WO 2023280280, WO 2023280136, WO 2023280026, WO 2023278600, WO2023274383, WO 2023327324, WO 2023246914, WO 2023246903, WO 2023246777, WO2023244713, WO 2023244615, WO 2023244604, WO 2023244600, WO 2023244599, WO2023230190, WO 2023226630, WO 2023225302, WO 2023225252, WO 2023220421, WO2023219941, WO 2023217148, WO 2023215802, WO 2023215801, WO 2023213269, WO2023212548, WO2023208005, WO 2023205719, WO 2023199180, WO 2023198191, WO2023197984, WO 2023190748, WO 2023185864, WO 2023183755, WO 2023183585, WO2023179703, WO 2023179629, WO 2023173017, WO 2023173016, WO 2023173014, WO2023172737, WO 2023171781, WO 2023159087, WO 2023159086, WO 2023154766, WO2023152255, WO 2023151674, WO 2023151621, WO 2023150394, WO 2023150284, WO2023143623, WO 2023143605, WO 2023143352, WO 2023143352, WO 2023143312, WO2023141570, WO 2023141300, WO 2023138662, WO 2023138601, WO 2023138589, WO2023138524, WO 2023133183, WO 2023133181, WO 2023130012, WO 2023125989, WO2023125627, WO 2023122662, WO 2023122154, WO 2023120742, WO 2023119677, WO2023117681, WO 2023116934, WO 2023116895, WO 2023114733, WO 2023105491, WO2023104018, WO 2023103906, WO 2023103523, WO 2023101928, WO 2023099624, WO2023099624, WO 2023099620, WO 2023099612, WO 2023099608, WO 2023099592, WO2023098832, WO 2023098425, WO 2023097227, WO 2023081840, WO 2023081476、WO2023078424、WO 2023077441、WO 2023072297、WO 2023072188、WO 2023066371、WO2023064857、WO 2023061463、WO 2023061294、WO2023057985, WO 2023056951, WO2023056421, WO 2023051586, WO 2023049697, WO 2023046135, WO 2023045960, WO2023041059, WO 2023041059, WO 2023040989, WO 2023040513, WO 2023039240, WO2023039020, WO 2023036282, WO 2023034290, WO 2023030517, WO 2023030495, WO2023030385, WO 2023030495, WO 2023030517, WO 2023030685, WO 2023030687, WO2023034290, WO 2023036282, WO 2023039240, WO 203020347, WO 2023025116, WO2023287896, WO 2023287730, WO 2023284881, WO 2023284730, WO 2023284537, WO2023283933, WO 2023283213, WO 2023280280, WO 2023280136, WO 2023280026, WO2023278600, WO 2023274383, WO 2023327324, WO 2023040989, WO 2023039240, WO2023039020, WO 2023036282, WO 2023034290, WO 2023030517, WO 2023030495, WO2023030385, WO 2023025116, WO 2023020523, WO 2023020521, WO 2023020519, WO2023020518, WO 2023020347, WO 2023018812, WO 2023018810, WO 2023018809, WO2023018699, WO 2023014979, WO 2023014006, WO 2023004102, WO 2023003417, WO2023001141, WO 2023001123, WO 2022271658, WO 2022269508, WO 2022266167, WO2022266069, WO 2022266015, WO 2022265974, WO 2022261154, WO2022261154, WO2022251576, WO 2022251296, WO 2022237815, WO 2022232332, WO 2022232331, WO2022232320, WO 2022232318, WO 2022223037, WO 2022221739, WO 2022221528, WO2022221386, WO 2022216762 (e.g., compound 44 or compound 66a), WO 2022212894, WO2022192794, WO 2022192790, WO 2022188729, WO 2022187411, WO 2022184178, WO2022173870, WO 2022173678, WO 2022135346, WO 2022133731, WO 2022133038, WO2022133345, WO 2022132200, WO 2022119748, WO 2022109485, WO 2022109487, WO2022066805, WO 2022002102, WO 2022002018, WO 2021259331, WO 2021257828, WO2021252339, WO 2021248095, WO 2021248090, WO 2021248083, WO 2021248082, WO2021248079, WO 2021248055, WO 2021245051, WO 2021244603, WO 2021239058, WO2021231526, WO 2021228161, WO 2021219090, WO 2021219090, WO 2021219072, WO2021218939, WO 2021217019, WO 2021216770, WO 2021215545, WO 2021215544, WO2021211864, WO 2021190467, WO 2021185233, WO 2021180181, WO 2021175199, 2021173923, WO 2021169990, WO 2021169963, WO 2021168193, WO 2021158071, WO2021155716, WO 2021152149, WO 2021150613, WO 2021147967, WO 2021147965, WO2021143693, WO 2021142252, WO2021141628, WO 2021139748, WO 2021139678, WO2021129824, WO 2021129820, WO 2021127404, WO 2021126816, WO 2021126799, WO2021124222, WO 2021121371, WO 2021121367, WO 2021121330, WO 2021113595, WO2021107160, WO 2021106231, WO 2021088458, WO 2021086833, WO 2021085653, WO2021081212, WO 2021058018, WO 2021057832, WO 2021055728, WO 2021031952, WO2021027911, WO 2021023247, WO 2020259513, WO 2020259432, WO 2020234103, WO2020233592, WO 2020216190, WO 2020178282, WO 2020146613, WO 2020118066、WO2020113071、WO 2020106647、WO 2020102730、WO 2020101736、WO 2020097537、WO2020086739、WO 2020081282、WO 2020050890、WO 2020047192、WO 2020035031、WO2020028706、WO 2019241157、WO 2019232419、WO 2019217691、WHERE 2019217307, WO2019215203, WO 2019213526, WO 2019213516, WO 2019155399, WO 2019150305, WO2019110751, WO 2019099524, WO 2019051291, WO 2018218070, WO 2018218071, WO2018218069, WO 2018217651, WO 2018206539, WO 2018143315, WO 2018140600, WO2018140599, WO 2018140598, WO 2018140514, WO 2018140513, WO 2018140512, WO2018119183, WO 2018112420, WO 2018068017, WO 2018064510, WO2017201161、WO2017172979、WO 2017100546、WO 2017087528、WO 2017058807、WO 2017058805、WO2017058728、WO 2017058902、WO 2017058792、WO 2017058768、WO 2017058915、WO2017015562、WO 2016168540、WO 2016164675、WO 2016049568、WO 2016049524、WO2015054572、WO 2014152588、WO 2014143659、WO 2013155223, KR 20240101190, KR20240101189, KR 20240041720, KR 20240041719, CN 118666870, CN 118666869, CN118580238, CN 118307563, CN 118221700, CN 118221699, CN 118221698, CN 118221685, CN118126064, CN 118078802, CN 118078801, CN 118005656, CN 117986263, CN 117986263, CN117946135, CN 117924327, CN 117903117, CN 117800990, CN 117800989, CN 117800976, CN117736226, CN 117683051, CN 117645627, CN 117624194, CN 117624190, CN 117586280, CN117486901, CN 117466917, CN 117462688, CN 117362315, CN 117327102, CN 117327094, CN117327074, CN 117285590, CN 117263959, CN 117247382、CN 117186095、CN 117164605、CN116969977、CN 116925075、CN 116891489、CN 116731045、CN 116731044、CN 116554208、CN116514846、CN 116478184、CN 116478141、CN 116410145、CN 116375742、CN 116354988、CN116332948、CN116332938、CN 116327956、CN 116262759、CN 116217592、CN 116199703、CN116162099、CN 116143806、CN 116143805、CN 116120315、CN 116102559、CN 115960105、CN115894520、CN 115872979、CN 115850267、CN 115785199、CN 115785124、CN 115724842、CN115724842、CN 115721720、CN 115716840、CN 115703775, CN 115611923, CN 115611898, CN115583937, CN 115572278, CN 115557949, CN 115521312, CN 115504976, CN 115490709, CN115466272, CN 115433183, CN 115433179, CN 115403575, CN 115385938, CN 115385937, CN115385912, CN 115381786, CN 115368383, CN 115368382, CN 115368381, CN 115353506、CN115322158、CN 115304623、CN 115304602、CN 115197245、CN 115181106、CN 114989195、CN114989166、CN 114989147、CN 114920741、CN114920739、CN 114907387、CN 114874234、CN114874201、CN 114716436、CN 114716435、CN 114685532、CN 114685460、CN 114591319、CN114539293、CN 114539286、CN 114539246、CN 114437107、CN 114437084、CN 114409653、CN114380827、CN 114195804、CN 114195788、CN 114437107、CN 114409653、CN 114380827、CN114195804、CN 114057776、CN 114057744、CN 114057743、CN 113999226、CN 113980032、CN113980014、CN113960193、CN 113929676、CN 113754653、CN 113683616、CN 113563323、CN113527299、CN 113527294、CN 113527293、CN 113493440、CN 113429405, CN 113321654, CN113248521, CN 113087700, CN 113024544, CN 113004269, CN 112920183, CN 112778284, CN112390818, CN 112390788, CN 112300196、CN The following patent applications are incorporated herein by reference in their entirety, including the RAS compound structures disclosed therein: 112300194, CN 112300173, CN 112225734, CN112142735, CN 112110918, CN 112094269, CN 112047937, CN 109574871, US2024270736, or EP 4389751.

[0280] In the current implementation plan, we suggest that RAS(OFF) suppression be used to suppress KRAS, for example, if you select one of the following options, select KRAS suppression: WO 2024206766, WO 2024206747, WO2024192424, WO 2024178313, WO 2024178304, WO 2024173842, WO2024153180, WO2024119277, WO 2024120433, WO 2024115890, WO 2024112654, WO 2024104453, WO2024104425, WO 2024107686, WO 2024104453, WO 2024103010, WO 2024085661, WO2024083246, WO 2024083168, WO 2024067575, WO 2024064335, WO 2024063578, WO2024063576, WO 2024051852, WO 2024051763, WO 2024046370, WO 2024044667, WO2024041621, WO 2024041606, WO 2024041589, WO 2024040131, WO 2024040109, WO2024032747, WO 2024032704, WO 2024032703, WO 2024032702, WO 2024031088, WO2024030647, WO 2024030633, WO 2024015262, WO 2024009191, WO 2024008068, WO2024002373, WO 2023287896, WO 2023274324, WO 2023246914, WO 2023246777, WO2023230190, WO 2023215802, WO 2023215801, WO 2023197984, WO 2023190748, WO2023183585, WO 2023179703, WO 2023173017, WO 2023173016, WO 2023173014, WO2023172737, WO 2023154766, WO 2023143352, WO 2023143312, WO 2023138589, WO2023133183, WO 2023122662, WO 2023114733, WO 2023099624, WO2023099623, WO2023099612, WO 2023099608, WO 2023099592, WO 2023097227, WO 2023064857, WO2023056421, WO 2023049697, WO 2023046135, WO 2023039240、WO 2023034290、WO2023020523、WO 2023020521、WO 2023020519、WO 2023020518、WO 2023001123、WO2022271823、WO 2022261210、WO 2022258974、WO 2022256459, WO 2022250170, WO2022248885, WO 2022228543, WO 2022216762, WO 2022072783, WO 2016161361, KR20240101190, KR 20240101189, KR 20240041720, KR 20240041719, CN 118221700, CN118126064, CN 117924327, CN 117946135, CN 117800990, CN 117800989, CN 117683051, CN117486901, CN CN 117263959, CN 116969977, or CN 116332948, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein. In some embodiments, combination therapies comprising the compounds of the present invention may include one or more additional RAS inhibitors, such as pan-KRAS inhibitors. In some embodiments, a combination therapy comprising a pan-KRAS inhibitor comprises ERAS-4001. In some embodiments, the pan-KRAS inhibitor is the pan-KRAS inhibitor as described in a patent application filed under the name of MedshineDiscovery, Inc. In some implementations, combinations of pan-KRAS inhibitor therapies include BGB-53038, BBO-11818, YL-17231, QTX3034, ABT-200, ADT-1004, AN9025, OC211, JAB-23425, BI-2865, BI-2493, ABREV01, A2A-03, or PF-07934040.

[0281] In any embodiment of the present invention employing a RAS(OFF) inhibitor, a RAS(OFF) degrading agent targeting the RAS-off state may be used. These degrading agents are known in the art. RAS degrading agents can be found in one or more of the following applications: WO 2024199266, WO 2024188281, WO 2024 / 159164, WO 2024 / 152247, WO 2024 / 149214, WO 2024131777, WO 2024120424, WO 2024119278, WO 2024118966, WO 2024118960, WO 2024083258, WO 2024083256, WO 2024055112, WO 2024054625, WO 2024050742, WO2024044334, WO 2024040080, WO 2024034657, WO 2024034593, WO 2024034591, WO2024034123, WO 2024029613, WO 2024020159, WO 2024019103, WO 2024017392, WO2023215906, WO 2023185864, WO 2023171781, WO 2023141570, WO 2023138524, WO2023130012, WO 2023116934, WO 2023099620, WO 2023081476, WO 2023077441, WO2022260482, CN The following applications are incorporated herein by reference in their entirety: CN 118725012, CN 118496502, CN 118496300, CN 118126040, or CN 115785199.

[0282] In some embodiments, RAS(OFF) inhibitors are peptide-based inhibitors. Peptide-based RAS(OFF) inhibitors have been developed that target specific regions of the RAS protein, such as the switch II region or the RAS-effector interface. Non-limiting examples include the K-Ras binding peptide (Krpep-2d), the Ras repressor peptide (RasIn), and LUNA18 (NCT05012618). Peptide-based RAS(OFF) inhibitors are a class of compounds that target RAS proteins by disrupting the interaction between the RAS protein and its downstream effectors or other signaling proteins. These inhibitors are typically designed to mimic the binding motifs of RAS-interacting proteins or other RAS effectors (e.g., RAF or PI3K). By binding to RAS at the same site as these effectors, peptide-based inhibitors can effectively compete with the protein and prevent activation of downstream signaling pathways. For example, see WO 2024176153, WO2024101402, WO 2024101386, WO 2023214576, WO 2023140329, WO 2022234853, WO2022234852, WO 2022234851 and WO 2022234639, each of which is incorporated herein by reference in its entirety.

[0283] Peptide-based RAS(OFF) inhibitors can be further divided into two main categories: those that target the RAS-effector interface and those that target other regions of the RAS protein. Peptide-based inhibitors targeting the RAS-effector interface are designed to bind to the switch region of RAS, which is crucial for the interaction of RAS with downstream effectors (such as RAF or PI3K). These inhibitors typically contain amino acid residues similar to those found in the binding motifs of RAS-interacting proteins or effectors, and are usually designed to form hydrogen bonds or other interactions with key residues on the RAS surface.

