RAS inhibitors

Abstract

The present invention relates to RAS inhibitors. The present disclosure features macrocyclic compounds capable of inhibiting the Ras protein, as well as pharmaceutical compositions and protein complexes thereof, as well as their use in the treatment of cancer.

Description

[0001] This application is a divisional application of the invention patent application filed on November 4, 2020, with application number 202080091075.9 and invention title "RAS Inhibitor".

[0002] Cross-reference of related applications This application claims priority to U.S. Application No. 62 / 930,406, filed November 4, 2019; U.S. Application No. 62 / 951,562, filed December 20, 2019; U.S. Application No. 63 / 000,355, filed March 26, 2020; and U.S. Application No. 63 / 043,523, filed June 24, 2020, all of which are hereby incorporated in their entirety. Background Technology

[0003] Most small molecule drugs work 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, thus preventing the enzyme from binding to its substrate. Indeed, the existence of many such drug / target interaction pairs may mislead one into believing that small molecule regulators targeting most (if not all) proteins can be discovered, thus justifying the amount of time, effort, and resources required. But this is far from the truth. Currently, it is estimated that only about 10% of all human proteins are suitable targets for small molecules. (Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019)). The remaining 90% are currently considered difficult to treat or manage with the aforementioned small molecule drugs. These targets are often referred to as “undruggable.” These undruggable targets comprise a large and often unexplored reservoir of medically important human proteins. Therefore, there is great interest in discovering novel molecular modalities capable of modulating the function of such undruggable targets.

[0004] The literature has well established that Ras proteins (K-Ras, H-Ras, and N-Ras) play a crucial role in various human cancers, thus making them 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 caused by 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-activating protein (GAP) dependence and intrinsic GTP hydrolysis rate, leading to oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, allowing it to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13D) and 61 (e.g., Q61K) in Ras also induce oncogenic activity in some cancers.

[0005] Despite extensive drug discovery efforts targeting Ras over the past decades, no drugs directly targeting Ras have been approved. Further efforts are needed to discover other medicines for cancers driven by various Ras mutations. Summary of the Invention

[0006] This document provides Ras inhibitors. The methods described herein require the formation of a high-affinity three-component complex 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 novel binding pocket in Ras by driving the formation of a high-affinity triple 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 their inhibitory effect on Ras is by spatially blocking the interaction sites between Ras and downstream effector molecules such as RAF and PI3K required for the propagation of oncogenic signals.

[0007] Therefore, in some embodiments, this disclosure is characterized by a compound of structural formula I or a pharmaceutically acceptable salt thereof: Formula I The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heteroarylene; B is -CH(R) 9 - or > C = CR 9 R 9’ In which carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R) 6 )-, where C binds to -C(R) 7 R 8 )-;-C(O)NH-CH(R 6 )-, where C binds to -C(R) 7 R 8 )-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5 It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 1 It is a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 6-membered cycloalkenyl group, an optionally substituted 3- to 6-membered heterocycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 It combines with the atoms it is attached to to form optional substituted 3- to 14-membered heterocyclic alkyl groups; R 2 It is absent, hydrogen, optionally substituted C1-C6 alkyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3 to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optional substituted C1-C6 alkyl group; R 10 It is hydrogen, halogenated, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R 10a It is hydrogen or halogenated; R 11 It is hydrogen or C1-C3 alkyl; and R 34It is hydrogen or a C1-C3 alkyl group (e.g., methyl).

[0008] Pharmaceutical compositions are also provided, comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] A conjugate or a salt thereof is also provided, the conjugate comprising the structure of formula IV: MLP Formula IV Where L is the connector; P is the monovalent organic fraction; and M has the structure of formula V: Formula V The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 - or > C = CR 9 R 9’ In which carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R) 6 )-, where C binds to -C(R) 7 R 8 )-;-C(O)NH-CH(R 6 )-, where C binds to -C(R) 7 R 8 )-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5 It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 1 It is a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 6-membered cycloalkenyl group, an optionally substituted 3- to 6-membered heterocycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 It combines with the atoms it is attached to to form optional substituted 3- to 14-membered heterocyclic alkyl groups; R 2 It is absent, hydrogen, optionally substituted C1-C6 alkyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3 to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optional substituted C1-C6 alkyl group; R 10 It is hydrogen, halogenated, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R 10a It is hydrogen or halogenated; R 11 It is hydrogen or C1-C3 alkyl; and R 34 It is hydrogen or a C1-C3 alkyl group (e.g., methyl).

[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 invention, or a pharmaceutically acceptable salt 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 thereof.

[0012] 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.

[0013] Specifically, upon careful consideration, any limitations discussed regarding one embodiment of the invention are applicable to any other embodiment of the invention. Furthermore, any compound or composition of the invention can be used in any method of the invention, and any method of the invention can be used to manufacture or utilize any compound or composition of the invention. Attached Figure Description

[0014] Figure 1A The compound of this invention, compound A, strongly and persistently inhibits oncogenic signals in a pancreatic CDX model (HPAC CDX model, PDAC, KRAS G12D / WT). In single-dose experiments, n = 3 animals / time point, all dose levels were well tolerated.

[0015] Figure 1B In vivo treatment with the compound of this invention, compound A, to induce tumor regression in a KRAS G12D tumor-driven pancreatic CDX model (HPAC CDX model, PDAC, KRAS G12D / WT). n = 10 animals / group. ***p<0.001. All dose levels were well tolerated.

[0016] Definitions and chemical terms In this application, unless clearly indicated from the context, (i) the term “a (a)” means “one or more”; (ii) the term “or” is used to mean “and / or” unless explicitly indicated that the term refers to an alternative as unique or that the alternatives are mutually exclusive, however, the definition supported by this disclosure refers to a unique alternative and “and / or”; (iii) the terms “comprising” and “including” should be understood to encompass the listed components or steps, whether presenting the components or steps alone or in combination with one or more additional components or steps; and (iv) when providing a scope, endpoints are included.

[0017] As used herein, the term "about" is used to indicate that a value includes the standard deviation of the error of the means or method used to determine that value. In some embodiments, the term "about" refers to a range of values ​​in any direction (greater or less than) within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or lower percentages of the value, unless otherwise specified or otherwise apparent from the context (e.g., when the figure would exceed 100% of the possible value).

[0018] As used herein, in the context of describing adjacent atoms, the term "adjacent" refers to divalent atoms directly connected by covalent bonds.

[0019] As used herein, “compounds of the present invention” and similar terms, whether explicitly indicated or not, refer to the Ras inhibitors described herein, including compounds of formula I and its subforms, as well as the compounds listed in Tables 1 and 2, and their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including transisomers) and tautomers.

[0020] The term "wildtype" refers to an entity that has the structure or activity seen in nature in a "normal" state or condition (as opposed to mutation, disease, alteration, etc.). Those skilled in the art will understand that wildtype genes and polypeptides often exist in many different forms (e.g., alleles).

[0021] 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 that atom, such as hydrogen being substituted with deuterium). Unless otherwise indicated or clearly apparent from the context, the structures depicted are to be understood as representing any such isomeric or isotopic forms, individually or in combination.

[0022] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are covered unless otherwise indicated. 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, such as by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers, such as alkenes and C=N double bonds, may also exist in the compounds described herein, and all such stable isomers are covered 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.

[0023] In some embodiments, one or more compounds described 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, accompanied by proton migration. In some embodiments, the tautomer form may be a proton-transfer 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-transfer tautomer form include keto-enol pairs, amide-imino pairs, lactam-lactamimide pairs, amide-imino pairs, enamine-imide pairs, and cyclic forms in which the proton may occupy two or more positions in the heterocyclic system, such as 1H-imidazole and 3H-imidazole, 1H-triazole, 2H-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole 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.

[0024] Unless otherwise specified, the structures described 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, such as... 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. Isotope-labeled compounds (e.g., labeled with...) 3 H and 14 Compounds of C can be used in the determination of the tissue distribution of compounds or substrates. Tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are available because they are easy to prepare and detect. Alternatively, heavier isotopes, such as deuterium (i.e.,...), can be used. 2 H) substitution can provide certain therapeutic benefits due to enhanced metabolic stability (e.g., increased half-life in vivo or reduced dose requirement). In some embodiments, one or more hydrogen atoms are... 2 H or 3 H substitution, or one or more carbon atoms being... 13 C or 14 Carbon-enriched carbon substitution. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F 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 generally be prepared by following a procedure similar to that disclosed for the compounds of the invention described herein, by replacing unlabeled reagents with isotopically labeled reagents.

[0025] 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 described or depicted herein can be provided in hydrate or solvate form.

[0026] Throughout this specification, substituents of the compounds disclosed herein are disclosed by group or by range. Specifically, this disclosure is intended to include every individual combination of members of each of the said groups and ranges. For example, the term "C1-C6 alkyl" specifically intends to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound comprises multiple positions, and where substituents are disclosed by group or by range at these positions, unless otherwise indicated, this disclosure is intended to cover the individual compounds and groups of compounds (e.g., species and subclasses) containing each individual combination of members at each position.

[0027] 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 group is optionally substituted”). It is not intended that the characteristic “X” (e.g., alkyl) itself is optional. As described 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, such as any of the substituents or groups described herein. Unless otherwise indicated, the “optionally substituted” group may have a suitable substituent at each substituted position of the 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 combinations of substituents contemplated in this disclosure are preferably combinations of substituents that form stable or chemically viable compounds. As used herein, the term "stable" means that a compound remains substantially unchanged when subjected to conditions that allow the compound to be produced, detected, and in some embodiments, to be recovered, purified, and used for one or more of the purposes disclosed herein.