[0284] Peptide-based RAS(OFF) inhibitors targeting other regions of the RAS protein are often designed to disrupt other interactions essential for RAS activation or signaling. For example, some peptide-based inhibitors are designed to bind to the hypervariable region of the RAS, which is thought to play a role in protein membrane localization and anchoring. By binding to this region, peptide-based inhibitors prevent the proper localization of RAS on the plasma membrane, which is necessary for RAS activation and signaling.

[0285] Several common motifs have been identified as important for the binding of RAS-interacting proteins and effectors, and are frequently used in the design of peptide-based inhibitors. One example is the RAF-binding domain (RBD), present in many RAS-interacting proteins and important for the interaction of RAS with downstream effectors such as RAF. The RBD contains a conserved amino acid sequence (Arg-Xaa-Arg) that is crucial for RAS binding, and this motif has been incorporated into several peptide-based inhibitors designed to disrupt the RAS-RAF interaction. Another example is the RAS-binding domain (RBD) of PI3K, which is important for the interaction of RAS with this downstream effector. The PI3K RBD contains several conserved amino acid residues crucial for RAS binding (e.g., Arg-Arg-Trp), and these motifs have been used in the design of peptide-based inhibitors targeting the RAS-PI3K interaction. Other common motifs used in peptide-based RAS(OFF) inhibitors include the Ras-binding domain (RBD) of other RAS-interacting proteins (such as RalGDS and SOS), as well as sequences that mimic the switch region structure of RAS itself. These motifs are often used to optimize the binding affinity and selectivity of the inhibitor to the desired target protein or interaction.

[0286] In some implementations, RAS(OFF) inhibitors are antibodies or antigen-binding peptides specific to RAS(OFF). Antibodies have been developed that bind to specific regions of RAS proteins (e.g., switch II regions or RAS-effector interfaces). For example, antibodies targeting switch regions of RAS proteins have been developed, regions essential for the activation of these proteins and their interaction with downstream effectors. Binding of these antibodies to switch regions prevents the conformational changes required for RAS activation and downstream signaling. Another approach involves using antibodies targeting RAS-interacting proteins or downstream effectors (e.g., RAF or PI3K). Binding of these antibodies to their target proteins disrupts RAS-dependent signaling pathways and inhibits cancer cell growth and survival. Additionally, antibodies that induce the internalization and degradation of RAS proteins, leading to their depletion and inhibition of downstream signaling have been developed. For example, antibodies that recognize the unique structure of mutant RAS proteins and target these proteins via the ubiquitin-proteasome pathway for degradation have been developed. Non-limiting examples of KRAS(OFF)-specific inhibitory antibodies include anti-p21ser and K27 (DARPin) (e.g., see Khan et al., Biochim Biophys Acta Mol Cell Res. 2020 Feb;1867(2):118570). See also WO 2024136608 and WO 2024111590, each incorporated herein by reference in its entirety.

[0287] RAS inhibitors can also be used to construct antibody-drug conjugates, such as WO 2024189481, which is incorporated herein by reference in its entirety, including the structures of the compounds disclosed therein.

[0288] ii) SOS1 inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more SOS1 inhibitors. The SOS1 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the SOS1 inhibitor is one or more of the following: RMC-5845, RMC-4948, RMC-0331, BI-1701963, BI-3406, SDR5, MRTX-0902, ZG2001, and BAY-293. In some embodiments, references to the term SOS1 inhibitor include any such SOS1 inhibitor disclosed in any of the following patent applications: WO 2023109929, WO 2023059597, WO 2023029833, WO 2023041049, WO2023022497, WO 2022157629, WO 2022184116, WO 2022170952, WO 2022170917, WO2022171184, WO 2022170802, WO 2022161461, WO 2022121813, WO 2022028506, WO2022139304, WO 2021228028, WO 2019122129, CN The patent applications CN 115215847, CN 115028644, CN114685488, CN 111393519, CN 115677702 and CN 115806560, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0289] iii) SHP inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more SHP inhibitors. The SHP inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the SHP inhibitor is an SHP1 inhibitor. In some embodiments, the SHP inhibitor is an SHP2 inhibitor. In some embodiments, the SHP1 inhibitor is SB8091 or SB6299 (also known as DA-4511). In some embodiments, the SHP2 inhibitor is one or more of the following: SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, SH3809, PF-07284892, or BBP-398. In some embodiments, references to the term "SHP2 inhibitor" include any such SHP2 inhibitor disclosed in any of the following patent applications: WO 2023282702, WO 2023280283, WO 2023280237, WO 2023018155, WO2023011513, WO 2022271966, WO 2022271964, WO 2022271911, WO 2022259157, WO2022242767, WO 2022241975, WO 2022237676, WO 2022237367, WO 2022237178, WO2022235822, WO 20222084008, WO 2022135568, WO 2022063190, WO 2022043865, WO2022042331, WO 2022033430, WO 2022017444, WO 2022007869, WO 2021259077, WO2021249449, WO 2021249057, WO 2021244659, WO 2021218755, WO 2021176072, WO2021171261, WO 2021149817, WO 2021148010, WO 2021147879, WO 2021143823, WO2021143701, WO 2021143680, WO 2021281752, WO 2021121397, WO 2021119525, WO2021115286, WO 2021110796, WO 2021088945, WO 2021073439, WO 2021061706、WO2021061515、WO 2021043077、WO2021033153, WO 2021028362, WO 2021033153, WO2021028362, WO 2021018287, WO 2020259679, WO 2020249079, WO 2020210384, WO2020201991, WO 2020181283, WO 2020177653, WO 2020165734, WO 2020165733, WO2020165732, WO 2020156243, WO 2020156242, WO 2020108590, WO 2020104635、WO2020094104、WO 2020094018, WO 2020081848, WO 2020073949, WO 2020073945, WO2020072656, WO 2020065453, WO 2020065452, WO 2020063760, WO 2020061103, WO2020061101, WO 2020033828, WO 2020033286, WO 2020022323, WO 2019233810, WO2019213318, WO 2019183367, WO 2019183364, WO 2019182960, WO 2019167000, WO2019165073, WO 2019158019, WO 2019152454, WO 2019051469, WO 2019051084, WO2018218133, WO 2018172984, WO 2018160731, WO 2018136265, WO 2018136264, WO2018130928, WO 2018129402, WO 2018081091, WO 2018057884, WO 2018013597, WO2017216706, WO 2017211303, WO 2017210134, WO 2017156397、WO 2017100279、WO2017079723、WO 2017078499、WO 2016203406、WO 2016203405、WO 2016203404、WO2016196591、WO 2016191328、WO 2015107495, WO 2015107494, WO 2015107493, WO2014176488, WO 2014113584, CN 115677661, CN 115677660, CN115611869, CN 115521305, CN 115490697, CN 115466273, CN 115394612, CN 115304613, CN 115304612, CN115300513, CN 115197225, CN 114957162, CN 114920759, CN 114716448, CN 114671879, CN114539223, CN 114524772, CN 114213417, CN 114195799, CN 114163457, CN 113896710, CN113248521, CN 113248449, CN 113135924, CN 113024508, CN 112920131, CN 112823796, CN112409334, CN 112402385, CN 112174935, 111848599, CN 111704611, CN 111393459, CN111265529, CN 110143949, CN 108113848, US 11179397, US 11044675, US 11034705, US11033547, US 11001561, US 10988466, US 10954243、US Patent applications 10934302 or 10858359, each incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0290] iv) MEK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more MEK inhibitors. The MEK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the MEK inhibitor is one or more of the following: pimasiteti, IMM-1-104, selmetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and bimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation selected from the following class I MEK1 mutations: D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is selected from the following class II MEK1 mutations: ΔE51-Q58; ΔF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N. In some embodiments, references to the term MEK inhibitor include any such MEK inhibitor disclosed in any of the following patent applications: WO2022221866, WO 2022125941, WO 2022208391, WO 2022015736, WO 2022177557, WO2021018866, WO 2021069486, WO 2021142144, WO 2021168283, WO 2021234097, WO2019076947, WO 2018233696, WO 2016188472, WO 2014063024, WO 2013019906, WO2011047238, WO 2007044515, US Patent applications 2023032403 and CN 115813930, each incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0291] v) RAF inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more RAF inhibitors. RAF inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the RAF inhibitor is VS-6766 or BTDX-4933. In some embodiments, the RAF inhibitor is a BRAF inhibitor. BRAF inhibitors that may be used in combination with the compounds of the present invention include, for example, VS6766, IK-595, vemurafenib, dabrafenib, and encorafenib. BRAF may contain three types of BRAF mutations. In some implementations, the three types of BRAF mutations are selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R and A762E. In some embodiments, references to the term RAF inhibitor include any such RAF inhibitor disclosed in any of the following patent applications: WO 2023076991, WO2022226626, WO 2022226261, WO 2019084459, WO 2018203219, WO 201851306, WO2017212442, WO 2015075483, WO 2013134243, WO 2013134298, WO 2011047238, WO2011025965, WO 2011025947, WO 2011025951, WO 2011025940, WO 2011025938, WO2010065893, WO WO 2009016460, WO 2009130015, WO 2009111278, WO 2009111279, WO2008028141 and WO 2006024834, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0292] vi) ERK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more ERK inhibitors. The ERK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the ERK inhibitor is an ERK1 / 2 inhibitor, such as ERAS-007. In some embodiments, the ERK inhibitor is an ERK5 inhibitor. In some embodiments, the ERK inhibitor is one or more of ASTX-029 or I-75. In some embodiments, references to the term ERK inhibitor include any such ERK inhibitor disclosed in any of the following patent applications: WO 2023076305, WO 2022259222, WO 2022221547, WO2021110169, WO 2021110168, WO 2021252316, WO 2020102686, WO 2020228817, WO2020107987, WO 2019233456, WO 2019233457, WO 2016025561, WO 2016192063, WO2016106029, WO 2016106009, WO 2015051341, WO 2014124230, WO Patent applications 2014052563, WO2011041152, WO 200910550, WO 2008153858, CN 114315837, CN 115057860, and CN 107973783 are each incorporated herein by reference in their entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0293] vii) MAPK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more mitogen-activated protein kinase (MAPK) inhibitors. The MAPK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the MAPK inhibitor is a p38MAPK inhibitor or a MAP3K8 inhibitor. In some embodiments, the MAPK inhibitor is one or more of tilpisertib (GS-4875) and neflamapidmod (VX-745). In some embodiments, reference to the term MAPK inhibitor includes any such MAPK inhibitor disclosed in any of the following patent applications: WO 2016029263, CN 114767674, CN 115850179, and CN 1743006, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0294] In some embodiments, therapeutic agents that can be combined with the compounds of the present invention are MAP2K4 inhibitors. A non-limiting example of a MAP2K4 inhibitor available according to this disclosure is HRX-0233.

[0295] c) Kinase inhibitors The compositions and methods described herein may include combinations of the compounds of the present invention with one or more kinase inhibitors. Tyrosine kinases and serine / threonine kinases play key roles in various cellular processes, such as cell signaling, growth, and differentiation. Kinase inhibitors known in the art have been developed for the treatment of various types of cancer, in addition to their use as therapies for disorders such as neurodegenerative diseases, autoimmune diseases, and inflammation.

[0296] i) PKA inhibitors In some embodiments, the compositions and methods described herein may include one or more protein kinase A (PKA) inhibitors. The PKA inhibitor may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the PKA inhibitor is H89. In some embodiments, reference to the term PKA inhibitor includes any such PKA inhibitor disclosed in any of the following patent applications: CN 106620678 and CN114632155, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0297] ii) FAK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more focal adhesion kinase (FAK) inhibitors. The FAK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the FAK inhibitor is one or more of the following: BI853520, defactinib, GSK2256098, PF-00562271, and VS-4718. In some embodiments, references to the term FAK inhibitor include any such FAK inhibitor disclosed in any of the following patent applications: WO 2022152315, WO 2021098679, WO 2020135442, WO 2020191448, WO 2012022408, WO2013134353, WO 2012110774, WO 2010062578, CN 111072571, and KR 101691536, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0298] iii) ROCK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more Rho-associated coil-and-coil protein kinase (ROCK) inhibitors. The ROCK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the ROCK inhibitor is GSK269962A. In some embodiments, references to the term "ROCK inhibitor" include any such ROCK inhibitor disclosed in any of the following patent applications: WO 2023051753, WO 2022237892, WO 2022012409, WO2021093795, WO 2021214200, WO 2020177292, WO 202011751, WO 2019014304, WO2019179525, WO 2019089868, WO 2019014300, WO 2018108156, WO 2018009627, WO2018009625, WO 2018009622, WO 2017123860, WO 2017205709, WO Patent applications 2016112236, WO2014068035, WO 2013030367, WO 2012146724, WO 2012067965, WO 2011107608, CN108129453, CN 108191821, CN 110917352, CN 108558823, CN 108047193, CN 107973777, CN108047197, CN 108129448, CN 115869304 and GB202214708, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0299] iv) MSK1 inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more mitogen-activated kinase (MSK1) inhibitors. The MSK1 inhibitor may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the MSK1 inhibitor is one or more of the following: SB-747651A, SB 747651A, Ro 320432, CGP 57380, GSK2830371, SR1664, LY-3214996, PFI-4, MSC-2363318A, and AS601245.

[0300] v) RSK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more ribosomal S6 kinase (RSK) inhibitors. RSK1 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the RSK inhibitor is one or more of the following: BI-D1870, LJH685, SL0101-1, FMK, BRD7389, BIX 02565, LJI308, LJI308-S, LJI308-1, and LJH685-S. In some embodiments, the RSK inhibitor is PMD-026. In some embodiments, references to the term RSK inhibitor include any such RSK inhibitor disclosed in any of the following patent applications: WO 2021249558, WO2020165646, WO 2017141116 and CN 113801139, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0301] vi) ALK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more anaplastic lymphoma kinase (ALK) inhibitors. ALK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some implementations, the ALK inhibitor is one or more of the following: crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa), brigatinib (Alunbrig), lorlatinib (Lorbrena), ensartinib (X-396), TAE684, ASP3026, TPX-0131, LDK378 (a ceritinib analog), CEP-37440; 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113. Additional examples of ALK kinase inhibitors are described in Examples 3 through 39 of WO05016894. In some embodiments, references to the term ALK inhibitor include any such ALK inhibitor disclosed in any of the following patent applications: WO 2019142095, WO 2019179482, WO 2018130928, WO 2018127184, WO 2017101803, WO2016192132, WO 2014100431, WO 2012082972, CN 111138492, CN 110526914, CN109836415, CN 105801603, CN 107987056, and CN 105878248, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0302] d) Receptor tyrosine kinase inhibitors The compositions and methods described herein may include combinations of the compounds of the present invention with one or more receptor tyrosine kinase inhibitors. Receptor tyrosine kinase (RTK) inhibitors are a class of molecules (e.g., small molecules, antibodies, and nucleic acids) that bind to and block the activity of receptor tyrosine kinases or their ligands. RTKs are proteins found on the cell surface that play key roles in cell signaling and growth and have been developed as therapeutics for a range of diseases, including cancer, diabetes, and autoimmune disorders. In some embodiments, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0303] i) EGFR inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more EGFR inhibitors. EGFR inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. EGFR inhibitors include (but are not limited to) small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Available antibody inhibitors for EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Other antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by natural ligands. Non-limiting examples of antibody-based EGFR inhibitors include those described in the following literature: Modjtahedi et al., Br. J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res. 1999, 59:1236-1243. EGFR inhibitors may be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999, ibid.) or Mab C225 (ATCC accession number HB-8508) or antibodies or antibody fragments having their binding specificity.