[0028] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group can be independently deuterium; 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 by R°; -(CH2)0-4O(CH2)0-1Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2)0-4O(CH2)0-1-pyridyl, which can be substituted by R°; 4 to 8-membered saturated or unsaturated heterocyclic alkyl groups (e.g., pyridyl). ); 3 to 8 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)O R°;-(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°;-SiR°3; -(C1-C4 straight-chain or branched-chain alkylene)ON(R°)2; or -(C1-C4 straight-chain or branched-chain alkylene)C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, -C1-C6 aliphatic group, -CH2Ph, -O(CH2)0-1Ph, -CH2- (5 to 6-membered heteroaryl ring), or a 3 to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, despite the above definitions, two independently existing R° together with their inserted atoms form a 3 to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0029] Suitable monovalent substituents on R° (or a ring formed by two independently existing R° and their inserted atoms) can be independently halogens, -(CH2)0-2R ● -(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)O-2SR ● , -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR ● -(CH2)0-2NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● -(C1-4 straight-chain or branched alkylene)C(O)OR ● or -SSR ● , where each R ● It is either unsubstituted or, in the case of being preceded by "halogenated," substituted only with one or more halogens, and independently selected from C1-C4 aliphatic groups, -CH2Ph, -O(CH2)0-1Ph, 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.

[0030] 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 R * When occurring independently, it is selected from hydrogen; a C1-C6 aliphatic group, which may be substituted as defined below; 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 adjacent substituted carbon of the "optionally substituted" group include: -O(CR * 2)2-3O-, where R * It is selected from hydrogen each time it appears independently; a C1-C6 aliphatic group, which may be substituted as defined below; or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0031] 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, if preceded by "halogenated", substituted with only one or more halogens, and is independently a C1-C4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0032] 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 C1-C6 aliphatic group, which may be substituted as defined below; an unsubstituted -OPh; or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, despite the above definitions, two independently existing R... † Together with the inserted atoms, they form 3 to 12 saturated, partially unsaturated, or aryl monocyclic or bicyclic rings with 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0033] 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 being preceded by "halogenated", substituted only by one or more halogens, and is independently a C1-C4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph, 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.

[0034] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0035] As used herein, the term "alkoxy" refers to -O-Cl-C 20 Alkyl group, wherein the alkoxy group is attached to the rest of the compound via an oxygen atom.

[0036] 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 non-branched (i.e., linear); in some embodiments, the alkyl group is branched. Alkyl groups are, for example, but not limited to, methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and neopentyl.

[0037] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight-chain or branched saturated hydrocarbon, and examples include methylene, ethylene, isopropylene, etc. The term "C" x -C y "Alkylene" indicates an alkylene group having between x and y carbons. Indicative values ​​of x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​of 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.

[0038] 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 are 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.

[0039] As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched chain group containing a carbon-carbon triple bond and having 2 to 20 carbons (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons), and examples of such groups include ethynyl and 1-propynyl.

[0040] As used herein, the term "alkynyl sulfone" indicates a structure containing The group, wherein R is any chemically feasible substituent described herein.

[0041] As used herein, the term "amino" signifies -N(R) † )2, for example -NH2 and -N(CH3)2.

[0042] As used herein, the term "aminoalkyl" refers to an alkyl moiety in which one or more carbon atoms are replaced by one or more amino moieties.

[0043] 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 said 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 hydroxyl valine, isoleucine, leucine, lysine, methionine, valine, ornithine, phenylalanine, proline, pyrrolidone, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0044] 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 an aromatic ring. Examples of aryl groups include phenyl, naphthyl, phenanthryl, and anthracene. An aromatic ring may be attached to its side group at any heteroatom or carbocyclic atom that produces a stable structure, and unless otherwise specified, any ring atom may optionally be substituted.

[0045] As used herein, the term “C0” signifies a bond. For example, a portion of the term -N(C(O)-(C0-C5 alkylene-H)- includes -N(C(O)-(C0 alkylene-H)-, also represented as -N(C(O)-H)-.

[0046] As used herein, the terms "carbocyclic" and "carbocyclic group" refer to a monovalent, optionally substituted 3- to 12-membered 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 a non-aromatic ring. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of carbocyclic groups include 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 group at any ring atom that produces a stable structure, and unless otherwise specifically stated, any ring atom may be optionally substituted.

[0047] As used herein, the term "carbonyl" refers to a C(O) group, which can also be represented as C=O.

[0048] As used herein, the term "carboxyl" means -CO2H, (C=O)(OH), COOH, or C(O)OH, or its unprotonated counterpart.

[0049] As used herein, the term "cyano" refers to the -CN group.

[0050] As used herein, the term "cycloalkyl" refers to 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 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0051] As used herein, the term "cycloalkenyl" refers to 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.

[0052] As used in this article, the term "diastereomer" means a stereoisomer that is not a mirror image of another and cannot be superimposed on another.

[0053] As used herein, the term "enantiomer" means each individual optically active form of the compound of the invention having 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% optical purity or enantiomer excess (as determined by standard methods in the art).

[0054] The term "guanidinyl" refers to a group having the following structure: Each R is independently any chemically feasible substituent described herein.

[0055] As used herein, the term "guanidinyl alkyl" refers to an alkyl moiety in which one or more carbon atoms are replaced by one or more guanidinyl moieties.

[0056] As used herein, the term "haloacetyl" refers to an acetyl group in which at least one hydrogen atom is replaced by a halogen.

[0057] As used herein, the term "haloalkyl" refers to an alkyl moiety in which one or more carbon atoms are replaced by one or more identical or different halogen moieties.

[0058] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0059] 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 be present in the middle or at the end of the group.

[0060] 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... n It has +2 π electrons and contains at least one heteroatom selected from N, O, or S in the aromatic ring. An illustrative unsubstituted heteroaryl group has 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 "heteroaryl" includes bicyclic, tricyclic, and tetracyclic groups fused to any of the aforementioned heteroaryl rings with one or more aromatic or carbocyclic rings, such as phenyl 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 group at any ring atom that produces a stable structure, and any ring atom may optionally be substituted unless otherwise specified. In one embodiment, the heteroaryl group is substituted with 1, 2, 3, or 4 substituents.

[0061] As used herein, the term "heterocyclic alkyl" means at least one ring is a non-aromatic ring and wherein the non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, in a monovalent, monocyclic, bicyclic, or polycyclic system, which may be a bridging ring, a fused ring, or a spirocyclic ring. Five-membered rings have zero to two double bonds, and six-membered and seven-membered rings have zero to three double bonds. Illustrative 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 means a heterocyclic compound having a bridging polycyclic structure, wherein one or more carbons or heteroatoms bridge a non-adjacent member of 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 and one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, such as aryl, cyclohexane, cyclohexene, cyclopentane, cyclopentene, pyridine, or pyrrolidine rings. Examples of heterocyclic alkyl groups include pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridinyl, and decahydronaphthidyl. Heterocyclic alkyl rings may be attached to their side groups at any ring atom that produces a stable structure, and unless otherwise specified, any ring atom may optionally be substituted.

[0062] As used herein, the term "hydroxyl group" refers to the -OH group.

[0063] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety in which one or more carbon atoms are replaced by one or more -OH moieties.

[0064] 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 compounds of the present invention may have one or more chiral centers or double bonds, and thus exist in stereoisomeric form, such as 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 described herein and therefore the compounds of the present invention cover 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 typically 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. The enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates, reagents, and catalysts via well-known asymmetric synthetic methods.

[0065] As used herein, the term "linker" refers to linking part B of a compound of formula I to part W, such that the resulting compound is a divalent organic moiety capable of obtaining an IC50 value of 2 μM or lower, as provided in the following examples and in the Ras-RAF destruction assay provided herein: The purpose of this biochemical assay was to measure the ability of the test compound to promote the formation of a ternary complex between a nucleotide-loaded Ras isoform and cyclic protein A; and to obtain the ternary complex disruption and BRAF. RBD The binding of the constructs suppresses Ras signal transduction through the RAF effector.

[0066] 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 cyclophilic protein A, His6-K-Ras-GMPPNP (or other Ras variants), and GST-BRAF were added. RBDCompounds were combined in 384-well plates at final concentrations of 25 µM, 12.5 nM, and 50 nM, respectively. The compounds present in each well were diluents that had undergone 10 consecutive 3-fold dilutions starting from a final concentration of 30 µM. After incubation at 25 °C for 3 hours, a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was added to the sample wells to achieve final concentrations of 10 nM and 50 nM, respectively, and the reaction was incubated for another 1.5 hours. The TR-FRET signal was read using a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that promoted the destruction of the Ras:RAF complex were identified as those that reduced the TR-FRET ratio relative to the DMSO control wells.

[0067] In some embodiments, the linker comprises 20 or fewer linear atoms. In some embodiments, the linker comprises 15 or fewer linear atoms. In some embodiments, the linker comprises 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.

[0068] As used herein, the "monovalent organic fraction" is less than 500 kDa. In some embodiments, the "monovalent organic fraction" is less than 400 kDa. In some embodiments, the "monovalent organic fraction" is less than 300 kDa. In some embodiments, the "monovalent organic fraction" is less than 200 kDa. In some embodiments, the "monovalent organic fraction" is less than 100 kDa. In some embodiments, the "monovalent organic fraction" is less than 50 kDa. In some embodiments, the "monovalent organic fraction" is less than 25 kDa. In some embodiments, the "monovalent organic fraction" is less than 20 kDa. In some embodiments, the "monovalent organic fraction" is less than 15 kDa. In some embodiments, the "monovalent organic fraction" is less than 10 kDa. In some embodiments, the "monovalent organic fraction" is less than 1 kDa. In some embodiments, the "monovalent organic fraction" is less than 500 g / mol. In some embodiments, the "monovalent organic fraction" is in the range between 500 g / mol and 500 kDa.

[0069] As used herein, the term "stereoisomer" refers to all possible different isomers and configurations that a compound (e.g., any compound of the formula described herein) may have, particularly all possible stereochemical and configurational isomers of the basic molecular structure, all diastereomers, enantiomers, or configurational 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.

[0070] As used herein, the term "sulfonyl" refers to the -S(O)2- group.

[0071] As used herein, the term "thiocarbonyl" refers to the -C(S)- group.

[0072] As used herein, the term "vinyl ketone" refers to a group containing a carbonyl group directly attached to a carbon-carbon double bond.

[0073] As used herein, the term “vinyl sulfone” refers to a group containing a sulfonyl group directly linked to a carbon-carbon double bond.

[0074] As used herein, the term "acetylenoid" refers to a structure containing The group, wherein R is any chemically feasible substituent described herein.

[0075] Those skilled in the art will understand from this disclosure that certain compounds described herein may be provided or utilized in any of a variety of forms, such as salt form, protected form, prodrug form, ester form, isomer form (e.g., optical or structural isomers), isotopic form, etc. In some embodiments, a specific compound mentioned may refer to a specific form of that compound. In some embodiments, a specific compound mentioned may refer to the compound in any form. In some embodiments, for example, a formulation of a single stereoisomer of a compound may be considered a different form of the compound rather than a racemic mixture of the compound; a specific salt of a compound may be considered a different form from another salt of the compound; a formulation of a configurational isomer ((Z) or (E)) containing a double bond may be considered a different form from a formulation of another configurational isomer ((E) or (Z)) containing the double bond; a formulation in which one or more isotopes differ from the isotopes present in a reference formulation may be considered a different form. Detailed Implementation

[0076] compound This document provides Ras inhibitors. The methods described herein require the formation of a high-affinity three-component 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 triple 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 their inhibitory effect on Ras is by spatially blocking the interaction sites between Ras and downstream effector molecules such as RAF required for the propagation of oncogenic signals.

[0077] Not bound by theory, the inventors hypothesize that the covalent and non-covalent interactions of the compounds of this invention with Ras and chaperone proteins (e.g., cyclic protein A) can contribute to the inhibition of Ras activity. In some embodiments, the compounds of this invention form covalent adducts with the side chains of Ras proteins (e.g., the -CH2-COOH or -CH2-COO- side chains of aspartic acid at positions 12 or 13 of mutant Ras proteins). Covalent adducts may also be formed with other side chains of Ras. Alternatively or additionally, non-covalent interactions may play a role: for example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, and combinations thereof, can contribute to the ability of the compounds of this invention to form complexes and act as Ras inhibitors. Therefore, the compounds of the present invention can inhibit a variety of Ras proteins (e.g., K-Ras, N-Ras, H-Ras and their mutants with mutations at positions 12, 13 and 61, such as G12C, G12D, G12V, G12S, G13C, G13D and Q61L, and other mutants described herein).

[0078] Methods for determining the formation of covalent adducts are known in the art. One method for determining the formation of covalent adducts is to perform a "crosslinking" determination, as described in the examples and below: Note: The following scheme describes the process for monitoring the crosslinking of K-Ras G12C (GMP-PNP) with the compounds of this invention. Preface. This approach can also be implemented using other Ras proteins or nucleotides, such as K-Ras G12D.

[0079] The purpose of this biochemical assay is to measure the covalently labeled components of the test compound. NucleotidesThe ability of K-Ras isoforms was demonstrated. In an assay buffer containing 12.5 mM HEPES pH 7.4, 75 mM NaCl, 1 mM MgCl2, 1 mM BME, 5 µM cyclic protein A, and 2 µM of the test compound, a 5 µM stock solution of K-Ras (1-169) G12C loaded with GMP-PNP was diluted 10-fold to a final concentration of 0.5 µM; and the final sample volume was 100 µL.

[0080] Samples were incubated at 25°C for up to 24 hours, followed by quenching with 10 µL of 5% formic acid. The quenched samples were centrifuged at 15,000 rpm for 15 minutes in a benchtop centrifuge, and then 10 µL aliquots were injected into a reversed-phase C4 column and eluted to a mass spectrometer using an increasing acetonitrile gradient in the mobile phase. Analysis of the raw data was performed using WatersMassLynx MS software, where the binding percentage was calculated from the deconvolution of labeled and unlabeled K-Ras protein peaks.

[0081] Therefore, this article provides a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof: Formula I The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heteroarylene; B is -CH(R) 9 - or > C = CR 9 R 9’ In which carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R) 6 )-, where C binds to -C(R) 7 R 8 )-;-C(O)NH-CH(R 6 )-, where C binds to -C(R) 7 R 8)-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5 It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 1 It is a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 6-membered cycloalkenyl group, an optionally substituted 3- to 6-membered heterocycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 It combines with the atoms it is attached to to form optional substituted 3- to 14-membered heterocyclic alkyl groups; R 2It is absent, hydrogen, optionally substituted C1-C6 alkyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3 to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optional substituted C1-C6 alkyl group; R 10 It is hydrogen, halogenated, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R 10a It is hydrogen or halogenated; and R 11 It is hydrogen or C1-C3 alkyl; and R 34 It is hydrogen or a C1-C3 alkyl group (e.g., methyl).

[0082] In some implementation schemes, R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl.

[0083] In some implementation schemes, R 34 It is hydrogen.

[0084] In some embodiments of the compounds of the present invention, G is optionally a substituted C1-C4 heteroalkylene group.

[0085] In some embodiments, the compounds of the present invention have the structure of formula Ia, or a pharmaceutically acceptable salt thereof: Formula Ia The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R)10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 )-, where carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5 and Y 6 Independently CH or N; R 1 It is cyano, 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. R 2It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl. R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R 11 It is hydrogen or C1-C3 alkyl.

[0086] In some embodiments of the compounds of the present invention, X 2 It is NH. In some implementations, X 3 It is CH.

[0087] In some embodiments of the compounds of the present invention, R 11 It is hydrogen. In some implementations, R 11 It is a C1-C3 alkyl group, such as methyl.

[0088] In some embodiments, the compounds of the present invention have the structure of formula Ib, or a pharmaceutically acceptable salt thereof: Formula Ib The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5 and Y 6 Independently CH or N; R 1 It is cyano, 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. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; and R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl.

[0089] In some embodiments of the compounds of the present invention, X 1 It is an optional substituted C1-C2 alkylene group. In some embodiments, X 1 It is methylene.

[0090] In some embodiments of the compounds of the present invention, R 4 It is hydrogen.

[0091] In some embodiments of the compounds of the present invention, R 5 It is hydrogen. In some implementations, R 5 It is an optional C1-C4 alkyl group substituted with a halogen. In some embodiments, R 5 It is a methyl group.

[0092] In some embodiments of the compounds of the present invention, Y 4 It is C. In some implementations, R 4 It is hydrogen. In some implementations, Y 5 It is CH. In some implementations, Y 6 It is CH. In some implementations, Y 1 It is C. In some implementations, Y 2 It is C. In some implementations, Y 3 It is N. In some implementations, R 3 It does not exist. In some implementations, Y 7 It's C.

[0093] In some embodiments, the compounds of the present invention have the structure of formula Ic, or a pharmaceutically acceptable salt thereof: Formula Ic Where A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; R 1 It is cyano, 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. R 2It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; and R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl.

[0094] In some embodiments of the compounds of the present invention, R 6 It is hydrogen.

[0095] In some embodiments of the compounds of the present invention, R 2 It is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 2 It is an optional substituted C1-C6 alkyl group, such as ethyl.

[0096] In some embodiments of the compounds of the present invention, R 7 It is an optional substituted C1-C3 alkyl group. In some embodiments, R 7 It is a C1-C3 alkyl group.

[0097] In some embodiments of the compounds of the present invention, R 8 It is an optional substituted C1-C3 alkyl group. In some embodiments, R 8 It is a C1-C3 alkyl group.

[0098] In some embodiments, the compounds of the present invention have the structure of formula Id, or a pharmaceutically acceptable salt thereof: FormulaId Where A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; R 1 It is cyano, 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. R 2 It is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; and R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl.

[0099] In some embodiments of the compounds of the present invention, R 1 It is a 5- to 10-membered heteroaryl group. In some implementations, R 1 It is either a 6-membered aryl group that is optionally substituted or a 6-membered heteroaryl group that is optionally substituted.

[0100] In some embodiments, the compounds of the present invention have the structure of formula Ie, or a pharmaceutically acceptable salt thereof: Formula Ie Where A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; R 2 It is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; and R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl. X e It is N or CH; and R 12 It is an optional substituted C1-C6 alkyl or an optional substituted C1-C6 heteroalkyl.

[0101] In some embodiments of the compounds of the present invention, X e It is N. In some implementations, X e It is CH.

[0102] In some embodiments of the compounds of the present invention, R 12 It is an optional substituted C1-C6 heteroalkyl group. In some embodiments, R 12 yes , or In some implementations, R 12 yes .

[0103] In some embodiments, the compounds of the present invention have the structure of formula If, or a pharmaceutically acceptable salt thereof: Formula If The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R)9 )-, where carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R) 6 )-, where C binds to -C(R) 7 R 8 )-;-C(O)NH-CH(R 6 )-, where C binds to -C(R) 7 R 8 )-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5 and Y 6 Independently CH or N; R1 It is cyano, 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. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl. R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R 11 It is hydrogen or C1-C3 alkyl.