[0304] Small molecule antagonists of EGFR include gefitinib (Iressa®), lazertinib, erlotinib (Tarceva®), and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some implementations, the EGFR inhibitor is osimertinib (Tagrisso®). In some embodiments, the EGFR inhibitor is one or more of the following: cetuximab, gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif). Other non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. The EGFR inhibitor may be ERAS-801. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family includes HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4). In some embodiments, the EGFR inhibitor may be bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, ruxolitinib, sunitinib, vemurafenib, abrocitinib, asciminib, futibatinib, ibrutinib, imatinib, pacritinib, or sorafenib. In some embodiments, reference to the term EGFR inhibitor includes any such EGFR inhibitor disclosed in any of the following patent applications: WO2023041071, WO 2023049312, WO 2023020600, WO 2023284747, WO 2022206797, WO2022258977, WO 2022033416, WO 2022033410, WO 2022105908, WO 2022100641, WO2022014639, WO 2022007841, WO 2021018009, WO 2021057882, WO 2021252661, WO2021018003, WO 2021073498, WO 2021238827, WO 2020254547, WO 2020216371, WO2020147838, WO 2020207483, WO 2020254572, WO 2020001350, WO 2021001351, WO2019164948, WO 2019218958, WO 2019046775, WO 2019015655, WO 2018121758, WO2018218963, WO 2017220007, WO 2017205459、WO 2017161937、WO 2016192609、WO199633980、WO 199630347、WO 199730034、WO 199730044、WO 199738994、WO 199749688、WO199802434、WO 199738983、WO 199519774、WO 199519970、WO 199713771、WO 199802437、WO199802438、WO 199732881、WHERE 199833798, WO 199732880, WO 199732880, WO 199702266, WO199727199, WO 199807726, WO 1997 / 34895, WO 199631510, WO 199814449, WO 199814450, WO 199814451, WO 199509847, WO 199719065, WO 199817662, WO 199935146, WO199935132, WO 199907701, WO 199220642、DE 19629652、EP 682027、EP 837063、EP0787772、EP 0520722、EP 0566226、CN 115960018、CN 110283162、CNPatent applications 114044774, CN111973601, CN 111973602 and CN 113896744, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0305] ii) HER2 inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more HER2 inhibitors. HER2 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the HER2 inhibitor is one or more of the following: tucatinib, rastuzumab (Herceptin), pertuzumab (Perjeta), lapatinib (Tykerb), ado-trastuzumab emtansine (Kadcyla), and neratinib (Nerlynx). Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); and small molecule tyrosine kinase inhibitors such as gefitinib (Iressa®), erlotinib (Tarceva®), pilitinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, and JNJ-26483327. In some embodiments, references to the term HER2 inhibitor include any such HER2 inhibitor disclosed in any of the following patent applications: WO 2021156178, WO 2021156180, WO 2021213800, WO 2021088987, WO2013561183, and WO 2013056108, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0306] iii) MET inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more MET inhibitors. The MET inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the MET inhibitor is one or more of the following: crizotinib (Xalkori), cabozantinib (Cometriq, Cabometyx), capmatinib (Tabrecta), terpotinib (Tepmetko), savolitinib (Volitinib), onartuzumab (MetMab), foretinib (GSK1363089), MGCD-265 (amuvatinib), SU11274, and SU5416. In some embodiments, references to the term "MET inhibitor" include any such MET inhibitor disclosed in any of the following patent applications: WO 2022226168, WO 2021222045, WO 2020047184, WO 2020015744, WO 2020244654, WO2020156453, WO 2019206268, WO 2018077227, WO 2017012539, WO 2016015653, WO2016012963, WO 2012015677, WO 2011162835, WO 2010089507, WO 2009091374, WO2009056692, WO 2008051547, WO US Patent Application No. 2007130468, US Patent Application No. 2012237524, CN Patent Application No. 103497177, CN Patent Application No. 107311983, CN Patent Application No. 107382968, CN Patent Application No. 110218191 and TW201331206, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0307] iv) AXL inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more AXL inhibitors. AXL inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. AXL is a receptor tyrosine kinase belonging to the TAM receptor family, which also includes TYRO3 and MERTK. In some embodiments, the AXL inhibitor is one or more of the following: bemcentib, BGB324, R428, SGI-7079, TP-0903, BMS-777607, UNC2025, and TP-0903. In some embodiments, references to the term "AXL inhibitor" include any such AXL inhibitor disclosed in any of the following patent applications: WO2023045816, WO 2022237843, WO 2022246179, WO 2021012717, WO 2021088787, WO2021067772, WO 2021239133, WO 2021204713, WO 2020238802, WO 2019039525, WO2019101178, WO 2019074116, WO 2017146236, WO 2016097918, WO 2015012298, WO2010005876, WO 2010083465, CN Patent applications JP 115073367 and JP 2022171109, each incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0308] v) IGFR inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more insulin-like growth factor receptor 1 (IGF-1R) inhibitors. IGFR inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. IGFR inhibitors have been developed to target the IGFR receptor, which plays a key role in cancer progression and metastasis. In some embodiments, the IGFR inhibitor is one or more of the following: linsitinib, AXL1717, OSI-906 (linsitinib), BMS-754807, BI836845, AZ12253801, PQIP (pyrrolo[1,2-a]quinoxaline), and NVP-AEW541. In some embodiments, references to the term "IGFR inhibitor" include any such IGFR inhibitor disclosed in any of the following patent applications: WO2022115946, WO 2022217923, WO 2021203861, WO 2021246413, WO 2020116398, WO2019046600, WO 2018195250, WO 2018221521, WO 2018204872, WO 2017072196, WO2016173682, WO 2015162291, WO 2015162292, WO 2010066868, WO Patent applications 2006069202 and CN112125916, each incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0309] vi) RET inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more transfection rearrangement (RET) inhibitors. RET inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. RETs play a crucial role in various cellular processes, including cell growth, differentiation, survival, and migration. RETs are activated by binding to their ligands, such as glial cell line-derived neurotrophic factor (GDNF) family ligands, which leads to the activation of downstream signaling pathways that promote these cellular processes. In some embodiments, the RET inhibitor is one or more of the following: pralsetinib, selpercatinib (LOXO-292), BLU-667, RXDX-105, TPX-0046, GSK3179106, molidustat (BAY 85-3934), and RPI-1 (Retrophin). In some embodiments, references to the term RET inhibitor include any such RET inhibitor disclosed in any of the following patent applications: WO 2021211380, WO 2021057963, WO 2021043209, WO 2021222017, WO 2020035065, WO 2020114487, WO2020200314, WO 2020200316, WO 2020114494, WO 2018071447, WO 2018213329, WO2017079140, WO 2014050781, CN 113943285, CN 113683610, CN 113683611, CN 113620944, CN The patent applications CN 113620945, CN 113527291, CN 113527292, CN 113527290, CN 113135896, CN111057075, CN 111233899 and CN 111362923, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0310] vii) ROS1 inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more c-ros oncogene 1 (ROS1) inhibitors. ROS1 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. ROS1 is a receptor tyrosine kinase belonging to the insulin receptor family and plays a role in various cellular processes, including cell growth, differentiation, survival, and migration. In some embodiments, the ROS1 inhibitor is one or more of the following: taletrectinib, DS-6051b, TPX-0131, GZD824, and PF-06463922. In some embodiments, reference to the term ROS1 inhibitor includes any such ROS1 inhibitor disclosed in any of the following patent applications: WO 2021098703, WO 2020024825, and US2017079972, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0311] viii) PDGFR inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more platelet-derived growth factor receptor (PDGFR) inhibitors. PDGFR inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. PDGFR is a family of receptor tyrosine kinases consisting of two members, PDGFRα and PDGFRβ. PDGFR is activated by binding to its ligand (e.g., platelet-derived growth factor (PDGF)), which leads to activation of downstream signaling pathways that promote cell growth, proliferation, and survival. In some embodiments, the PDGFR inhibitor is one or more of the following: CP-673451, imatinib, nintedanib (ofev), sunitinib, pazopanib (votrient), regorafenib (stivarga), and dasatinib (sprycel).

[0312] ix) FGF inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with fibroblast growth factor (FGF) inhibitors. FGF inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. FGFRs are a family of receptor tyrosine kinases consisting of four members, FGFR1 through FGFR4. FGFRs are activated by binding to their ligands (fibroblast growth factor (FGF)), which leads to activation of downstream signaling pathways that promote cell growth, differentiation, and survival. In some embodiments, the FGFR inhibitor is an FGFR2 inhibitor. In some embodiments, the FGFR inhibitor is an FGFR4 inhibitor. In some embodiments, the FGFR inhibitor is one or more of the following: fabatinib (TAK-659), erdafitinib (balversa), infigratinib (Truseltiq), Debio 1347, and rogaratinib (BAY 1163877). In some embodiments, references to the term "FGFR inhibitor" include any such FGFR inhibitor disclosed in any of the following patent applications: WO 2022033472, WO 2022152274, WO 2022166469, WO 2022206939, WO2021037219, WO 2021089005, WO 2021113462, WO 2020185532, WO 2019213544, WO2020164603, WO 2019154364, WO 2019034076, WO 2019213506, WO 2019223766, WO2018028438, WO 2018153373, WO 2018121650, WO Patent applications 2018010514, WO 2017028816, WO2017118438, WO 2016134320, WO 2015008844, WO 2014172644, WO 2014007951, WO2013179033, WO 2013087578, WO 2012047699, CN 105906630, CN 115869315, CN115141176, CN 115043832, and CN 115028634, each of which is incorporated herein by reference in its entirety. In some embodiments, the FGF pathway inhibitor targets an FGF ligand. Such FGF pathway inhibitors include FGF ligand traps and antibodies.Non-limiting examples include FP-1039, an FGF ligand trap composed of the fusion of the extracellular domain of FGFR1 with the Fc moiety of human IgG1, designed to isolate FGF ligands and inhibit FGF signaling; and MFGR1877S, a monoclonal antibody targeting FGF ligands, designed to block FGF-mediated signaling, including the compound structures disclosed herein, which are expressly incorporated herein by reference.

[0313] x) VEGF inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more vascular endothelial growth factor (VEGF) signaling inhibitors. VEGF (vascular endothelial growth factor) signaling inhibitors are a class of drugs that target VEGF and its receptor-mediated signaling pathways. VEGF plays a crucial role in angiogenesis (the process of forming new blood vessels from existing ones), and VEGF is overexpressed in many cancer types, making it an attractive target for cancer therapy. VEGF inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, VEGF inhibitors are antibodies or antigen-binding regions that specifically bind to VEGF (e.g., bevacizumab), or antibodies or antigen-binding regions that specifically bind to soluble VEGF receptors or their ligand-binding regions (e.g., VEGF-TRAP™), and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind to VEGF receptors). In some implementations, the VEGF inhibitor is one or more of the following: bevacizumab, aflibercept, ramucirumab, sorafenib, sunitinib, and pazopanib.

[0314] e) PI3K / mTOR pathway inhibitors The compositions and methods described herein may include combinations of the compounds of the present invention with one or more inhibitors of the PI3K-AKT-TOR signaling pathway. The PI3K-AKT-mTOR signaling pathway is a key intracellular pathway regulating numerous cellular processes, including cell growth, proliferation, metabolism, and survival. This pathway is initiated when growth factors, such as insulin or IGF-1, bind to cell surface receptors and activate phosphatidylinositol 3-kinase (PI3K). Activated PI3K then phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to produce phosphatidylinositol 3,4,5-triphosphate (PIP3), which in turn activates AKT. Activated AKT then phosphorylates multiple downstream targets, including the tuberous sclerosis complex (TSC1 / TSC2), leading to activation of mTOR (a mammalian target of rapamycin) complex 1 (mTORC1). Activated mTORC1 promotes protein synthesis and cell growth by phosphorylating key regulators of translation initiation, such as S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1).

[0315] i) PI3K inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more PI3K inhibitors. PI3K inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. PI3K inhibitors include (but are not limited to) wortmannin; 17-hydroxywortmannin analogs as described in WO06 / 044453; 4-[2-(1H-indazol-4-yl)-6-[[4-(methanesulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941, and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ) 235, and described in WO06 / 122806); (S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinylthieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyprop-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinylpyridino-[3',2':4,5]furano[3,2-d]pyrimidin-2-yl]phenol hydrochloride (available from Axon Medchem); PIK 75 (2-Methyl-5-nitro-2-[(6-bromoimidazolo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazine-benzenesulfonic acid monohydrochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)nicotinamide (available from Axon Medchem); AS-252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidin-2,4-dione (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one (available from Axon Medchem) Medchem obtained); XL-765; and XL-147.Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136. In some formulations, the PI3K inhibitor is alpelisib or copanlisib.

[0316] ii) AKT inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more AKT inhibitors. AKT inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. AKT inhibitors include (but are not limited to) ipatasertib, GSK-2141795, Akt-1-1 (inhibiting Aktl) (Barnett et al., Biochem. J. 2005, 385(part 2): 399-408); Akt-1-1,2 (inhibiting Akl and 2) (Barnett et al., Biochem. J. 2005, 385(part 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91:1808-12); 1-H-imidazo[4,5-c]pyridyl compounds (e.g., WO 05 / 011700); indole-3-methanol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li J Nutr. 2004, 134(12 Supplement):3493S-3498S); perifoxine (e.g., interfering with Akt membrane localization; Dasmahapatra et al., Clin. Cancer Res. 2004, 10(15):5242-52); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res. 2004, 64:4394-9). PI3K / AKT inhibitors may include (but are not limited to) one or more PI3K / AKT inhibitors described in Cancers (Basel) Sep 2015; 7(3):1758-1784. For example, PI3K / AKT inhibitors may be selected from one or more of the following: NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; and GSK2126458.