[0104] In some embodiments, the compounds of the present invention have the structure of formula VI, or a pharmaceutically acceptable salt thereof: Style VI The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group (e.g., phenyl or phenol); or optionally substituted 5 to 10-membered heteroarylene group; B is -CH(R) 9 - or > C = CR 9 R 9’ In which carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R) 6 )-, where C binds to -C(R) 7 R 8 )-;-C(O)NH-CH(R 6 )-, where C binds to -C(R)7 R 8 )-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5 It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 2 It is absent, hydrogen, optionally substituted C1-C6 alkyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3 to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optional substituted C1-C6 alkyl group; R 10 It is hydrogen, halogenated, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R 10a It is hydrogen or halogenated; R 11 It is hydrogen or C1-C3 alkyl; R 34 It is hydrogen or C1-C3 alkyl; and X e and X f It can be either N or CH.

[0105] In some embodiments, the compounds of the present invention have the structure of formula VIa, or a pharmaceutically acceptable salt thereof: VIA Wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylene. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; R 2 It is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; and R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl. X e and X f Independently N or CH; R 11 It is hydrogen or C1-C3 alkyl; and R 21 It is hydrogen or C1-C3 alkyl.

[0106] In some embodiments of the compounds of the present invention, X e It is N, and X f It is CH. In some implementations, X e It is CH, and X f It is N.

[0107] In some embodiments, the compounds of the present invention have the structure of formula VIb, or a pharmaceutically acceptable salt thereof: Formula VIb Wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylene. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; and X e and X f It can be either N or CH.

[0108] In some embodiments of the compounds of the present invention, X e It is N, and X f It is CH. In some implementations, X e It is CH, and X f It is N.

[0109] In some embodiments, the compounds of the present invention have the structure of formula VII, or a pharmaceutically acceptable salt thereof: Equation VII The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heteroarylene; B is -CH(R) 9 - or > C = CR 9 R 9’ In which carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R) 6 )-, where C binds to -C(R) 7 R 8 )-;-C(O)NH-CH(R 6)-, where C binds to -C(R) 7 R 8 )-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5 It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 1 yes or ; R 2 It is absent, hydrogen, optionally substituted C1-C6 alkyl, 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; R 3 Does not exist, or R2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3 to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optional substituted C1-C6 alkyl group; R 10 It is hydrogen, halogenated, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R 10a It is hydrogen or halogenated; R 11 It is hydrogen or C1-C3 alkyl; and R 34 It is hydrogen or a C1-C3 alkyl group (e.g., methyl).

[0110] In some embodiments of the compounds of the present invention, A is an optionally substituted 6-membered aryl group. In some embodiments, A has the following structure: Where R 13 It is hydrogen, hydroxyl, amino, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. In some embodiments, R 13 It is hydrogen. In some implementations, R 13 It is a hydroxyl group.

[0111] In some embodiments of the compounds of the present invention, B is -CHR. 9 -. In some implementations, R 9 It is an optionally substituted C1-C6 alkyl or an optionally substituted 3- to 6-membered cycloalkyl. In some embodiments, R 9 yes: , or In some implementations, R 9 yes: In some implementations, R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl.

[0112] In some embodiments, B is an optionally substituted 6-membered aryl group. In some embodiments, B is a 6-membered aryl group. In some embodiments, B is: .

[0113] In some embodiments of the compounds of the present invention, R 7 It is a methyl group.

[0114] In some embodiments of the compounds of the present invention, R 8 It is a methyl group.

[0115] In some implementation schemes, R 34 It is hydrogen.

[0116] In some embodiments of the compounds of the present invention, the linker has the structure of Formula II: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Formula II Where A 1 It is the bond between the connector and B; A 2 It is the bond between W and the connector; B 1 B 2 B 3 and B 4 Each is independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NR. N ;R N It is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl; C 1 and C 2 Each is independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl groups; f, g, h, i, j, and k are each independently 0 or 1; and D 1 The C1-C that can be arbitrarily replaced. 10 Alkylene, optionally substituted C2-C 10 alkenyl groups, optionally substituted C2-C 10Alynyl group, optionally substituted 3- to 14-membered heterocyclic alkyl group, optionally substituted 5- to 10-membered heteroaryl group, optionally substituted 3- to 8-membered heterocyclic alkyl group, optionally substituted 6- to 10-membered aryl group, optionally substituted C2-C group 10 Polyethylene glycol or optionally substituted C1-C 10 Heteroalkyl, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -Connected to -(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 The chemical bonds. In some embodiments, the linker is an acyclic linker. In some embodiments, the linker has the structure of formula IIa: Formula IIa Where X a It either does not exist or is N; R 14 It is a C1-C6 alkyl group that is absent, contains hydrogen, or is optionally substituted; and L 2 It is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene, wherein X a R 14 or L 2 At least one of them is present. In some embodiments, the connector has the following structure: In some embodiments, the linker is or contains a cyclic group. In some embodiments, the linker has the structure of formula IIb: Formula IIb Where o is 0 or 1; R 15 It is hydrogen or an optional substituted C1-C6 alkyl group; Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heteroalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroalkylene; and L 3It is absent, -SO2-, optionally substituted C1-C4 alkylene, or optionally substituted C1-C4 heteroalkylene. In some embodiments, the linker has the following structure: In some implementations, the connector of Formula II is selected from the group consisting of: .

[0117] In some embodiments of the compounds of the present invention, W comprises carbodiimide. In some embodiments, W has the structure of formula IIIa: Formula IIIa Where R 14 It is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocycloalkyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, W has the following structure: .

[0118] In some embodiments, W comprises oxazoline or thiazoline. In some embodiments, W has the structure of formula IIIb: Formula IIb Where X 1 Is it O or S? X 2 Does not exist or NR 19 ; R 15 R 16 R 17 and R 18 Independently hydrogen or optionally substituted C1-C6 alkyl; and R 19It is hydrogen, C(O) (optionally substituted C1-C6 alkyl), optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocyclic alkyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, W is... .

[0119] In some embodiments, W comprises chloroethylurea, chloroethylthiourea, chloroethyl carbamate, or chloroethyl thiocarbamate. In some embodiments, W has the structure of formula IIIc: Formula IIIc Where X 3 Is it O or S? X 4 It is O, S, NR 26 ; R 21 R 22 R 23 R 24 and R 26 Independently hydrogen or optionally substituted C1-C6 alkyl; and R 25 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocyclic alkyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, W is... .

[0120] In some embodiments, W comprises azacyclopropane. In some embodiments, W has a structure of formula IIId1, IIId2, IIId3, or IIId4: Where X 5 Does not exist or NR 30 ; Y is absent or is C(O), C(S), S(O), SO2 or optionally substituted C1-C3 alkylene groups; R 27 It is hydrogen, -C(O)R 32 -C(O)OR 32 -SOR 33 -SO2R 33 Optionally substituted C1-C6 alkyl, Optionally substituted 6- to 10-membered aryl, Optionally substituted 3- to 14-membered heterocyclic alkyl or Optionally substituted 5- to 10-membered heteroaryl; R 28 and R 29 Independently hydrogen, CN, C(O)R 31 CO2R31 C(O)R 31 R 31 Optionally substituted C1-C6 alkyl, Optionally substituted 3- to 10-membered cycloalkyl, Optionally substituted 6- to 10-membered aryl, Optionally substituted 3- to 14-membered heterocycloalkyl or Optionally substituted 5- to 10-membered heteroaryl; Each R 31 Independently, it is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocyclic alkyl, or optionally substituted 5- to 10-membered heteroaryl. R 30 It is hydrogen or an optionally substituted C1-C6 alkyl group; and R 32 and R 33 Independently, it is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocyclic alkyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, W is: .

[0121] In some embodiments, W comprises an epoxide. In some embodiments, W is... .

[0122] In some embodiments, W is a crosslinking group bound to an organic portion, which is a Ras-binding portion, i.e., RBM-W, wherein upon contact between the RBM-W compound and the Ras protein, the RBM-W binds to the Ras protein to form a conjugate. For example, the W portion of the RBM-W compound may bind to an amino acid of the Ras protein, for example, through crosslinking, to form a conjugate. In some embodiments, the Ras-binding portion is a K-Ras-binding portion. In some embodiments, the K-Ras-binding portion binds to residues of the K-Ras Switch-II binding pouch of the K-Ras protein. In some embodiments, the Ras-binding portion is an H-Ras-binding portion that binds to residues of the H-Ras Switch-II binding pouch of the H-Ras protein. In some embodiments, the Ras-binding portion is an N-Ras-binding portion that binds to residues of the N-Ras Switch-II binding pouch of the N-Ras protein. The W of the RBM-W compound may include any W described herein. The molecular weight of the Ras-binding portion is typically less than 1200 Da. For a description of the domains of the Ras protein, see, for example, Johnson et al., 292:12981-12993 (2017), which is incorporated herein by reference.

[0123] In some embodiments, the compounds of the present invention are selected from Table 1, or pharmaceutically acceptable salts or stereoisomers thereof.

[0124] Table 1: Some compounds of the present invention *Assuming the stereochemistry of aziridine carbon.

[0125] It should be noted that bonds in some compounds are shown as straight lines or wedges. In some cases, the relative stereochemistry of the stereoisomers has been determined; in others, the absolute stereochemistry has been determined. In some cases, a single example number corresponds to a mixture of stereoisomers. All stereoisomers of the compounds in the table above are covered in this invention. In certain embodiments, the transisomers of the compounds in the table above are covered.

[0126] In some embodiments, compounds from Table 2 are provided, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of the present invention are selected from Table 2, or pharmaceutically acceptable salts or stereoisomers thereof.

[0127] Table 2: Some compounds of the present invention .

[0128] It should be noted that bonds in some compounds are shown as straight lines or wedges. In some cases, the relative stereochemistry of the stereoisomers has been determined; in others, the absolute stereochemistry has been determined. All stereoisomers of the compounds in the table above are covered in this invention. In certain embodiments, the transisomers of the compounds in the table above are covered.

[0129] In some embodiments, the compounds of the present invention are or are used as prodrugs, such as for administration to cells or to a subject in need.