[0317] iii) mTOR inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more mTOR inhibitors. The mTOR inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. mTOR inhibitors include (but are not limited to) ATP-competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO94 / 09010); and ridaforolimus. (Also known as deforolimus or AP23573); rapalog, such as those disclosed in WO98 / 02441 and WO01 / 14387, such as AP23464 and AP23841; 40-(2-hydroxyethyl)rapalog; 40-[3-hydroxy(hydroxymethyl)methylpropionate]-rapalog (also known as CC1779); 40-epi-(tetrazole)-rapalog (also known as ABT578); 32-deoxyrapalog; 16-pentyneoxy-32(S)-dihydrorapalog; derivatives disclosed in WO05 / 005434; U.S. Patent No. 5,25 Derivatives disclosed in Nos. 8,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842 and 5,256,790, and in WO94 / 090101, WO92 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g. WO05 / 016252). In some implementations, the mTOR inhibitor is a bisteric inhibitor (e.g., see WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552.

[0318] iv) MNK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more mitogen-activated protein kinase-interacting kinase (MNK) inhibitors. MNK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. MNK proteins are activated downstream of the mitogen-activated protein kinase (MAPK) signaling pathway, which plays a key role in the regulation of cell proliferation, differentiation, and survival. MNK phosphorylates eIF4E, a key component of the eukaryotic translation initiation complex, which enhances the translation of specific mRNAs, including those encoding proteins involved in cell cycle regulation and tumorigenesis. In some embodiments, the MNK inhibitor is one or more of the following: tomisetin (tomoivosertib) (eFT508), CGP57380, and SEL201. In some embodiments, references to the term MNK inhibitor include any such MNK inhibitor disclosed in any of the following patent applications: WO 2021098691, WO 2020108619, WO 2020086713, WO 2018152117, WO 2018228275, WO2015200481 and CN 115583942, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0319] v) eIF4 inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more eukaryotic initiation factor 4A (eIF4A) inhibitors. The eIF4A inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. eIF4A is a key component of the eukaryotic translation initiation complex, in which it acts as an RNA helicase to unravel the secondary structure of mRNA and facilitate ribosome binding. eIF4A is required for the translation of many cancer-related genes, making it an attractive therapeutic target for cancer treatment. In some embodiments, the eIF4A inhibitor is one or more of the following: zotatifin (eFT226), silvestrol, pateamine A, and rocaglate. In some embodiments, references to the term eIF4A inhibitor include any such eIF4A inhibitor disclosed in any of the following patent applications: WO 2023034813, WO 2021195128, and WO 2017091585, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0320] In some embodiments, the compositions and methods described herein may include one or more eukaryotic initiation factor 4G (eIF4G) inhibitors. eIF4G inhibitors may be administered or formulated in combination with compounds of the present invention and / or any additional therapeutic agents described herein. The eIF4G family includes several proteins involved in protein translation initiation. eIF4G acts as a scaffold for other proteins, including eIF4E and eIF4A, to form the eIF4F complex, which is responsible for binding to the 5' cap of mRNA and unwinding the secondary structure of the mRNA to allow ribosome scanning and translation initiation. In some embodiments, the eIF4G inhibitor is one or more of patamide A and hippuristanol.

[0321] f) DNA damage response inhibitors The compositions and methods described herein may include combinations of the compounds of the present invention with one or more DNA damage response (DDR) inhibitors. The DDR pathway is a key cellular pathway activated in response to DNA damage and is essential for maintaining genomic stability, thereby preventing cancer development. However, cancer cells often have defects in the DDR pathway, making them more sensitive to DDR inhibitors. DDR inhibitors have shown promise as potential cancer therapeutics in preclinical studies, especially in combination with other agents.

[0322] i) Wee1 inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more Wee1 inhibitors. Wee1 is a kinase that plays a key role in regulating the cell cycle by inhibiting the activity of cyclin-dependent kinases (CDKs) and preventing the progression of cells through the G2 / M checkpoint. Wee1 is overexpressed in several cancer types and is associated with tumor growth and survival. In some embodiments, the Wee1 inhibitor is one or more of the following: imp7068, adavosertib, azenosertib, or ZNL-02-096. In some embodiments, references to the term Wee1 inhibitor include any such Wee1 inhibitor disclosed in any of the following patent applications: WO 2022011391, WO 2022247641, WO 2021043152, WO 2020221358, WO2020083404, WO 2020192581, WO 2019085933, WO 2018133829, WO 2015115355, WO2015183776, WO 2014085216, and CN 114831993, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0323] ii) CHK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more checkpoint kinase (CHK) inhibitors. CHK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. CHK1 kinase is a key regulator of cell cycle and DNA damage response pathways. In some embodiments, the CHK inhibitor is a CHK1 inhibitor. In some embodiments, the CHK inhibitor is a CHK2 inhibitor. In some embodiments, the CHK1 inhibitor is one or more of the following: BBI-355, rabusertib, LY2606368, GDC-0575, and MK-8776. In some embodiments, references to the term CHK1 inhibitor include any such CHK1 inhibitor disclosed in any of the following patent applications: WO 2021113661, WO2021104461, WO 2019012030, WO 2010118390, WO 2008067027, WO 2002070494, and TW202126818, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0324] iii) ATM inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more ataxia-capillary dilatation mutation (ATM) inhibitors. ATM inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. ATMs play a role in regulating replication stress responses and maintaining genomic stability. In some embodiments, the ATM inhibitor is one or more of the following: M4076, AZD0156, KU-60019, and VE-821. In some embodiments, reference to the term ATM inhibitor includes any such ATM inhibitor disclosed in any of the following patent applications: WO 2021197339, WO 2021098734, WO 2021260580, WO2007026157, WO 2006085067, and US 2016113935, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0325] iv) ATR inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more ataxia-telangiectasia and Rad3-related (ATR) inhibitors. The ATR inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the ATR inhibitor is one or more of the following: ceralaertib, VE-821, RP-350, AZ20, VX-970, abd110, VX-803, and BAY 1895344. In some embodiments, references to the term ATR inhibitor include any such ATR inhibitor disclosed in any of the following patent applications: WO 2023016529, WO 2022237875, WO 2022268025, WO2021012049, WO 2021023272, WO 2021260579, WO 2021228758, WO 2019050889, WO2019154365, WO 2019133711, WO 2017059357, WO 2013049859, WO 2007046426, WO2007015632, and CN 113797341, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0326] v) PARP inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. Seventeen members of the PARP (also known as end-anchored polymerase) family have been identified. PARP enzymes play a crucial role in DNA damage repair, particularly in the repair of single-strand DNA breaks. PARP inhibitors block the activity of PARP enzymes, leading to the accumulation of DNA damage and ultimately cell death. In some embodiments, the PARP inhibitor is one or more of the following: olaparib, rucaparib, niraparib, and veliparib (ABT-888).In some embodiments, references to the term PARP inhibitor include any such PARP inhibitor disclosed in any of the following patent applications: WO 2023051812, WO2023051807, WO 2023051716, WO 2023278592, WO 2022228387, WO 2022022664, WO2022000946, WO 2022222921, WO 2021163530, WO 2020122034, WO 2020239097, WO2020142583, WO 2020156577, WO 2020098774, WO 2020196712, WO 2019200382, WO2018125961, WO 2018205938, WO 2018192576, WO 2018218025, WO 2017032289, WO2017177838, WO 2017029601, WO 2017088723, WO 2016155655, WO 2015154630, WO2013097225, WO 2012130166, WO 2011006794, WO 2009046205, WO 2009063244, WO2008084261, WO 2007138351, WO 2006110816, WO 2005053662, WO Patent applications 2005012524, CN113698356, CN113603647, CN115073544, CN108938634, CN104887680, CN110343088, CN108976236 and CN107629071, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0327] vi) DNA-PK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more DNA-dependent protein kinase (DNA-PK) inhibitors. The DNA-PK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. DNA-dependent protein kinases (DNA-PK) are serine / threonine protein kinases that play a crucial role in DNA repair and the maintenance of genome stability. In some embodiments, the DNA-PK inhibitors are one or more of the following: NU7441, AZD7648, VX-984, M3814, and CC-115. In some embodiments, references to the term DNA-PK inhibitor include any such DNA-PK inhibitor disclosed in any of the following patent applications: WO 2022187965, WO 2021197159, WO 2021260583, WO2021204111, WO 2021104277, WO 2021098813, WO 2021022078, WO 2020259613, WO2019143678, WO 2019143675, WO 2019201283, WO 2015058031, WO 2014159690, WO2012028233, WO 2009010761, WO 2006032869, WO 2006109084, CN Patent applications 112574179, CN112300132 and CN 112300126, each incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0328] g) Cell cycle inhibitors The compositions and methods described herein may include combinations of the compounds of the present invention with one or more cell cycle inhibitors. Cell cycle inhibitors target specific proteins involved in regulating the cell cycle, the process by which cells divide and replicate their DNA. Non-limiting examples of cell cycle proteins include cyclin-dependent kinases (CDKs), aurora kinases, and polo-like kinases (PLKs). CDKs are a family of kinases involved in regulating the cell cycle. CDK inhibitors block the activity of these kinases, leading to cell cycle arrest and / or apoptosis. Aurora kinases are a family of serine / threonine kinases that play a key role in regulating mitosis. Aurora kinase inhibitors block the activity of these kinases, leading to mitotic arrest and cell death. PLKs are a family of serine / threonine kinases involved in regulating multiple stages of the cell cycle. PLK inhibitors block the activity of these kinases, leading to cell cycle arrest and / or apoptosis.

[0329] i) CDK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more CDK inhibitors. CDK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. Cyclin-dependent kinases are a family of protein kinases that regulate cell division and proliferation. Cell cycle progression is controlled by cyclins and their associated cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, and CDK6), while other CDKs (e.g., CDK7, CDK8, and CDK9) are essential for transcription. CDKs bind to cyclins to form heterodimeric complexes that phosphorylate their substrates at serine and threonine residues, thereby initiating events required for cell cycle transcription and progression. In some embodiments, the CDK inhibitor is a CDK2 inhibitor. In some embodiments, the CDK inhibitor is a CDK4 / 6 inhibitor. In some embodiments, the CDK inhibitor is a CDK7 inhibitor. In some embodiments, the CDK inhibitor is a CDK9 inhibitor. In some embodiments, the CDK inhibitor is one or more of the following: palbociclib, ribociclib, abemaciclib, and trilaciclib. In some embodiments, the CDK inhibitor is one or more of the following: tagtociclib (PF-07104091), seliciclib, voruciclib, P1446A-05, BLU-222, dinaciclib, AT-7519, RGB286638, and AZD4573.

[0330] In some embodiments, references to the term CDK inhibitor include any such CDK inhibitor disclosed in any of the following patent applications: WO 2022166793, WO 2022187611, WO 2022130304, WO2021227906, WO 2021057867, WO 2020207260, WO 2020138370, WO 2020125513, WO2020148635, WO 2020215156, WO 2020052627, WO 2017177837, WO 2017162215, WO2017177836, WO 2016193939, WO 2016014904, WO 2016015598, WO The following patent applications are incorporated herein by reference in their entirety, including but not limited to: WO2016015605, WO2015181737, WO 2012061156 A1, WO 2012038411, WO 2010020675, WO 2010125004, WO2007139732, WO 2006024945, CN 114478529, CN 108794496, CN 105294737, CN 107652284, KR 20180106188, and US 2017152269.

[0331] ii) Aurora kinase inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more aurora kinase inhibitors. Aurora kinase inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. Aurora kinases belong to the serine / threonine kinase family and play a crucial role in regulating cell division and maintaining genome stability. The aurora kinase family consists of three members: aurora A, aurora B, and aurora C. In some embodiments, the aurora kinase inhibitor is one or more of the following: palbociclib, ribociclib, and abeciclib. In some embodiments, the aurora kinase inhibitor is one or more of the following: alisertib, danusertib, barasertib, and MLN8237. In some embodiments, references to the term "aurora kinase inhibitor" include any such aurora kinase inhibitor disclosed in any of the following patent applications: WO2021110009, WO 2021008338, WO 2020112514, WO 2019129234, WO 2016077161, WO2013143466, WO 2011103089, WO 2010081881, WO 2010133794, WO 2009134658, WO2008001886, WO 2007095124, WO 2007003596, WO 2006129064, CN 114276227, CN108078991, CN 106543155, CN Patent applications 104211692 and CN 104098551 are each incorporated herein by reference in their entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0332] iii) PLK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more polo-like kinase (PLK) inhibitors. PLK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. PLKs belong to the serine / threonine kinase family, which play a crucial role in regulating cell division, DNA damage responses, and mitotic progression, and consist of four members: PLK1, PLK2, PLK3, and PLK4. In some embodiments, the PLK inhibitor is one or more of the following: volasertib, onvansertib, BI 2536, and GSK461364. In some embodiments, references to the term PLK inhibitor include any such PLK inhibitor disclosed in any of the following patent applications: WO 2011012534 A1, WO2010065134, WO 2009130453, WO 2009042806, WO 2004043936, WO 2007030361, WO2006021547, CN 115804777, and EP 2325185, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0333] iv) The kinesin superfamily of microtubule motor protein inhibitors In some embodiments, the compositions and methods described herein may include a combination of the compounds of the present invention with one or more kinesin spindle protein (KSP) inhibitors. In some embodiments, the compositions described herein may include one or more kinesin family (KIF) inhibitors. In some embodiments, the KSP inhibitor may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. KSP and KIF are subsets of the kinesin superfamily of microtubule motor proteins. KSP, also known as Eg5, is a member of the kinesin superfamily of motor proteins and plays a key role in spindle formation and cell division during mitosis. KSP inhibitors selectively target rapidly dividing cancer cells by disrupting spindle formation and inducing mitotic arrest. In some embodiments, the KSP inhibitor is one or more of the following: SB743921, monastrol, S-triphenylmethyl-L-cysteine ​​(STLC), and filanesib (ARRY-520). In some embodiments, the KIF inhibitor is an inhibitor of kinesin-8 family microtubule motor proteins. In some embodiments, the kinesin-8 family protein is KIF18A. In some embodiments, the KIF inhibitor is one or more of the following: AMG650, BTB-1, K03861, and SJ000291942. In some embodiments, references to the term "microtubule motor protein kinin superfamily inhibitor" include any such microtubule motor protein kinin superfamily inhibitor disclosed in any of the following patent applications: WO 2015114854, WO 2015114855, WO2010084186, WO 2006101761, WO 2006110390, WO 2006044825, WO 2006078574, WO2005060654, WO 2004092147, WO 2004037171, WO 2004058700, WO 2003050064, WO2003105855, WO 2022037665, WO 2018114804, WO 2017162663, WO Patent applications 2016207089, WO2012073375, JP 2014162787, JP 2019189590, JP2013166713 and KR 20220145566, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0334] v) DYRK1 inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more dual-specific tyrosine phosphorylation-regulated kinase 1 (DYRK1) inhibitors. DYRK1 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. DYRK1 is a member of the DYRK (dual-specific tyrosine phosphorylation-regulated kinase) family of protein kinases. It plays an important role in various cellular processes, including cell cycle regulation, neuronal development, and transcriptional control. In some embodiments, the DYRK1 inhibitor is one or more of the following: caryophyllene, INDY, D4476, and AZ191. In some embodiments, references to the term DYRK1 inhibitor include any such DYRK1 inhibitor disclosed in any of the following patent applications: WO 2023277331 A1, WO2023140846 A1, WO 2017181087 A1, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0335] h) Anti-apoptotic protein inhibitors The compositions and methods described herein may include combinations of the compounds of the present invention with one or more anti-apoptotic protein inhibitors. In some embodiments, the anti-apoptotic protein inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. Anti-apoptotic inhibitors target proteins that function in preventing apoptosis (a form of programmed cell death). Apoptosis is a key mechanism for eliminating damaged or unwanted cells. Anti-apoptotic proteins are a family of proteins that inhibit apoptotic pathways, thereby preventing cell death. Several known classes of anti-apoptotic inhibitors exist, including Bcl-2 inhibitors, XIAP inhibitors, survivin inhibitors, Mcl-1 inhibitors, and FLIP inhibitors. These inhibitors function by binding to specific anti-apoptotic proteins and inhibiting their activity, thereby promoting cell death in cancer cells. In some embodiments, the compositions described herein may include one or more anti-apoptotic protein inhibitors. The anti-apoptotic protein inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. In some embodiments, the anti-apoptotic protein inhibitors include MCL-1 inhibitors. Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845. Myeloid leukemia-1 (MCL-1) protein is a key anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is strongly associated with tumor progression and resistance to targeted therapies, not only conventional chemotherapy but also BCL-2 inhibitors such as ABT-263. In some embodiments, anti-apoptotic protein inhibitors include BCL protein inhibitors. Examples of BCL protein inhibitors include (but are not limited to) Venclexta, Navitoclax (ABT-263), A-1331852, S63845, and AT-101.

[0336] i) Autophagy inhibitors The compositions and methods described herein may include combinations of the compounds of the present invention with one or more autophagy inhibitors. In some embodiments, the autophagy inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. Autophagy inhibitors include (but are not limited to) chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), spautin-1, SAR405, bafilomycin A1, 5-amino-4-imidazolamide riboside (AICAR), leucocyanidin, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vincristine. Additionally, antisense or siRNAs that inhibit the expression of proteins including (but not limited to) ATG5 (which is involved in autophagy) may also be used. In some embodiments, the one or more additional therapies include autophagy inhibitors.

[0337] a) ULK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more Unc-51-like kinase (ULK) inhibitors. ULK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the ULK inhibitor is a ULK1 / 2 inhibitor. In some embodiments, the ULK inhibitor is one or more of the following: ULK-101, MRT68921, SBI-0206965, MRT67307, MRT68920, MRT68922, MRT199665, LY3009120, and doxomorphin.

[0338] b) VPS inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more vacuole protein sorting (VPS) inhibitors. VPS inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. VPS proteins are a family of proteins that play a key role in autophagy by regulating the formation and function of autophagosomes (structures that phagocytose cellular components and transport them to lysosomes for degradation). Dysregulation of VPS proteins leads to a variety of diseases, including cancer, neurodegenerative diseases, and infectious diseases. In some embodiments, the VPS inhibitor is a VPS34 inhibitor. In some embodiments, the VPS inhibitor is one or more of the following: PIK-III, VPS34-IN1, SAR405, Spautin-1, and NSC185058.

[0339] c) Macropinocytosis inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more macropinocytosis inhibitors. Macropinocytosis inhibitors may be administered or formulated in combination with the RAS(ON) inhibitors described herein and / or any additional therapeutic agents. Macropinocytosis inhibitors are compounds that can block or reduce the macropinocytosis process. In some embodiments, macropinocytosis inhibitors are one or more of the following: EIPA (ethylisopropylamiloride), Wortmannin, amiloride, apilimod, Dyngo-4a, and latrunculin B.

[0340] j) Inhibitors of the WNT / β-catenin pathway The compositions and methods described herein may include combinations of the compounds of the present invention with one or more WNT / β-catenin pathway inhibitors. In some embodiments, the WNT / β-catenin pathway inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. The WNT / β-catenin pathway is an important signaling pathway that plays a crucial role in development, tissue homeostasis, and disease. Dysregulation of this pathway leads to various cancers, making it an attractive target for cancer therapy. WNT / β-catenin pathway inhibitors target various components of the pathway, including WNT ligands, receptors, and downstream effectors.

[0341] i) β-catenin inhibitors In some embodiments, the compositions and methods described herein may include the compounds of the present invention and one or more β-catenin inhibitors. β-catenin inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. β-catenin is a protein that plays an important role in the WNT signaling pathway, which regulates various cellular processes including cell proliferation, differentiation, and migration. In normal cells, β-catenin levels are tightly regulated by a disruption complex that marks β-catenin for degradation. However, in many cancer cells, the disruption complex is impaired, leading to the accumulation of β-catenin in the cell nucleus and activation of target genes involved in tumor growth and metastasis.In some implementations, the WNT / β-catenin inhibitor is one or more of the following: FOG-001, OMP-131R10, Foxy-5, LGK974, RXC004, ETC-159, OMP-54F28, Niclosamide, OMP-18R5, OTSA-101, BNC101, DKN-01, Sulindac, Pyridinium, E7449, BC2059, PRI-724, SM08502, IWP1, IWP2, IWP3, IWP4, IWP12, IWP L6, C59, GNF-6231, GNF-1331, DK-520, DK-419, IgG-2919, Fz7-21, RHPD-P1, SRI37892, 1094-0205, 2124-0331, 3235-0367, NSC36784, NSC654259, IgG-2919, Salinomycin, BMD4702, 3289-8625, J01-017a, FJ9, KY-02061, KY-02327, NSC668036, Peptide Pen-N3, SSTC3, CCT031374, TCS 183, XAV939, AZ1366, G007-LK, MSC2504877, G244-LM, IWR-1, JW74, JW55, K-756, NVP-TNKS656, MN-64, RK-287107, WIKI4, KY1220, KYA1797K, MSAB, PKF115-584, CGP049090, AV-65, PNU-74654, Windorphen, IQ-1 (tegavivant), foscenvivant, PNPB-29, ZW4864, SAH-BCL9, Carnosic acid, xStAx-VHL, NRX-252114, Septuximab vedotin), PF-06647020, LGR5-mc-vc-PAB-MMAE, LGR5-NMS818, CWP232291, PRI-724 (also known as ICG-001), C-82, and BC2059. In some embodiments, references to the term β-catenin inhibitor include any such β-catenin inhibitor disclosed in any of the following patent applications: CN104388427 and CN 103830211, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0342] ii) PORCN inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more porcupine protein (PORCN) inhibitors. PORCN inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. PORCN is a membrane-bound O-acyltransferase that plays a key role in the WNT signaling pathway by mediating palmitoylation of WNT ligands. This palmitoylation is important for the secretion and signaling activity of WNT proteins. Inhibition of PORCN results in reduced WNT signaling activity. In some embodiments, the PORCN inhibitor is one or more of the following: LGK974 (WNT974), ETC-1922159, CGX1321, and CWP232291.

[0343] iii) GSK3 inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more glycogen synthase kinase (GSK3) inhibitors. GSK3 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. The GSK3 family consists of two closely related serine / threonine kinases: GSK3α and GSK3β. These kinases are involved in a variety of cellular processes, including glucose metabolism, cell cycle regulation, and Wnt signaling. GSK inhibitors have been investigated as potential therapeutic agents for a variety of diseases, including cancer, diabetes, Alzheimer's disease, and bipolar disorder. In some embodiments, the GSK3 inhibitor is one or more of the following: tideglusib, laduviglusib, LiCl (lithium chloride), CHIR99021, SB216763, AZD1080, and LY2090314. In some embodiments, references to the term GSK3 inhibitor include any such GSK3 inhibitor disclosed in any of the following patent applications: WO 2017153834, WO2014059383, WO 2010012398, WO 2009017455, WO 2003037891, CN 107151235, and CN102258783, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0344] iv) CLK inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more Cdc2-like kinase (CLK) inhibitors. CLK inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. CLK (Cdc2-like kinases) are a family of serine / threonine kinases that play a crucial role in the regulation of pre-mRNA splicing, specifically selective splicing. The CLK family has four members: CLK1, CLK2, CLK3, and CLK4. The CLK kinase family has been shown to be involved in several diseases, including cancer, neurodegenerative diseases, and viral infections. In some embodiments, the CLK inhibitor is a CLK2 inhibitor. In some embodiments, the CLK2 inhibitor is one or more of the following: Lorecivivint, SM08502, SM04690, TG003, KH-CB19, Cmpd-1, T3.5, and CX-4945. In some embodiments, references to the term CLK inhibitor include any such CLK inhibitor disclosed in WO 2020006115, which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0345] k) JAK / STAT pathway inhibitors The compositions and methods described herein may include combinations of the compounds of the present invention with one or more JAK / STAT pathway inhibitors. In some embodiments, the JAK / STAT pathway inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. The Janus kinase / signal transducer and activator of transcription (JAK / STAT) pathway is a signaling pathway involved in a variety of cellular processes, including immune responses, cell growth, and differentiation. Dysregulation of this pathway is associated with a variety of diseases, including inflammatory conditions, cancer, and autoimmune diseases. Inhibitors of the JAK / STAT pathway can be used to treat these diseases. In some embodiments, the JAK / STAT pathway inhibitor is an inhibitor of JAK1, JAK2, and / or JAK3. In some implementations, the JAK inhibitor is one or more of the following: ruxotinib (Jakafi®), paclinib, fetratinib, tofacitinib (Xeljanz®), abrutinib, filgotinib, olatinib, peficitinib, upadacitinib, deucravacitinib, delgocitinib, and baricitinib (Olumiant®).In some embodiments, references to the term JAK inhibitor include any such JAK inhibitor disclosed in any of the following patent applications: WO2023011301, WO 2023201044, WO 2022143629, WO 2022251434, WO 2022067106, WO2022033551, WO 2021244323, WO 2021238817, WO 2021238818, WO 2021178991, WO2021136345, WO 2021190647, WO 2020219639, WO 2020182159, WO 2020155931, WO2020038457, WO 2020219524, WO The patent applications 2020173400, WO 2018204233, WO 2018204238, WO2018169875, WO 2018117152, WO 2017215630, WO 2016070697, WO 2016027195, CN117815195, CN 117815367 and CN 115969796, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0346] In some embodiments, the JAK / STAT pathway inhibitor is a STAT inhibitor. In some embodiments, the STAT inhibitor is an inhibitor of STAT3 and / or STAT5. In some embodiments, the STAT inhibitor is a STAT3 degrader. In some embodiments, the STAT inhibitor is one or more of the following: TTI-101, C-188-9, WP1066, VVD-130850, LLL12B, STA-21, SD-36, Static, S3I-201, OPB-31121, and Napabucasin (BBI608). In some embodiments, references to the term STAT inhibitor include any such STAT inhibitor disclosed in any of the following patent applications: WO 2024030628, WO 2023164680, WO 2023192960, WO2023133336, WO2020206424, WO 2023107706, WO 2021150543, WO 2008151037, and CN109288845, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0347] l) Epigenetic regulators The compositions and methods described herein may include combinations of the compounds of the present invention with one or more epigenetic regulators. Epigenetic regulators are a class of therapeutic agents that target enzymes responsible for modifying the structure and function of chromatin, a complex of DNA and proteins that makes up chromosomes. These enzymes (including histone deacetylases (HDACs), histone methyltransferases (HMTs), and DNA methyltransferases (DNMTs)) play a crucial role in gene expression and regulation by modifying DNA packaging and influencing its reading and transcription. Epigenetic regulators exert their effects by altering the activity of these enzymes (by inhibiting or enhancing their function), thereby regulating gene expression in specific ways. By targeting specific epigenetic modifications, such as acetylation, methylation, and DNA methylation, these therapies have the potential to treat a wide range of diseases, including cancer, inflammatory conditions, and neurological disorders.

[0348] i) HDAC inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more histone deacetylase (HDAC) inhibitors. HDAC inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. Several classes of HDACs exist, including class I, IIa, IIb, III, and IV. Class I HDACs are further subdivided into HDAC1, HDAC2, HDAC3, and HDAC8, while class IIa HDACs include HDAC4, HDAC5, HDAC7, and HDAC9. Class IIb HDACs consist of HDAC6 and HDAC10, and class III HDACs are referred to as sirtuins. HDAC inhibitors can target different classes of HDACs, and their specific effects on gene expression may vary depending on the HDAC they target. In some implementations, the HDAC inhibitor is one or more of the following: vorinostat (Zolinza), romidepsin (Istodax), belistat (Beleodaq), panobinostat (Farydak), entinostat (MS-275), valproic acid (Depakene), trichostatin A (TSA), sodium butyrate, and mocetinostat (MGCD0103). Non-limiting examples of HDAC inhibitors include trichostatin, sodium butyrate, aspirin, succinyl aniline hydrochloride, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat. In some embodiments, references to the term HDAC inhibitor include any such HDAC inhibitor disclosed in any of the following patent applications: WO 2022110958, WO 2021252628, WO 2019204550, WO2018178060, WO 2016126724, WO 2014143666, WO 2013041480, and WO 2006120456, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0349] ii) BET inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more bromodomain and superterminal (BET) protein inhibitors. BET inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. BET (bromodomain and superterminal) proteins are a family of epigenetic reader proteins that recognize and bind to acetylated lysine residues on histones, thereby leading to chromatin remodeling and regulation of gene expression. There are four BET proteins in humans: BRD2, BRD3, BRD4, and BRDT. BET inhibitors specifically target the bromodomain of BET proteins, thereby inhibiting their binding to acetylated lysine residues on histones and leading to alterations in gene expression. BET inhibitors can be used to treat cancer and other diseases characterized by dysregulation of gene expression. In some embodiments, the BET inhibitor is one or more of the following: JQ1, I-BET762, OTX015, RVX-208, and CPI-0610. In some embodiments, references to the term BET inhibitor include any such BET inhibitor disclosed in any of the following patent applications: WO 2022046682, WO 2022182857, WO 2021107657, WO 2021107656, WO 2020221006, WO 2020053660, WO 2018097977, WO 2017222977, WO 2017142881, WO 2015075665, WO2015011084, and CN 113264930, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0350] iii) EZH2 inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more Zeste enhancer homologue 2 (EZH2) inhibitors. EZH2 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. EZH2 is a histone-lysine N-methyltransferase, a member of the polycomb repressive complex 2 (PRC2) family. EZH2 plays a crucial role in gene expression regulation, specifically by catalyzing the trimethylation of histone H3 at lysine 27 (H3K27me3), thereby leading to transcriptional repression of target genes. EZH2 has been found to be overexpressed in several types of cancer and is associated with tumor progression and poor prognosis. In some embodiments, the EZH2 inhibitor is one or more of the following: tazemetostat, GSK2816126, and CPI-1205 (lirametostat). In some embodiments, references to the term "EZH2 inhibitor" include any such EZH2 inhibitor disclosed in any of the following patent applications: WO 2023030299, WO 2022179584, WO2020224607, WO 2021243060, WO 2021086069, WO 2019206155, WO 2018133795, WO2018137639, WO 2017184999, WO 2017218953, WO 2016201328, WO 2015195848, WO2013155317, WO 2013138361, and CN. Patent application No. 114621191, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0351] iv) Co-REST inhibitors In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more Co-REST inhibitors. Co-REST inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. Co-REST is a transcriptional co-repressor protein that interacts with a variety of transcription factors to regulate gene expression. Co-REST works by recruiting histone deacetylases (HDACs) to chromatin, thereby inhibiting gene expression. Inhibition of Co-REST has been proposed as a potential therapeutic strategy for treating a variety of diseases, including neurodegenerative diseases and cancer. In some embodiments, the co-REST inhibitor is one or more of the following: nocodazole, NSC 1892, and astaxanthin.