[0130] Pharmaceutical compositions are also provided, comprising the compounds of the present invention or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0131] A conjugate or a salt thereof is also provided, the conjugate comprising the structure of formula IV: MLP Formula IV Where L is the connector; P is the monovalent organic fraction; and M has the structure of Va: Va The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 - or > C = CR 9 R 9’ In which carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R) 6 )-, where C binds to -C(R) 7 R 8 )-;-C(O)NH-CH(R 6 )-, where C binds to -C(R) 7 R 8 )-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5 It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 1It is a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 6-membered cycloalkenyl group, an optionally substituted 3- to 6-membered heterocycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 It combines with the atoms it is attached to to form optional substituted 3- to 14-membered heterocyclic alkyl groups; R 2 It is absent, hydrogen, optionally substituted C1-C6 alkyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; or R 9 L and the atoms to which they are attached combine to form optionally substituted 3 to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optional substituted C1-C6 alkyl group; R 10 It is hydrogen, halogenated, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R 10a It is hydrogen or halogenated; and R 11 It is hydrogen or C1-C3 alkyl.

[0132] In some embodiments, the conjugate has the structure of formula IV: MLP Formula IV Where L is the connector; P is the monovalent organic fraction; and M has the structure of Vb: Vb The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 )-, where carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R) 6 )-, where C binds to -C(R) 7 R 8 )-;-C(O)NH-CH(R 6 )-, where C binds to -C(R) 7 R 8 )-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5 and Y 6 Independently CH or N; R 1It is cyano, 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. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl. R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R 11 It is hydrogen or C1-C3 alkyl.

[0133] In some embodiments, the conjugate has the structure of formula IV: MLP Formula IV Where L is the connector; P is the monovalent organic fraction; and M has the structure of Vc: Vc Wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylene. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; X e and X f Independently N or CH; R 2 It is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; and R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl. R 11 It is hydrogen or C1-C3 alkyl; and R 34 It is hydrogen or C1-C3 alkyl.

[0134] In some embodiments of the compounds of the present invention, X e It is N, and X f It is CH. In some implementations, X e It is CH, and X f It is N.

[0135] In some embodiments, the conjugate has the structure of formula IV: MLP Formula IV Where L is the connector; P is the monovalent organic fraction; and M has the structure of Vd: Vd Wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene (e.g., phenyl or phenol), or an optionally substituted 5- to 6-membered heteroarylene. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; and X e and X f It can be either N or CH.

[0136] In some embodiments of the compounds of the present invention, X e It is N, and X f It is CH. In some implementations, X e It is CH, and X f It is N.

[0137] In some embodiments of the conjugate of the present invention, the linker has the structure of Formula II: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Formula II Where A 1 It is the bond between the connector and B; A 2 It is the bond between P and the linker; B 1 B 2 B 3 and B 4 Each is independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NR. N ;R NIt is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl; C 1 and C 2 Each is independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl groups; f, g, h, i, j, and k are each independently 0 or 1; and D 1 The C1-C that can be arbitrarily replaced. 10 Alkylene, optionally substituted C2-C 10 alkenyl groups, optionally substituted C2-C 10 Alynyl group, optionally substituted 3- to 14-membered heterocyclic alkyl group, optionally substituted 5- to 10-membered heteroaryl group, optionally substituted 3- to 8-membered heterocyclic alkyl group, optionally substituted 6- to 10-membered aryl group, optionally substituted C2-C group 10 Polyethylene glycol or optionally substituted C1-C 10 Heteroalkyl, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -Connected to -(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 The chemical bonds. In some embodiments of the conjugates of the present invention, the linker is bonded to the monovalent organic moiety by a bond with the carboxyl group of an amino acid residue.

[0138] In some embodiments of the conjugates of the present invention, the monovalent organic moiety is a protein. In some embodiments, the protein is a Ras protein. In some embodiments, the Ras protein is K-Ras G12D or K-Ras G13D.

[0139] A method for treating a subject with cancer is also provided, 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 G12D or K-Ras G13D. Other Ras mutations are also described herein.

[0140] A method for treating Ras protein-related conditions in a subject of need is also provided, comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0141] A method for inhibiting Ras protein in cells is also provided, 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 G12D or K-Ras G13D. Other Ras proteins are also described herein. The cells may be cancer cells, such as pancreatic cancer cells, colorectal cancer cells, non-small cell lung cancer cells, acute myeloid leukemia cells, multiple myeloma cells, thyroid adenocarcinoma cells, myelodysplastic syndrome cells, or squamous cell lung cancer cells. Other cancer types are also described herein. The cells may be in vivo or in vitro.

[0142] For the compounds of this invention, one stereoisomer may exhibit a stronger inhibitory effect than another stereoisomer. For example, one transisomer may exhibit an inhibitory effect, while another transisomer may exhibit very little or no inhibitory effect.

[0143] In some embodiments, the methods or uses described herein further include administering additional anticancer therapies. In some embodiments, the additional anticancer 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. In some embodiments, the additional anticancer therapy is an SHP2 inhibitor. Other additional anticancer therapies are also described herein.

[0144] Synthesis method The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic methods.

[0145] The compounds of this invention can be prepared by a variety of methods well known to those skilled in the art of organic synthesis. For example, the compounds of this invention can be synthesized using the methods described in the following schemes, as well as synthetic methods known in synthetic organic chemistry techniques or modifications thereof as understood by those skilled in the art. These methods include, but are not limited to, those described in the following schemes.

[0146] The compounds in Table 1 of this document were prepared using the methods disclosed herein, or using the methods disclosed herein in combination with the knowledge of those skilled in the art. The compounds in Table 2 were prepared using the methods disclosed herein, or using the methods disclosed herein in combination with the knowledge of those skilled in the art.

[0147] Scheme 1. General Synthetic Methods for Macrocyclic Esters Scheme 1 outlines the general synthetic method for macrocyclic esters. Appropriately substituted aryl-3-(5-bromo-1-ethyl-1-yl) H -Indol-3-yl)-2,2-dimethylprop-1-ol(1) can utilize protected 3-(5-bromo-2-iodo-1- H Starting with indol-3-yl)-2,2-dimethylprop-1-ol and appropriately substituted boric acids, the mixture was prepared in three steps, including palladium-mediated coupling, alkylation, and deprotection reactions.

[0148] The amino-hexahydropyridazine-3-carboxylate methyl ester-boronate (2) can be prepared in three steps, including protection, iridium catalyst-mediated boronization, and reaction with ( S Coupling of methyl hexahydropyridazine-3-carboxylate.

[0149] The final macrocyclic ester can be prepared by reacting amino-hexahydropyridazine-3-carboxylate methyl borate (2) with aryl-3-(5-bromo-1-ethyl-1-yl) H (1)-Indol-3-yl)-2,2-dimethylprop-1-ol (1) is coupled in the presence of a Pd catalyst, followed by hydrolysis and macrocyclic lactone esterification steps to obtain a suitably protected macrocyclic intermediate (4). Additional deprotection or functionalization steps are required to prepare the final compound. For example, those skilled in the art will be able to load the desired -BLW group of the compound of formula (I) into the macrocyclic ester, wherein B, L, and W are as defined herein, including by using methods illustrated in some of the following schemes and in the Examples section herein.

[0150] Option 2. Substitute General Synthetic Methods for Macrocyclic Esters Alternatively, macrocyclic esters can be prepared as described in Scheme 2. A suitably protected bromo-indole group (5) can be coupled with a borate ester (3) in the presence of a Pd catalyst, followed by iodination, deprotection, and ester hydrolysis. Subsequently, it is combined with ( SCoupling with methyl hexahydropyridazine-3-carboxylate, followed by hydrolysis and macrocyclic lactone formation, yields an iodine intermediate (6). Coupling with a suitably substituted borate ester in the presence of a Pd catalyst yields a fully protected macrocycle (4). Additional deprotection or functionalization steps are required to prepare the final compound. For example, those skilled in the art will be able to load the desired -BLW group into the macrocyclic ester of formula (I), wherein B, L, and W are as defined herein, including by using methods illustrated in some of the following schemes and in the Examples section herein.

[0151] Scheme 3. General synthetic method for macrocycles containing nitrogen-containing heterocyclic propanes As shown in Scheme 3, such compounds can be prepared by reacting a suitable amine (1) with a carboxylic acid (2) containing a nitrogen-containing heterocyclic propane in the presence of a standard amide coupling reagent, if R 1 If it is a protecting group, then the aziridine is subsequently deprotected, and if necessary, the phenol is deprotected to obtain the final compound (4).

[0152] Scheme 4. General synthetic method for macrocycles containing carbodiimide As shown in Scheme 4, such compounds can be prepared by reacting a suitable amine (1) with a thiourea-containing carboxylic acid (2) in the presence of a standard amide coupling agent, followed by converting thiourea (3) into carbodiimide (4) in the presence of 2-chloro-1-methylpyridin-1-onium iodide.

[0153] Scheme 5. General synthetic method for macrocyclic compounds containing chloroethylurea As shown in Scheme 5, such compounds can be prepared by reacting a suitable amine (1) with an isocyanate (2) under basic conditions, followed by deprotection of the phenol if necessary, to produce the final compound (4).

[0154] Scheme 6. General synthetic method for macrocycles containing aminooxazoline As shown in Scheme 6, such compounds can be prepared by cyclizing an appropriate chloroethylurea (1) at high temperature to produce the final compound (2).

[0155] Scheme 7. General synthetic method for macrocycles containing epoxy groups As shown in Scheme 7, such compounds can be prepared by reacting a suitable amine (1) with an epoxy-containing carboxylic acid (2) in the presence of a standard amide coupling agent to produce the final compound (3).