[0352] v) EP300 In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more E1A-binding protein p300 (EP300) inhibitors. EP300 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. EP300 is a transcriptional coactivator involved in regulating a variety of cellular processes, including chromatin remodeling, DNA damage responses, and cell cycle progression. EP300 acts as a histone acetyltransferase, catalyzing the transfer of acetyl groups to lysine residues on histones, leading to changes in chromatin structure and gene expression. EP300 activity is associated with diseases such as cancer, cardiovascular diseases, and neurological disorders. In some embodiments, the EP300 inhibitor is one or more of the following: C646, A-485, NU9056, and L002. In some embodiments, references to the term EP300 inhibitor include any such EP300 inhibitor disclosed in any of the following patent applications: WO 2021213521 and WO 2016044694, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0353] vi) LSD1 In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more lysine-specific demethylase 1 (LSD1) inhibitors. LSD1 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. LSD1 is an enzyme that plays a crucial role in regulating gene expression via histone modification. It specifically removes a methyl group from lysine 4 on histone 3, thereby leading to gene repression. Dysregulation of LSD1 is associated with a variety of diseases, including cancer and neurodegenerative diseases. In some embodiments, the LSD1 inhibitor is one or more of the following: GSK2879552, IMG-7289, ORY-1001, IMG-8419, SP-2577, CC-90011, HCI-2509, and INCB059872. In some embodiments, references to the term "LSD1 inhibitor" include any such LSD1 inhibitor disclosed in any of the following patent applications: WO 2021095840, WO2021175079, WO 2021058024, WO 2020047198, WO 2020052649, WO 2020015745, WO2020052647, WO 2018137644, WO 2017184934, WO 2017027678, WO 2017116558, WO2017149463, WO 2016161282, WO 2015123465, WO 2015123424, WO 2013057322, WO2013057320, WO The patent applications 2012135113, CN 114805261, CN 111072610, CN 107174584, CN 110478352, CN 106432248 and CN 106045881 are each incorporated herein by reference in their entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0354] vii) PRMT5 In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more protein arginine methyltransferase 5 (PRMT5) inhibitors. PRMT5 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. PRMT5 is a member of the PRMT family that catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to a nitrogen atom of an arginine residue in a target protein. PRMT5 is involved in a variety of biological processes, including gene expression regulation, signal transduction, and DNA repair. In some embodiments, the PRMT5 inhibitor is one or more of the following: TNG908, TNG462, AMG193, GSK591, EPZ015666, TC-E 5003, and MS023. In some embodiments, references to the term PRMT5 inhibitor include any such PRMT5 inhibitor disclosed in any of the following patent applications: WO 2023001133, WO 2022206964, WO 2022153161, WO 2021068953, WO2021088992, WO 2020259478, WO 2020205660, WO 2020250123, WO 2020033288, WO2019102494, WO 2019112719, WO 2019180631, WO 2018065365, WO 2017153186, WO2017212385, WO 2017032840, WO Patent applications 2016022605, WO2014100695, WO 2014145214, WO2014100719, CN 111825656, CN 114558014, CN 11304554 and CN 112778275, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0355] viii) MAT2A In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more methionine adenosyltransferase 2A (MAT2A) inhibitors. MAT2A inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. MAT2A is an enzyme that catalyzes the production of S-adenosylmethionine (SAM), an important cofactor in various biological processes including DNA methylation, protein methylation, and polyamine synthesis. Elevated MAT2A expression is associated with various cancers. In some embodiments, the MAT2A inhibitor is one or more of the following: cyclic leucine and 2-hydroxy-4-methylthiobutyric acid. In some embodiments, references to the term MAT2A inhibitor include any such MAT2A inhibitor disclosed in any of the following patent applications: WO 2022256808, WO2022256806, WO 2019191470 and CN 115716831, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0356] ix) DOT1L In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more telomere silencing interferon 1 (DOT1L) inhibitors. DOT1L inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. DOT1L is a histone methyltransferase that catalyzes the methylation of lysine 79 on histone H3. This modification is associated with transcriptional elongation and is important for maintaining gene expression programs. The DOT1L family includes enzymes involved in epigenetic regulation and transcriptional control, and their dysregulation is associated with a variety of diseases, including cancer. In some embodiments, the DOT1L inhibitor is one or more of EPZ-5676 (pinometostat) and EPZ-004777. In some embodiments, references to the term DOT1L inhibitor include any such DOT1L inhibitor disclosed in any of the following patent applications: WO 2016090271, WO 2014100662, and CN108997480, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0357] iix) UBA1 In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more ubiquitin activator enzyme inhibitors (e.g., UBA1 inhibitors). UBA1 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. UBA1, also known as ubiquitin activator enzyme 1, is a key enzyme involved in ubiquitination, a fundamental cellular mechanism of protein degradation and regulation. Ubiquitination involves the covalently linking of ubiquitin molecules to target proteins, thereby labeling them for degradation by the proteasome or regulating their activity, localization, or interaction within the cell. Several inhibitors have been developed to modulate UBA1 activity with the aim of disrupting ubiquitination-mediated processes in diseased cells. These inhibitors include (but are not limited to) adenosine-based inhibitors, which typically compete with ATP for binding to the active site of UBA1, thereby preventing ubiquitin activation (e.g., PYR-41 and MLN7243); covalent inhibitors, which form irreversible bonds with specific amino acid residues at the active site of UBA1, thereby inhibiting its activity (e.g., TAK-243 (formerly known as MLN4924)); allotropic inhibitors, which bind to sites on UBA1 different from the active site, thereby inducing conformational changes that inhibit its catalytic activity (e.g., compound 2i); and fragment-based inhibitors, which are designed based on smaller molecular fragments that bind to UBA1. In some embodiments, the UBA1 inhibitor is one or more of the following: PYR-41, MLN7243, and TAK-243. In some embodiments, references to the term UBA1 inhibitor include any such UBA1 inhibitor disclosed in any of the following patent applications: WO2016069393 A1, WO 2016069392 A1 and JP 2013237627 A2, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0358] m) Additional therapeutic agents that can be used in combination therapy In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more farnesyltransferase inhibitors. Farnesyltransferase inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. Farnesyltransferase inhibitors (FTIs) are a class of drugs that target farnesyltransferases, which function in a process called protein isoprenylation. Protein isoprenylation is an important step in the activation of certain proteins involved in signal transduction, cell growth, and differentiation. In some embodiments, the farnesyltransferase inhibitor is one or more of the following: tipifarnib, lonafarnib, and rilapladib. In some embodiments, references to the term farnesyltransferase inhibitor include any such farnesyltransferase inhibitor disclosed in any of the following patent applications: WO2010057028, WO 2007042465, WO 200136395, WO 200064891, WO 200042849, WO 199938862, WO 199928315, WO 199829390, WO 199426723, CN 107312000, CN 107365310, KR100375421, KR 100388790, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0359] In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more casein kinase inhibitors. In some embodiments, the casein inhibitor is SR-3029, a potent and ATP-competitive inhibitor of CK1δ and CK1ε.

[0360] In some embodiments, the compositions and methods described herein may include combinations of one or more FLT3 inhibitors with the compounds of the invention disclosed herein. FLT3 (Fms-like tyrosine kinase 3), also known as CD135, is a receptor tyrosine kinase (RTK) that plays a crucial role in regulating hematopoiesis (the process of forming blood cells). It is primarily expressed on hematopoietic stem cells (HSCs) and progenitor cells in the bone marrow, where it controls cell proliferation, survival, and differentiation. In some embodiments, FLT3 inhibitors include (but are not limited to) midostaurin, gilteritinib, sorafenib, quizartinib, crenolanib, ponatinib, and quizartinib.

[0361] In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more TGFb pathway inhibitors. In some embodiments, the compositions and methods described herein may include one or more TGFb inhibitors. TGFb inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. TGFb (transforming growth factor beta) is a multifunctional cytokine involved in various cellular processes, including cell growth, differentiation, apoptosis, and immune responses. Dysregulation of the TGFb signaling pathway is associated with a variety of diseases, including cancer, fibrosis, and autoimmune disorders. In some embodiments, the TGFb inhibitor is one or more of the following: galunisertib (LY2157299) and vactosertib (TEW-7197). In some implementations, the TGFb inhibitor is one or more of the following: galucert, LY2157299, fresolimumab, lerdelimumab, Trabersen, curcumin, resveratrol, and small interfering RNA (siRNA) to silence TGFb receptor expression. In some embodiments, references to the term TGFb inhibitor include any such TGFb inhibitor disclosed in any of the following patent applications: WO2023043473, WO 2020104648, WO 2020128850, WO 2016140884, WO 2007018818, WO2004024159, WO 200226935, WO 2002062753, WO 2002062776 and JP 2012087076, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0362] In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more HSP90 inhibitors. HSP90 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. HSP90, also known as heat shock protein 90, is a molecular chaperone protein that plays a crucial role in regulating the folding, stability, and activity of a large number of client proteins involved in various cellular processes, including cell cycle progression, signal transduction, and apoptosis. In some embodiments, the HSP90 inhibitor is one or more of the following: gerdanamycin and its derivatives (e.g., 17-AAG, 17-DMAG), KOS 953, radicicol and its derivatives (e.g., PU-H71), SNX-2112, Ganettespib, AT13387, Onalespib, Luminespib, and KW-2478. In some embodiments, references to the term HSP90 inhibitor include any such HSP90 inhibitor disclosed in any of the following patent applications: WO 2021137665, WO 2018200534, WO 2017151425, WO 2015200514, WO 2013053833, WO 2013009657, WO2013119985, WO 2012138894, WO 2011044394, WO 2009097578, WO 2008115719, CN105237533, and CN 104030904, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0363] In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more glutathione peroxidase 4 (GPX4) inhibitors. GPX4 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. GPX4 is an antioxidant enzyme that plays a crucial role in protecting cells from oxidative stress-induced cell death. GPX4 catalyzes the reduction of lipid hydroperoxides to their corresponding alcohols and acts as a regulator of ferroptosis (a regulated form of cell death driven by lipid peroxidation). In some embodiments, the GPX4 inhibitor is one or more of the following: RSL3, ML162, DPI7, FINO2, MCB-613, CBS9106, ML210, ODSH, and TLN232. In some embodiments, references to the term GPX4 inhibitor include any such GPX4 inhibitor disclosed in any of the following patent applications: WO 2021132592, US 2021244715, and KR20220115536, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0364] In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more NRF2 inhibitors. NRF2 inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. NRF2 is a transcription factor that regulates the expression of genes involved in cellular antioxidant responses, detoxification, and other cellular protective pathways. It plays a key role in cellular defense mechanisms against oxidative stress and other forms of cellular damage. In some embodiments, the NRF2 inhibitor is one or more of the following: ML385, crotonol, CDDO-Im, RTA-408, and trigonelline. In some embodiments, reference to the term NRF2 inhibitor includes any such NRF2 inhibitor disclosed in any of the following patent applications: WO 2023051088, WO 2021202720, KR2022013610, and CN 107519168, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0365] In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more TEA domain (TEAD) inhibitors. TEAD inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. TEADs are a family of transcription factors that play a crucial role in regulating gene expression and tissue homeostasis during embryonic development. The four members of the TEAD family (TEAD1-4) are transcriptional coactivators that bind to DNA via their conserved TEA domains and interact with other transcription factors to activate the expression of target genes. In some implementations, the TEAD inhibitor is one or more of the following: VT-107, pan-TEAD, VT-104, verteporfin, CA3, IAG933, K-975, IK-595, and statins (e.g., see Chapeau, Emilie, and Schmelzle, Tobias (2023) IAG933, an oral selective YAP1-TAZ / pan-TEAD protein-protein interaction inhibitor (PPIi) with pre-clinical activity in monotherapy and combinations with MAPK inhibitors. Nature cancer). In some embodiments, references to the term TEAD inhibitor include any such TEAD inhibitor disclosed in any of the following patent applications: WO 2023280254, WO 2023031781, WO 2022258040, WO 2020070181, WO 2018185266, and WO 2017064277, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0366] In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more NOTCH / γ secretase inhibitors. The NOTCH / γ secretase inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. In some embodiments, the NOTCH / γ secretase inhibitor is nirogacestat. In some embodiments, references to the term NOTCH / γ secretase inhibitor include any such NOTCH / γ secretase inhibitor disclosed in any of the following patent applications: WO2020208572, WO 2017200969, WO 2014047390, WO 2014047372, WO 2011041336, WO2010090954, WO 2009008980, WO 2009087130, WO 2007110335, CN 103664904, CN105560244, and KR 20200077480, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0367] In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more Hedgehog inhibitors. Hedgehog inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. The hedgehog (Hh) protein family are secreted signaling molecules that play a crucial role in adult embryonic development and tissue homeostasis. The Hh signaling pathway is involved in regulating cell growth, differentiation, and survival. In some embodiments, hedgehog inhibitors are one or more of the following: Vismodegib (Erivedge), Sonidegib (Odomzo), and Glasdegib (Daurismo). In some embodiments, reference to the term hedgehog inhibitor includes any such hedgehog inhibitor disclosed in any of the following patent applications: WO 2011063309 and CN 107163028, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0368] The compositions and methods described herein may include combinations of the compounds of the present invention with one or more NF-κB pathway inhibitors. NF-κB inhibitors may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. NF-κB (NFκB) is a family of transcription factors involved in the regulation of various cellular processes, including inflammation, immunity, cell survival, and proliferation. Non-limiting examples of NF-κB inhibitors include bortezomib (Velcade), curcumin, parthenolide, IKK inhibitors (e.g., IKK-16, BAY 11-7082), resveratrol, andrographolide, and proteasome inhibitors (e.g., MG132, lactocinol).