[0156] Furthermore, the compounds of this disclosure can be synthesized using the methods described in the following examples, as well as synthetic methods known in synthetic organic chemistry, or modifications thereof as understood by those skilled in the art. These methods include, but are not limited to, those described in the following examples. For instance, those skilled in the art will be able to load the desired -BLW group of the compound of formula (I) into a macrocyclic ester, wherein B, L, and W are as defined herein, including by using methods exemplified in some of the above schemes and in the Examples section herein.

[0157] Pharmaceutical Compositions and Methods of Use Pharmaceutical Compositions and Administration The compounds involved 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.

[0158] As used herein, the term "pharmaceutical composition" refers to a compound formulated with a pharmaceutically acceptable excipient, such as the compounds of this invention, or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the compound is present in the pharmaceutical composition in a unit dose suitable for administration in a treatment regimen, and the compound shows a statistically significant likelihood of achieving the intended 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 liquids (aqueous or non-aqueous solutions or suspensions), tablets (e.g., intended for buccal, sublingual, and systemic absorption), pills, powders, granules, or 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; surface 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 administration; ocular administration; transdermal administration; or nasal, pulmonary, and other mucosal surfaces.

[0160] As used herein, “pharmaceuticalally acceptable excipient” means any inactive ingredient (e.g., a medium that suspends or dissolves an active compound) that is non-toxic and non-inflammatory in the body of a subject. Typical excipients include, for example: anti-adhesion agents, antioxidants, adhesives, coating agents, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film-forming agents or coating agents, flavoring agents, fragrances, flow enhancers, lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water for hydration. Excipients include, but are not limited to: optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, croscarmellose, croscarmellose, citric acid, croscarmellose, cysteine, ethyl cellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, 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 starch), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those skilled in the art understand a variety of reagents and materials that can be used as excipients. See, for example, 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.

[0161] Unless explicitly stated otherwise, the compounds described herein, whether or not explicitly stated, may be provided or used in salt form, for example, in a pharmaceutically acceptable salt form. As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound described herein that, to the extent of reasonable medical judgment, is suitable for use in contact with human tissues without excessive toxicity, irritation, allergic reactions, etc., and is 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 PHStahl and CGWermuth), Wiley-VCH, 2008. The salts may be prepared in situ during the final separation and purification of the compounds described herein, or separated by reacting the free basic groups with a suitable organic acid.

[0162] 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, if 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.

[0163] Representative acid addition salts include acetates, adipates, alginates, ascorbic acid salts, aspartate salts, benzenesulfonates, benzoates, hydrogen sulfates, borates, butates, camphorates, camphor sulfonates, citrates, cyclopentanepropionates, disaccharides, dodecyl sulfates, ethanesulfonates, transbutenedioates, glucoheponicates, glycerol phosphates, hemisulfates, heptanates, hexanoates, hydrobromates, hydrochlorides, hydroiodates, and 2-optionally substituted hydroxy-ethyl groups. Alkane sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methane sulfonates, 2-naphthalene sulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, dihydroxynaphthalates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, neopentanoates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, toluene sulfonates, undecanoates, valerates, etc. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts, 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.

[0164] 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., rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cattle, primate, or pig). 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.

[0165] 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, the amount is an amount (or a portion thereof) of a unit dose suitable for administration according to a dosing regimen that is 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.

[0166] As used herein, the term "dosing regimen" refers to a set of unit doses (typically more than one unit dose) individually administered to a subject, said unit doses typically spaced at intervals of time. In some embodiments, a given therapeutic compound (e.g., the compound of the present invention) has a recommended dosing regimen that 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 with at least two distinct time intervals separating the individual doses. In some embodiments, all doses within the dosing regimen are amounts of the same unit dose. In some embodiments, the different doses within the dosing regimen are different amounts. In some embodiments, the dosing regimen comprises a first dose in the amount of a first dose, followed by one or more additional doses in the amount of a second dose different from that first dose. In some embodiments, the dosing regimen comprises a first dose in the amount of a first dose, followed by one or more additional doses in the amount of a second dose identical to that first dose. In some embodiments, the dosing regimen, when administered to a relevant population (i.e., a therapeutic dosing regimen), is associated with desired or beneficial outcomes.

[0167] "Treatment regimen" refers to a dosage regimen in which a patient is administered a treatment to a population in relation to the desired or beneficial therapeutic outcome.

[0168] The term "treatment" ("treatment / treat / treating") in its broadest sense refers to any application of a substance (e.g., the compounds of this invention) that partially or completely relieves, 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 decreases its occurrence. 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 or additionally, in some embodiments, treatment may be administered to a subject exhibiting one or more defined signs of the relevant disease, condition, or disorder. In some embodiments, treatment may be used on a subject diagnosed with the relevant disease, condition, or disorder. In some embodiments, treatment may be used on a subject known to have one or more susceptibility factors that are statistically associated with an increased risk of developing the relevant disease, condition, or disorder.

[0169] The term "therapeuticly effective amount" means an amount sufficient to treat a disease, condition, or disorder when administered according to a therapeutic dosing regimen to a population suffering from or susceptible to that disease, condition, or disorder. 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 the desired successful treatment in a particular individual. In fact, a therapeutically effective amount can be an amount that provides a specific desired pharmacological response in a substantial number of subjects when administered to a patient requiring the treatment. It is particularly important to understand that a particular subject may actually be "therapeuticly effective" and "treatment-resistant." In some embodiments, the reference to a therapeutically effective amount may refer to an amount measured in one or more specific tissues (e.g., tissues affected by the disease, condition, or disorder) or 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 dose may be formulated as multiple doses, for example, as part of a dosing regimen, or administered in multiple doses.

[0170] 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 the parameters described. An overview of such techniques can be found in [link to relevant documentation]. Remington: The Science and Practice of Pharmacy , No. 21st edition ,Lippincott Williams&Wilkins, (2005); and Encyclopedia of Pharmaceuticals Technology , J. Swarbrick and JC Boylan (eds.), 1988–1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0171] 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 amount of the compounds described herein or pharmaceutically acceptable salts thereof may be, by weight, 1-95% of the total amount of the pharmaceutical composition.

[0172] The composition may be provided in dosage forms suitable for administration as follows: intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, skin, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intracystic, intraurethral, ​​intrathecal, epidural, ocular, or by injection, inhalation, or direct contact with the nasal, genitourinary, genital, or oral mucosa. Therefore, the pharmaceutical composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, solutions, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, formulations suitable for iontophoresis delivery, or aerosols. The composition may be formulated according to conventional pharmaceutical practice.

[0173] As used herein, the term "administration" means administering 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) can be performed via any suitable route. For example, in some embodiments, administration can be via bronchial (including bronchial infusion), buccal, intestinal, intradermal, intraarterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intrasacral, mucosal, nasal, oral, rectal, subcutaneous, sublingual, surface, tracheal (including intratracheal infusion), percutaneous, vaginal, or vitreous administration.

[0174] Formulations can be prepared in a manner suitable for systemic or topical administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous) or those prepared for transdermal, transmucosal, or oral administration. Formulations will generally include diluents and, in some cases, adjuvants, buffers, preservatives, etc. Compounds or pharmaceutically acceptable salts thereof may also be administered as liposomal compositions or as microemulsions.

[0175] For injection, formulations can be prepared in conventional forms, such as liquid solutions or suspensions, or in solid forms, or emulsions, suitable for preparation as solutions or suspensions in liquids prior to injection. Suitable excipients include, for example, water, physiological saline, dextrose, glycerin, etc. These compositions may also contain a certain amount of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, dehydrated sorbitol monolaurate, etc.

[0176] Various sustained-release drug delivery systems have also been designed. See, for example, U.S. Patent No. 5,624,677.

[0177] Systemic administration may also include relatively non-invasive methods such as 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. It will be understood in the art that suitable forms include syrups, capsules, and tablets.

[0178] Each compound described herein, or its pharmaceutically acceptable salt, can be formulated in a variety of ways known in the art. For example, the first and second agents in a combination therapy can be formulated together or separately. Other modalities of combination therapy are also described herein.

[0179] Individual or separately formulated pharmaceutical preparations may be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and powder, suppositories, or liquids in vials, two types of topical creams, etc. The kit may include optional components to facilitate the administration of a unit dose to a subject, such as vials for reconstitution of the powder form, syringes, custom IV delivery systems, inhalers, etc. Additionally, the unit dose kit may contain instructions for the preparation and administration of the composition. The kit 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 treatment progression); or the kit may contain multiple doses suitable for administration to multiple subjects (“integrated package”). The kit components may be assembled in cartons, blister packs, bottles, tubes, etc.

[0180] Formulations for oral use include tablets containing a mixture of an active ingredient and a non-toxic, pharmaceutically acceptable excipient. The 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.

[0181] Two or more compounds may be mixed together in tablets, capsules or other media, or they may be separated. In one embodiment, the first compound is contained on the inside of the tablet and the second compound is on the outside, thereby releasing the majority of the second compound before the first compound is released.

[0182] Formulations for oral use may also be provided as chewable tablets or as hard gelatin capsules, 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 as soft gelatin capsules, wherein the active ingredient is mixed with an aqueous or oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and fine 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.

[0183] Controlled release through dissolution or diffusion can be achieved by appropriately coating the compound with tablets, capsules, fine 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, such as 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 hydrogel, 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.

[0184] 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, appropriately flavored syrups, aqueous or oily suspensions, emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical mediators.

[0185] 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 derived therefrom.

[0186] In some embodiments, the pharmaceutical composition may further comprise additional compounds having antiproliferative activity. Depending on the administration mode, the compound or a pharmaceutically acceptable salt thereof will be formulated to suit the composition for delivery. Each compound or pharmaceutically acceptable salt thereof in the combination therapy may be formulated in a variety of ways known in the art. For example, the first and second agents in the combination therapy may be formulated together or separately. Desirably, the first and second agents are formulated together so that the agents are administered simultaneously or nearly simultaneously.