[0369] In some embodiments, the additional therapy is the administration of a side effect mitigator (e.g., an agent designed to reduce the occurrence or severity of treatment side effects). For example, in some embodiments, the compounds of the present invention may also be used in combination with a therapeutic agent for treating nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0370] In some embodiments, the one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies include therapeutic agents (e.g., compounds or biologics that are anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, the one or more additional therapies include both non-pharmacological treatments (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biologics that are anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors).

[0371] Examples of non-pharmacological treatments include (but are not limited to) radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical removal of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0372] In some embodiments, the compounds of the present invention can be used as postoperative adjuvant therapy. In some embodiments, the compounds of the present invention can be used as preoperative neoadjuvant therapy.

[0373] Radiation therapy can be used to inhibit abnormal cell growth or treat hyperproliferative conditions, such as cancer, in subjects (e.g., mammals, such as humans). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered via one or a combination of several methods, including (but not limited to) external beam therapy, internal radiation therapy, implanted radiation, stereotactic radiosurgery, whole-body radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by radioactive material inserted into or near a site of tumor or other proliferative tissue disease in the body. The term is intended to (but is not limited to) include exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu). Suitable radioactive sources used as cytomodulation agents of this disclosure include both solid and liquid forms. As a non-limiting example, the radioactive source may be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material may also be a fluid prepared from a solution of any radionuclide (e.g., a solution of I-125 or I-131), or the radioactive fluid may be generated from a slurry of a suitable fluid containing small solid radionuclide particles, such as Au-198 or Y-90. Furthermore, the radionuclide may be embedded in a gel or radioactive microspheres.

[0374] In some embodiments, the compounds of the present invention can make abnormal cells more sensitive to radiotherapy, thereby killing or inhibiting the growth of such cells. Therefore, this disclosure further relates to a method for sensitizing abnormal cells in a mammal to radiotherapy, the method comprising administering to the mammal a quantity of a compound of the present disclosure, said quantity being effective in sensitizing the abnormal cells to radiotherapy. The amount of the compound in this method may be determined according to the manner used to determine the effective amount of such compounds set forth herein. In some embodiments, the compounds of the present invention can be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0375] In some embodiments, the non-pharmacological treatment is adoptive T-cell transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells may be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. The source of the T cells is obtained from a subject before the T cells are expanded and genetically modified. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments of this disclosure, a variety of T cell lines available in the art may be used. In some embodiments, the T cells are autologous T cells. Before or after genetically modifying T cells to express a desired protein (e.g., CAR), the T cells can typically be activated and expanded using methods described, for example, in the following U.S. patents: 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041.

[0376] In some embodiments, the compositions and methods described herein may include combinations of the compounds of the present invention with one or more Claudin-18 targets. Claudin-18 targets may be administered or formulated in combination with the compounds of the present invention and / or any additional therapeutic agents described herein. Claudin-18 (e.g., claudin 18.2; CLDN18.2) has emerged as a promising target for the treatment of patients with gastrointestinal malignancies such as gastric cancer (GC), gastroesophageal junction (GEJ) cancer, esophageal cancer, and pancreatic cancer due to its limited expression in healthy tissues and aberrant overexpression in a range of malignancies. Numerous clinical trials of CLDN18.2-targeted therapies (including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies) are underway, some showing promising early results. Malignant transformation of gastric epithelial tissue leads to disruption of cell polarity and subsequently exposure of the CLDN18.2 epitope on the cell surface. Although targeting monoclonal antibodies are largely unable to access CLDN18.2 in the tight-linked supramolecular complex located in normal tissues, cell polarity perturbation that exposes the CLDN18.2 epitope could theoretically allow CLDN18.2 targets to bind to CLDN18.2 in malignant tissues with minimal off-target effects, making CLDN18.2 an attractive therapeutic target. In some embodiments, Claudin-18 targets are one or more of the following: zobetuximab, ASKB589, oxemitamab (TST001), PT886 (a bispecific antibody targeting CLDN18.2 and CD47), TJ-CD4B, CMG901 (an ADC consisting of an anti-CLDN18.2 monoclonal antibody conjugated to the cytotoxic payload monomethyl auristatin E), and CT041 (genetically engineered autologous T cells expressing a CLDN18.2-targeting CAR).In some embodiments, references to the term "Claudin-18 target" include any such Claudin-18 target disclosed in any of the following patent applications: WO2024081544, WO 2024131683, WO 2024137619, WO 2024140670, WO 2024136594, WO2023034922, WO 2023046202, WO 2022203090, WO 2022133169, WO 2022100613, WO2022256449, WO 2022136642, WO 2021155380, WO 2021129765, WO 2021011885, WO2021058000, WO The patent applications 2021218874, WO 2021027850, WO 2020156554, WO 2020025792, WO2020114480, WO 2020211792, WO 2020239005, WO 2019219089, WO 2018157147, WO2018108106, WO 2016166122, WO 2014146778, CN 118290582, CN 118203658 and CN118286201, each of which is incorporated herein by reference in its entirety, including the compound structures disclosed therein, which are expressly incorporated herein by reference.

[0377] In some embodiments, the therapeutic agent used in combination therapy may be a steroid. Therefore, in some embodiments, the one or more additional therapies include steroids. Suitable steroids may include (but are not limited to) acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, and cortisone. Cortivazol, Deflazacort, Desonide, Desoximetasone, Dexamethasone, Diflorasone, Diflucortolone, Difluuprednate, Enoxolone, Fluazacort, Fiucloronide, Flumethasone, Flunisolide, Fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednoletabonate), mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 2,5-diethylaminoacetic acid prednisolone, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0378] Other examples of therapeutic agents that can be used in combination therapies with the compounds of the present invention include compounds set forth in the following patents: U.S. Patents 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and International Patents. Patent applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089 and WO00 / 02871.

[0379] Additional therapeutic agents may be biologics (e.g., cytokines such as interferon or interleukins like IL-2) used to treat cancer or related symptoms. In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that activates a target to stimulate an anticancer response or antagonizes antigens important to cancer. Antibody-drug conjugates are also included.

[0380] The additional therapeutic agent may be an immunomodulator. For example, the additional therapeutic agent may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent that inte...

Claims

1. A compound having the structure of formula I': Formula I' in: A is a optionally substituted 3- to 6-membered cycloalkylene group, an optionally substituted 3- to 10-membered heteroalkylene group, or an optionally substituted C. 6-10 arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C2-C6 alkylene or optionally substituted C2-C6 alkenyl or -L 1 -L 2 -, where L 1 It is a 3- to 6-membered cyclohexane or C 1-6 Alkylene and L 2 -O- or C 1-6 Alkylene; L represents a bond or -CH(R) 20 )-N(R 21 )-C(O)-, where R 20 and R 21 Each independently represents the C that can be arbitrarily replaced. 1-6 Alkyl; or R 20 and R 21 Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic alkyl groups; W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 The substituted C1-C6 alkyl, substituted C2-6 alkenyl, substituted C2-6 ynyl, substituted C1-C6 heteroalkyl, substituted 3- to 10-membered cycloalkyl, substituted 3- to 6-membered cycloalkenyl, substituted 3- to 15-membered heterocycloalkyl, substituted 6- to 10-membered aryl or substituted 5- to 10-membered heteroaryl. R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl; R 3 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C6 cycloalkyl or optionally substituted 4- to 6-membered heterocycloalkyl; or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 R 7 R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl group; or R 5 With R 7 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; or R 4 With R 6 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 5 R 5a R 6a R 7 and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; or R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; or R 5 and R 5a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; or R 6 and R 6a Together with the atoms to which they are attached, they form optionally substituted cycloalkyl or optionally substituted heteroalkyl groups; or R 7 and R 7a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; or R 5 With R 6 Together they form bonds; R 10 For H, -OR 11 or -NR 12 R 13 ; R 11 R 12 and R 13 Each of the following is independently a optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 4- to 14-membered heterocyclic alkyl group, or an optionally substituted C3-C... 10 cycloalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; and When R 10 When H is present, ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl, and R 2 Hydrogen, substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Or its pharmaceutically acceptable salt.

2. The compound of claim 1, having the structure of formula I': Formula I' in: A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. L represents a bond or -CH(R) 20 )-N(R 21 )-C(O)-, where R 20 and R 21 Each independently represents the C that can be arbitrarily replaced. 1-6 Alkyl; or R 20 and R 21 Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic alkyl groups; W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl group; or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; or R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; or R 5 and R 5a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; or R 6 and R 6a Together with the atoms to which they are attached, they form optionally substituted cycloalkyl or optionally substituted heteroalkyl groups; or R 7 and R 7a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; or R 5 With R 6 Together they form bonds; R 10 For H, -OR 11 or -NR 12 R 13 ; R 11 R 12 and R 13 Each of the following is independently a optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 4- to 14-membered heterocyclic alkyl group, or an optionally substituted C3-C... 10 cycloalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; and When R 10 When H is present, ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl, and R 2 Hydrogen, substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Or its pharmaceutically acceptable salt.

3. The compound of claim 1 or 2, wherein the portion of formula I' is... Selected from: , , , , , , , , , , , , , , , , , and ;in: R 5a H, halogen or C 1-6 alkyl; R 6a H, halogen or C 1-6 alkyl; Each R 23 Independently halogen or C 1-6 Alkyl; and Each p is an independent integer of 0, 1, or 2.

4. The compound according to claim 1 or 2, having a structure of formula I'-a: Formula I'-a in: A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. L represents a bond or -CH(R) 20 )-N(R 21 )-C(O)-, where R 20 and R 21 Each independently represents the C that can be arbitrarily replaced. 1-6 Alkyl; or R 20 and R 21 Together with the atoms they are attached to, they form 4- to 10-membered heterocyclic alkyl groups; W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl group; R 10 For H, -OR 11 or -NR 12 R 13 ; R 11 R 12 and R 13 Each of the following is independently a optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 4- to 14-membered heterocyclic alkyl group, or an optionally substituted C3-C... 10 cycloalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; and When R 10 When H is present, ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl, and R 2 Hydrogen, substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Or its pharmaceutically acceptable salt.

5. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, having the structure of formula I: Formula I in: A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 10 For H, -OR 11 or -NR 12 R 13 ; R 11 R 12 and R 13 Each of the following is independently a optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 4- to 14-membered heterocyclic alkyl group, or an optionally substituted C3-C... 10 cycloalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; and When R 10 When H is present, ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl, and R 2 Hydrogen, substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; Or its pharmaceutically acceptable salt.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: Ring A is optionally substituted with 2,4-oxazol-diyl or optionally substituted with 2,5-oxazol-diyl; R 2 Hydrogen, substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 10 For H.

7. The compound according to any one of claims 1 to 2 and 4 to 6, having a structure of formula I'-b: Formula I'-b Or its pharmaceutically acceptable salt. Where R 22 H, CN, OH, or optionally substituted C 1-6 Alkyl groups, optionally substituted C 1-6 Alkoxy groups, optionally substituted C groups 3-6 Cycloalkyl or optionally substituted 4- to 6-membered heterocycloalkyl; and R 2 The substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 2 Optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5- or 6-membered heteroaryl.

9. The compound according to any one of claims 1 to 2 and 4 to 8, having the structure of formula I: Formula I Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, a substituted 5- to 6-membered heteroarylene, a substituted C2-C4 alkylene, or a substituted C2-C4 alkenylene. W is a substituted 3- to 10-membered heterocyclic alkyl group or a substituted 3- to 10-membered cycloalkyl group; X 4 It is CH2 or NH; R 1 The substituted C1-C6 alkyl, the substituted C1-C6 heteroalkyl, the substituted 3- to 6-membered cycloalkyl, the substituted 3- to 6-membered cycloalkenyl, the substituted 3- to 15-membered heterocycloalkyl, the substituted 6- to 10-membered aryl or the substituted 5- to 10-membered heteroaryl. R 2 The substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; and R 3 It is hydrogen; or R 2 and R 3 Together with the atoms to which they are attached, they form optionally substituted 8- to 14-membered heterocyclic alkyl groups; R 4 R 5 R 6 and R 7 Each of them is hydrogen; or R 4 and R 6 It is hydrogen and R 5 and R 7 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; or R 5 and R 7 It is hydrogen and R 4 and R 6 Together with the atoms to which they are attached, they form optionally substituted 4-membered cycloalkyl groups; R 10 For -OR 11 or -NR 12 R 13 ;and R 11 R 12 and R 13 Each is independently a optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, or R 12 With R 13 Combining to form optionally substituted 3- to 10-membered heterocyclic alkyl groups; Or its pharmaceutically acceptable salt.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X 4 It is NH.

11. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein X 4 It is CH2.

12. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the structure of formula Ia: Formula Ia.

13. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure of formula Ib: Formula Ib.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 R 6 and R 7 Each of them is hydrogen.

15. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the structure of formula Ic: Formula Ic.

16. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the structure of formula Id: FormulaId.

17. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the structure of formula Ie: Formula Ie.

18. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 5- or 6-membered heteroaryl group.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein A is an oxazole-dimethyl or a thiazole-dimethyl.

20. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure of formula Ic-1: Formula Ic-1.

21. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure of formula Id-1: Formula Id-1.

22. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the structure of formula Ie-1: Formula Ie-1.

23. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the structure of formula Ic-2: Formula Ic-2.

24. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure of formula Id-2: Formula Id-2.

25. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure of formula Ie-2: Formula Ie-2.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen.

27. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R 2 With R 3 Combining them to form optional substituted 8- to 14-membered heterocyclic alkyl groups.

28. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a C1-C6 heteroalkyl group that is optionally substituted or a 3- to 7-membered heterocyclic alkyl group that is optionally substituted.

29. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R 2 These are optional C1-C6 heteroalkyl groups.

30. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a 3- to 7-membered heterocyclic alkyl group that is optionally substituted.

31. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the structure of formula Ic-3: Formula Ic-3 Each R 14 Independently, it is a C1-C3 alkyl group; and n can be 0, 1, 2, or 3.

32. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure of formula Id-3: Formula Id-3 Each R 14 Independently, it is a C1-C3 alkyl group; and n can be 0, 1, 2, or 3.

33. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure of formula Ie-3: Formula Ie-3 Each R 14 Independently, it is a C1-C3 alkyl group; and n can be 0, 1, 2, or 3.

34. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure of formula Ic-4: Formula Ic-4 Each R 14 Independently, it is a C1-C3 alkyl group; and n can be 0, 1, 2, or 3.

35. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure of formula Id-4: Formula Id-4 Each R 14 Independently, it is a C1-C3 alkyl group; and n can be 0, 1, 2, or 3.

36. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure of formula Ie-4: Formula Ie-4 Each R 14 Independently, it is a C1-C3 alkyl group; and n can be 0, 1, 2, or 3.

37. The compound of any one of claims 31 to 36, or a pharmaceutically acceptable salt thereof, wherein each R 14 It is a methyl group.

38. The compound of any one of claims 31 to 37 or a pharmaceutically acceptable salt thereof, wherein n is 1.

39. The compound of any one of claims 31 to 37 or a pharmaceutically acceptable salt thereof, wherein n is 2.

40. The compound of any one of claims 31 to 36 or a pharmaceutically acceptable salt thereof, wherein n is 0.

41. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the structure of formula Ic-5: Formula Ic-5 Where R 15 It is a C1-C3 alkyl or a C3-C6 cycloalkyl.

42. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the structure of formula Id-5: Formula Id-5 Where R 15 It is a C1-C3 alkyl or a C3-C6 cycloalkyl.

43. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the structure of formula Ie-5: Formula Ie-5 Where R 15 It is a C1-C3 alkyl or a C3-C6 cycloalkyl.

44. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure of formula Ic-6: Formula Ic-6 Where R 15 It is a C1-C3 alkyl or a C3-C6 cycloalkyl.

45. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the structure of formula Id-6: Formula Id-6 Where R 15 It is a C1-C3 alkyl or a C3-C6 cycloalkyl.

46. ​​The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having a structure of formula Ie-6: Formula Ie-6 Where R 15 It is a C1-C3 alkyl or a C3-C6 cycloalkyl.

47. The compound of any one of claims 41 to 46, or a pharmaceutically acceptable salt thereof, wherein R 15 It is a C3-C6 cycloalkyl group.

48. The compound of claim 47, wherein R 15 It is cyclopropyl.

49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein R 1 It is hydrogen.

50. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein R 1 for Where X 3 For N or CH; m is 1 or 2; R 15 R 16 R 17 and R 18 Each is independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R 16 and R 17 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 17 and R 18 The atoms to which it is attached combine to form optionally substituted 3- to 8-membered heterocyclic alkyl groups; or R 17 and R 15 The atoms to which they are attached combine to form optionally substituted 4- to 8-membered heterocyclic alkyl groups.

51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 1 for 。 52. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 1 for 。 53. The compound of any one of claims 50 to 52, or a pharmaceutically acceptable salt thereof, wherein R 16 It is a methyl group.

54. The compound of any one of claims 50 to 52, or a pharmaceutically acceptable salt thereof, wherein R 16 It is cyclopropyl.

55. The compound of any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof, wherein W is optionally a substituted 3- to 10-membered heterocyclic alkyl group.

56. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 4- to 6-membered heterocyclic alkyl group.

57. The compound of claim 55 or 56 or a pharmaceutically acceptable salt thereof, wherein the heterocyclic alkyl group comprises an oxygen atom.

58. The compound of claim 55 or 56 or a pharmaceutically acceptable salt thereof, wherein the heterocyclic alkyl group comprises a nitrogen atom.

59. The compound of any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3- to 10-membered heterocyclic alkyl group.

60. The compound of claim 59 or a pharmaceutically acceptable salt thereof, wherein W is a optionally substituted 3- to 6-membered heterocyclic alkyl group.

61. The compound of claim 60 or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted cyclopropyl group.

62. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R 10 For -OR 11 .

63. The compound of claim 62 or a pharmaceutically acceptable salt thereof, wherein R 11 The C1-C6 alkyl group is optionally substituted.

64. The compound of claim 62 or a pharmaceutically acceptable salt thereof, wherein R 11 These are optional C1-C6 heteroalkyl groups.

65. The compound of claim 62 or a pharmaceutically acceptable salt thereof, wherein R 10 It is -OCH2CH3.

66. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R 10 For -NR 12 R 13 .

67. The compound of claim 66 or a pharmaceutically acceptable salt thereof, wherein R 12 With R 13 Combining them to form optionally substituted 3- to 10-membered heterocyclic alkyl groups.

68. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein R 12 With R 13 Combining them forms optionally substituted pyrrolidines.

69. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein R 12 With R 13 Combining them forms optional substituted nitrogen-containing heterocyclic butanes.

70. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R 10 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , -OCH3, -N(CH3)2, -OCH2CH(CH3)2 or -OCH2SO2CH3, each of which may be optionally substituted.

71. A compound listed in Table 1 or a pharmaceutically acceptable salt thereof.

72. A compound listed in Table 2 or a pharmaceutically acceptable salt thereof.

73. A pharmaceutical composition comprising the compound of any one of claims 1 to 72 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

74. A method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of any one of claims 1 to 72, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 73.

75. The method of claim 74, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer, or uterine cancer.

76. The method of claim 75, wherein the cancer comprises a Ras mutation.

77. The method of claim 76, wherein the Ras mutation is K-Ras G12V.

78. A method of treating a subject with Ras protein-related disease, the method comprising administering to the subject a therapeutically effective amount of any one of claims 1 to 72 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 73.

79. The method of any one of claims 74 to 78, wherein the method further comprises administering an additional anticancer agent or therapy to the subject.

80. The method of claim 79, wherein the additional anticancer agent or therapy is an EGFR inhibitor, a second Ras inhibitor, an SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

81. A compound of formula V: (V) in: R 4 R 5 R 6 R 7 R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl group; or R 5 With R 7 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; or R 4 With R 6 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 5 R 5a R 6a R 7 and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; or R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; or R 5 and R 5a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; or R 6 and R 6a Together with the atoms to which they are attached, they form optionally substituted cycloalkyl or optionally substituted heteroalkyl groups; or R 7 and R 7a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 3- to 7-membered heterocycloalkyl groups; or R 5 With R 6 Together they form bonds; X 4 It can be NH or CH2; Z 1 For O or S; PG is an amino protecting group; R 24 For H or C 1-6 alkyl; R 25 It is a halogen; and R 12 and R 13 Each is independently a optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, or R 12 and R 13 Together with the nitrogen atom to which it is attached, it forms optionally substituted 3- to 11-membered heterocyclic alkyl groups.

82. The compound of claim 81, wherein X 4 It is NH.

83. The compound of claim 81 or 82, wherein R 24 C 1-6 alkyl.

84. The compound according to any one of claims 81 to 83, wherein PG is Boc or Cbz.

85. The compound according to any one of claims 81 to 84, wherein R 25 It can be Br or I.

86. The compound according to any one of claims 81 to 85, wherein R 12 and R 13 Together with the nitrogen atom to which it is attached, it forms an optionally substituted 7- to 11-membered spirochetal alkyl group.

87. The compound according to any one of claims 81 to 86, wherein R 5 With R 7 Together they form methylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl.

88. The compound according to any one of claims 81 to 87, wherein the portion of formula (V) for , or R 5 With R 7 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 4 R 5 R 5a R 6 R 6a R 7 and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl.

89. The compound according to any one of claims 81 to 88, wherein Z 1 It is O.

90. The compound according to any one of claims 81 to 88, wherein Z 1 Let it be S.

91. A compound of formula (VI): (WE) in: Z 1 For O or S; PG is an amino protecting group; R 24 For H or C 1-6 Alkyl; and R 25 It is a halogen.

92. The compound of claim 91, wherein Z 1 It is O.

93. The compound of claim 91, wherein Z 1 Let it be S.

94. The compound according to any one of claims 91 to 93, wherein PG is Boc or Cbz.

95. The compound according to any one of claims 91 to 94, wherein R 24 C 1-6 alkyl.

96. The compound according to any one of claims 91 to 95, wherein R 25 It can be Br or I.

97. The compound of claim 91, wherein Z 1 For O, R 25 For I, PG is Boc and R 14 For Et.

98. A compound of formula VII: (VII) in: R 1 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 ynyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl, -B(OH)2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl; R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl; R 26 It is a halogen, toluenesulfonyloxy group, CH3SO3-, CF3SO3-, or -B(OH)2; and R 27 -CH2-OH, -CH2O-PG 1 -COOH or -COOR 28 ; R 28 C 1-6 Alkyl or NR 29 R 29 ; R 29 For H or independently for C 1-6 Alkyl; and PG 1 It is a hydroxyl protecting group.

99. The compound of claim 98, wherein R 1 It is H, 4-methylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, -B(OH)2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl.

100. The compound of claim 98 or 99, wherein R 2 For H, C 1-6 Alkyl, 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl or 3-cyanocyclobutyl.

101. The compound according to any one of claims 98 to 100, wherein R 26 It can be Br or I.

102. The compound according to any one of claims 98 to 101, wherein PG 1 For TBDPS.

103. The compound according to any one of claims 98 to 102, wherein R 27 It is -CH2OH.

104. The compound of claim 98, wherein the compound is selected from: , , , and .

105. A compound of formula (VIII): (VIII) in: Z 1 For O or S; PG is protected by H or an amino group; R 30 and R 31 Each is H; or R 30 and R 31 Together with the nitrogen atom to which it is attached, it forms optionally substituted 7- to 11-membered spirochetal alkyl groups; R 24 For H or C 1-6 Alkyl; and R 25 It can be Br or I.

106. The compound of claim 105, wherein R 24 For H.

107. The compound of claim 105 or 106, wherein PG is Boc.

108. The compound according to any one of claims 105 to 107, wherein R 30 and R 31 Each is represented by H.

109. The compound according to any one of claims 105 to 107, wherein R 30 and R 31 Together with the nitrogen atom to which it is attached, it forms an optionally substituted 7- to 11-membered spirochetal alkyl group.

110. The compound according to any one of claims 105 to 109, wherein Z 1 It is O.

111. The compound according to any one of claims 105 to 109, wherein Z 1 Let it be S.

112. The compound of claim 105, wherein the compound is: or .

113. A compound of formula (IX): (IX) in: Z 1 For O or S; PG is an amino protecting group; PG 2 It is a hydroxyl protecting group; and R 25 It can be Br or I.

114. The compound of claim 113, wherein PG is Boc.

115. The compound of claim 113 or 114, wherein PG 2 It is -C(O)CH3.

116. The compound according to any one of claims 113 to 115, wherein Z 1 It is O.

117. The compound according to any one of claims 113 to 115, wherein Z 1 Let it be S.

118. The compound according to any one of claims 113 to 117, wherein R 25 It is Br.

119. A compound of formula (X): (X) in: PG is protected by H or an amino group; Z 1 For O or S; R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl; R 32 It is a halogen, -B(OH)2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane-2-yl; R 4 R 5 R 6 R 7 R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl group; Or R 5 With R 7 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; Or R 4 With R 6 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 5 R 5a R 6a R 7 and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; Or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 5 and R 5a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 6 and R 6a Together with the atoms to which they are attached, they form optionally substituted cycloalkyl or optionally substituted heteroalkyl groups; Or R 7 and R 7a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 5 With R 6 They form bonds together.

120. The compound of claim 119, wherein PG is Boc.

121. The compound of claim 119 or 120, wherein R 2 H or C that is optionally substituted 1-6 alkyl.

122. The compound according to any one of claims 119 to 121, wherein R 32 It is 4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl, Br, or I.

123. The compound according to any one of claims 119 to 122, wherein Z 1 It is O.

124. The compound according to any one of claims 119 to 122, wherein Z 1 Let it be S.

125. The compound according to any one of claims 119 to 124, wherein R 4 R 5 R 6 R 7 R 5a R 6a and R 7a Each is hydrogen.

126. The compound according to any one of claims 119 to 124, wherein R 5 With R 7 Together they form methylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is hydrogen.

127. A compound of formula (XI): (XI) in: PG is protected by H or an amino group; Z 1 For O or S; R 1 The substituted C1-C6 alkyl, substituted C2-6 alkenyl, substituted C2-6 ynyl, substituted C1-C6 heteroalkyl, substituted 3- to 10-membered cycloalkyl, substituted 3- to 6-membered cycloalkenyl, substituted 3- to 15-membered heterocycloalkyl, substituted 6- to 10-membered aryl or substituted 5- to 10-membered heteroaryl. R 2 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted 4- to 10-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl; R 4 R 5 R 6 R 7 R 5a R 6a and R 7a Each is independently hydrogen, halogroup, or C1-C6 alkyl group; Or R 5 With R 7 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; Or R 4 With R 6 Together they form methylene or ethylene bridges between the carbon atoms they are connected to, and R 5 R 5a R 6a R 7 and R 7a Each is independently hydrogen, halogen, or C 1-6 alkyl; Or R 5 and R 6 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 5 and R 5a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 6 and R 6a Together with the atoms to which they are attached, they form optionally substituted cycloalkyl or optionally substituted heteroalkyl groups; Or R 7 and R 7a Together with the atoms to which they are attached, they form optionally substituted 3- to 7-membered cycloalkyl groups or optionally substituted 4- to 7-membered heterocycloalkyl groups; Or R 5 With R 6 They form bonds together.

128. The compound of claim 127, wherein PG is H or Boc.

129. The compound of claim 127 or 128, wherein R 1 H or optionally substituted heterocyclic alkyl.

130. The compound according to any one of claims 127 to 129, wherein R 2 H or C that is optionally substituted 1-6 alkyl.

131. The compound according to any one of claims 127 to 130, wherein Z 1 It is O.

132. The compound according to any one of claims 127 to 130, wherein Z 1 Let it be S.

133. The compound according to any one of claims 127 to 132, wherein R 4 R 5 R 6 R 7 R 5a R 6a and R 7a Each is hydrogen.

134. The compound according to any one of claims 128 to 132, wherein R 5 With R 7 Together they form methylene bridges between the carbon atoms they are connected to, and R 4 R 5a R 6 R 6a and R 7a Each is hydrogen.

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