[0187] 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 such one or more other desired therapeutic agents or medical procedures. The specific combination of each therapy (therapeutic agent or procedure) used 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 should also be understood that the therapies employed may achieve the desired effect for the same condition, or these therapies may achieve different effects (e.g., control any adverse effects).

[0188] As described in this article, each drug in the combination therapy can be administered independently, one to four times daily, for one day to one year, or even for the subject's lifetime. Long-term administration is also applicable.

[0189] 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.

[0190] 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 site, 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.

[0191] 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 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 treatable 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: bronchogenic carcinoma (squamous cell lung cancer, undifferentiated small cell lung cancer, undifferentiated large cell lung cancer, lung 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, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), 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, Wilm's 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; Skeletal tumors, such as: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondrogenic osteoid), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; Nervous system, such as: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma; Gynecological conditions, such as: uterus (endometrial cancer, uterine cancer, endometrial cancer), cervix (cervical cancer, cervical precancerous dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer); Hematopoietic system, such as: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodyplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin conditions, such as: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal glands, for example: neuroblastoma.

[0192] 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 with 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 with 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; (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 includes K-Ras mutations selected from the group consisting of: G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K, and Q61L. In some embodiments, the cancer includes N-Ras mutations selected from the group consisting of: G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer includes H-Ras mutations selected from the group consisting of Q61H and Q61L. In some embodiments, the cancer includes Ras mutations selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer comprises at least two Ras mutations selected from the group consisting of: G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the present invention inhibit multiple Ras mutants. For example, the compounds may inhibit both K-Ras G12C and K-Ras G13C. The compounds may inhibit both N-Ras G12C and K-Ras G12C. The compounds may inhibit both N-Ras G12C and K-Ras G12C. In some embodiments, the compounds may inhibit both K-Ras G12C and K-Ras G12D. In some embodiments, the compounds may inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, the compounds may inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, the compounds of the present invention inhibit Ras WT and one or more additional Ras mutations (e.g., K, H, or N-Ras). WT And K-RasG12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V; K, H or N-Ras WT And H-RasQ61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R; or K, H or N-Ras WTAnd N-Ras (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). In some embodiments, the compounds of the present invention inhibit Ras amp and one or more additional Ras mutations (e.g., K-, H-, or N-Ras). amp And K-Ras 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; K-, H- or N-Ras amp And H-Ras 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; or K-, H- or N-Ras amp And N-Ras 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).

[0193] Methods for detecting Ras mutations are known in the art. These methods include, but are not limited to, direct sequencing and the use of highly sensitive diagnostic assays (using CE-IVD markers), such as those described in Domagala et al., Pol J Pathol 3: 145-164 (2012), which are incorporated herein by full reference, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreenPyro. See also, for example, WO 2020 / 106640.

[0194] In some embodiments, the cancer is non-small cell lung cancer, and the Ras mutation includes a K-Ras mutation, such as K-RasG12C, K-RasG12V, or K-RasG12D. In some embodiments, the cancer is colorectal cancer, and the Ras mutation includes a K-Ras mutation, such as K-RasG12C, K-RasG12V, or K-RasG12D. In some embodiments, the cancer is pancreatic cancer, and the Ras mutation includes a K-Ras mutation, such as K-RasG12D or K-RasG12V. In some embodiments, the cancer is pancreatic cancer, and the Ras mutation includes an N-Ras mutation, such as N-RasG12D. In some embodiments, the cancer is melanoma, and the Ras mutation includes an N-Ras mutation, such as N-RasQ61R or N-RasQ61K. In some embodiments, the cancer is non-small cell lung cancer, and the Ras protein is K-Ras... amp In any of the foregoing, unless otherwise specified, the compound may also inhibit Ras. WT (e.g., K-, H-, or N-Ras) WT ) or Ras amp (e.g., K-, H-, or N-Ras) amp ).

[0195] In some implementations, the cancer includes Ras mutations and STK11. LOF KEAP1, EPHA5, or NF1 mutations. In some embodiments, the cancer is non-small cell lung cancer and contains a K-Ras G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and contains a K-Ras G12C mutation and STK11. LOF Mutations. In some implementations, the cancer is non-small cell lung cancer and contains K-Ras G12C and STK11 mutations. LOF Mutations. In some implementations, the cancer includes K-RasG13C Ras mutations and STK11 mutations. LOFKEAP1, EPHA5, or NF1 mutations. In some embodiments, the cancer is non-small cell lung cancer and contains a K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and contains a K-Ras G12V mutation. In some embodiments, the cancer is colorectal cancer and contains a K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and contains a K-Ras G12D mutation. In some embodiments, the cancer is pancreatic cancer and contains a K-Ras G12V mutation. In some embodiments, the cancer is endometrial cancer and contains a K-Ras G12C mutation. In some embodiments, the cancer is gastric cancer and contains a K-Ras G12C mutation. In any of the foregoing embodiments, the compound may also inhibit Ras WT (e.g., K-, H-, or N-Ras) WT ) or Ras amp (e.g., K-, H-, or N-Ras) amp ).

[0196] 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. The cancer cells may belong to any type of cancer described herein. The cells may be in vivo or in vitro.

[0197] Combination therapy The methods of this invention may include the compounds of this invention used alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). When administered alone, the dose of one or more of the additional therapies (e.g., non-pharmacological treatments or therapeutic agents) may be reduced relative to a standard dose. For example, the dose may be determined empirically based on the combination and arrangement of drugs, or inferred by isoradiometric measurements (e.g., Black et al.). Neurology 65:S3-S6 (2005)).

[0198] The compounds of the present invention may be administered before, after, or simultaneously with one or more of the additional therapies. When combined, the dose of the compounds of the present invention and the dose of the one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). The compounds of the present invention and additional therapies, such as anticancer agents, may be administered together, such as in the form of a single pharmaceutical composition, or separately, and when administered separately, the administration may occur simultaneously or sequentially. Such sequential administration may be proximate or staggered in time.

[0199] In some embodiments, the additional therapy is the administration of a side effect limiter (e.g., an agent intended 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.

[0200] 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 as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, the one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biologics as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors). In other embodiments, the one or more additional therapies include two therapeutic agents. In still other embodiments, the one or more additional therapies include three therapeutic agents. In some embodiments, the one or more additional therapies include four or more therapeutic agents.

[0201] In this section on combination therapies, all references are incorporated by way of citation for the drugs described, whether or not they are explicitly stated.

[0202] Non-drug therapy Examples of non-pharmacological treatments include, but are not limited to, radiotherapy, cryotherapy, hyperthermia, surgery (e.g., surgical removal of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0203] 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.

[0204] 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 by one or a combination of several methods, including but not limited to external beam therapy, internal radiation therapy, implantation radiation, stereotactic radiosurgery, whole-body radiation therapy, radiotherapy, and sustained or transient proximal therapy. As used herein, the term "proximal therapy" refers to radiation therapy delivered by inserting a radioactive material into or near a space defined by a tumor or other proliferative tissue disease site within the body. This term is intended, but is not limited to, 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 radiation sources used as cell conditioning agents of the present invention include solids and liquids. As a non-limiting example, the radioactive source can 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 can also be a fluid made from a solution of any radionuclide, such as a solution of I-125 or I-131, or the radioactive fluid can be prepared using a slurry containing small solid radionuclide particles such as Au-198 or Y-90. Furthermore, the radionuclide can be embedded in a gel or radioactive microspheres.

[0205] In some embodiments, the compounds of the present invention can sensitize abnormal cells to radiotherapy, thereby killing or inhibiting the growth of such cells. Therefore, the present invention further relates to a method for sensitizing abnormal cells in a mammal to radiotherapy, the method comprising administering to the mammal a quantity of the compound of the present invention, the quantity of which effectively sensitizes the abnormal cells to radiotherapy. The amount of the compound in the method may be determined according to the manner used to determine the effective amount of the compound described herein. In some embodiments, the compounds of the present invention can be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0206] 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 the 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 the site of infection, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments of the invention, 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 T cell genes are modified to express the desired protein (e.g., CAR), these T cells can generally 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.

[0207] Therapeutic agents Therapeutic agents can be compounds used to treat cancer or its related symptoms.

[0208] For example, the therapeutic agent 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 cortisol. sone, cortivazol, deflazacort, desonide, deoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortinbutyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasolPropionate, halometasone, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, 25-diethylaminoacetic acid prednisolone, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone Triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0209] Other examples of therapeutic agents that can be used in combination therapies with the compounds of the present invention include compounds described 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.

[0210] Therapeutic agents can be biological agents (e.g., cytokines such as interferon or interleukins like IL-2) used to treat cancer or related symptoms. In some embodiments, the biological agent is an immunoglobulin-based biological agent, 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 an antigen important for cancer. Antibody-drug conjugates are also included.

[0211] The 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, a humanized or fully human antibody. 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 interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is an agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or a fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PDL-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PDL-2 inhibitor or antagonist (e.g., an inhibitory antibody or an Fc fusion or a small molecule inhibitor) (e.g., a PDL-2 / Ig fusion protein). In some implementations, checkpoint inhibitors are inhibitors or antagonists (e.g., inhibitory antibodies or small molecule inhibitors) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In some implementations, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibodies such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or checkpoint inhibitors disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including but not limited to ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0212] Therapeutic agents can be anti-TIGIT antibodies, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0213] Therapeutic agents can be drugs used to treat cancer or related symptoms (e.g., cytotoxic agents, non-peptide small molecules, or other compounds that can be used to treat cancer or related symptoms, collectively referred to as "anticancer agents"). Anticancer agents can be, for example, chemotherapy agents or targeted therapy agents.

[0214] Anticancer agents include mitosis inhibitors, insertional antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complexes, anthrone-substituted urea, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progesterone, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Other anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, the one or more additional therapies comprise two or more anticancer agents. The two or more anticancer agents can be used in a mixture for combined or separate administration. Suitable dosing regimens for combined anticancer agents are known in the art and described, for example, by Saltz et al. Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0215] Other non-limiting examples of anticancer agents include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; and azacyclopropanes such as benzodopa, carboquone, and meturedopa. And uredopa; ethyleneimine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and tris(hydroxymethylmelamine); polyacetyl (especially bulbatacin and bulbatacinone); camptothecin (including its synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin and bizelesin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (Including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin A; spongistatin;Nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, and uracil. Mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as acetylenic antibiotics (e.g., calicheamicin, such as calicheamicin γ-II and calicheamicin ω-II (see example); Agnew, Chem. Intl. Ed Engl.33:183-186 (1994)); dynemicin, such as dynemicin A; bisphosphonates, such as clodronate; esperamicin; neocarzinostatin chromophore and related chromogens, aclacinomysin, actinomycin, autramycin, azaserine, bleomycin, actinomycin C (cactinomycin), calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins, dactinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, adriamycin (doxorubicin), N-morpholinodoxorubicin, cyanomorpholinodoxorubicin, (2-pyrrololino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (e.g., mitomycin C), mycophenolic acid Drugs containing: nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); and folic acid analogues such as denopterin, pteropterin, and trimetrexate.Purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-thiazopyrimidine, carmofur, cytarabine, doxifluridine, enocitabine, and fluxuridine; and androgens, such as calusterone and dromostanolone. Propionate, epitiostanol, mepitiostane, testolactone; anti-adrenergics such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate); epothilone, such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; (2-ethylhydrazine; procarbazine);PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes, such as T-2 toxin, verracurin A, roridin A. A) and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids such as Taxol® (paclitaxel), Abraxane® (a nanoparticle formulation of paclitaxel without polyoxyethylene hydrogenated castor oil and albumin-engineered), and Taxotere® (docetaxel); chloranbucil; tamoxifen. (Nolvadex™); raloxifene; aromatase inhibitor 4(5)-imidazole; 4-hydroxytamoxifen; trioxifene; keoxifene; LY 117018; onapristone; toremifene (Fareston®); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; gemcitabine®; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® (vinorelbine);Novotroxone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperamicins; capecitabine (e.g., Xeloda®); and pharmaceutically acceptable salts of any of the above.

[0216] Additional, non-restricted examples of anticancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicine, abagovomab, and acridine. Carboxamide, adecatumumab, demethoxygeldanamycin, alpharadin, alvocidib, thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antitumor drugs (e.g., cell cycle nonspecific antitumor agents and other antitumor agents described herein), antitumor herbs, apaziquone, atipremod, azathioprine, belotecone, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, butionine sulfoxidesulfoximine), CBV (chemotherapy), calyculin, dichloroacetic acid, discormolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven Laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, naproxen, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, halosporin A (salinosporamide A), sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tri(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0217] Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (e.g., vincristine, vinorelbine, and vinorelbine), epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin / actinomycin D), donomycin, and idarubicin), anthracycline, mitoxantrone, bleomycins, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase, which systemically metabolizes L-asparagine and removes cells that cannot synthesize asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustard (e.g., methicillin, cyclophosphamide, and analogues melphalan and chlorambucil), ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors such as abexilide). maciclib), ribociclib, palbociclib, seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638 and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and similar compounds),And streptozocin), trazenes-dacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites (such as folic acid analogs), pyrimidine analogs (such as fluorouracil, azuridine, and cytarabine), purine analogs and related inhibitors (such as mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (such as anastrozole, exemestane, and letrozole), and platinum coordination complexes (such as cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, amylglutathione, histone deacetylase (HDAC) inhibitors (such as trichostatin, sodium butyrate, apicidan, and suberoylanilide hydroamic acid). The following are listed as potential medications: oxaliplatin, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat; mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus); KSP (Eg5) inhibitors (e.g., Array 520); DNA binding agents (e.g., Zalypsis®); PI3K inhibitors such as PI3K δ inhibitors (e.g., GS-1101 and TGR-1202); PI3K δ and γ inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib; multi-kinase inhibitors (e.g., TG02 and sorafenib); hormones (e.g., estrogens and hormone agonists).Examples of inhibitors include luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38)), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS 953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), and anti-CD138. (e.g., BT062), Torcl / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targets (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists.

[0218] In some implementations, the anticancer agent is selected from methicillin, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any of the aforementioned analogues or derivative variants.

[0219] In some implementations, the anticancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); 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, JNJ-26483327, and JNJ-26483327.

[0220] In some implementations, the anticancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; 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 3-39 of WO05016894.

[0221] In some embodiments, the anticancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., SHP2 inhibitors (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, RLY-1971), an SOS1 inhibitor (e.g., BI-1701963, BI-3406), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., an mTORC1 inhibitor or an mTORC2 inhibitor). In some embodiments, the anticancer agent is JAB-3312. In some embodiments, the anticancer agent is an additional Ras inhibitor (e.g., AMG 510, MRTX1257, MRTX849, ARS-853, ARS-1620, ARS-3248). (or JNJ-74699157, LY3499446) or Ras vaccines or other treatments designed to directly or indirectly reduce the carcinogenic activity of Ras.Other examples of Ras inhibitors that can be combined with the Ras inhibitor of the present invention are provided in the following patents (which are incorporated herein by reference in their entirety): WO2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO 2019241157, WO2019232419, WO 2019217691, WO 2019217307, WO 2019215203, WO 2019213526, WO2019213516, WO 2019155399, WO 2019150305, WO 2019110751, WO 2019099524, WO2019051291, WO 2018218070, WO 2018217651, WO 2018218071, WO 2018218069, WO2018206539, WO 2018143315, WO 2018140600, WO 2018140599, WO 2018140598, WO2018140514, WO 2018140513, WO 2018140512, WO 2018119183, WO 2018112420, WO2018068017, WO 2018064510, WO 2017201161, WO 2017172979, WO 2017100546, WO2017087528, WO 2017058807, WO 2017058805, WO 2017058728, WO 2017058902, WO2017058792, WO 2017058768, WO 2017058915, WO 2017015562, WO 2016168540, WO2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO2014143659 and WO 2013155223.

[0222] In some embodiments, therapeutic agents that can be combined with the compounds of the present invention are MAP kinase (MAPK) pathway inhibitors (or "MAPK inhibitors"). MAPK inhibitors include, but are not limited to, one or more MAPK inhibitors described in Cancer (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. November 25, 2014; 9(11) in; and GSK1120212 (or JTP-74057, described in Clin Cancer Res. March 1, 2011; 17(5):989-1000). MAPK inhibitors may be PLX8394, LXH254, GDC-5573 or LY3009120.

[0223] In some implementations, the anticancer agent is a disruptor or an inhibitor of the RAS-RAF-ERK, PI3K-AKT-TOR, or PI3K-AKT signaling pathway. PI3K / AKT inhibitors may include, but are not limited to, one or more PI3K / AKT inhibitors described in Cancer (Basel) Sep 2015; 7(3): 1758–1784. For example, the PI3K / AKT inhibitor may be selected from one or more of the following: NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.

[0224] In some implementations, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0225] In some implementations, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapy. In some implementations, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0226] IGF-1R inhibitors include linsitinib or its pharmaceutically acceptable salts.

[0227] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of 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 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 can be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999, ibid.) or MabC225 (ATCC accession number HB-8508) or antibodies or antibody fragments that have binding specificity to EGFR.

[0228] Small molecule antagonists of EGFR include gefitinib (Iressa®), 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®). Other non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in the following patent publications, and all pharmaceutically acceptable salts of such EGFR inhibitors: EP 0520722; EP 0566226; WO96 / 33980; U.S. Patent No. 5,747,498; WO96 / 30347; EP0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; WO97 / 49688; EP 837063; WO98 / 02434; WO97 / 38983; WO95 / 19774; WO95 / 19970; WO97 / 13771; WO98 / 02437; WO98 / 02438; WO97 / 32881; DE 19629652; WO98 / 33798; WO97 / 32880; WO97 / 32880; EP 682027; WO97 / 02266; WO97 / 27199; WO98 / 07726; WO97 / 34895; WO96 / 31510; WO98 / 14449; WO98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; U.S. Patent No. 5,789,427; U.S. Patent No. 5,650,415; U.S. Patent No. 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and WO92 / 20642. 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.In some implementations, EGFR inhibitors are ERBB inhibitors. In humans, the ERBB family includes HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0229] MEK inhibitors include, but are not limited to, pimasetinib, selumetinib, 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.

[0230] 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-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyprop-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholino)-8-phenyl-4H-l-benzopyran-4-one (purchased from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinopyridino[3',2':4,5]furano[3,2-d]pyrimidin-2-yl]phenol hydrochloride (purchased from Axon Medchem); PIK 75 (2-Methyl-5-nitro-2-[(6-bromoimidazolo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazine-benzenesulfonic acid monohydrochloride) (purchased from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)nicotinamide) (purchased from Axon Medchem); AS-252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidin-2,4-dione) (purchased from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one) (purchased from Axon Medchem) Medchem); 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.

[0231] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibiting Aktl) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); Akt-1-1,2 (inhibiting Akl and 2) (Barnett et al., Biochem. J. 2005, 385(Pt. 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., US 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).

[0232] 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); Deforolimus (also known as deforolimus or AP23573); Rapamycin analogs, such as those disclosed in WO98 / 02441 and WO01 / 14387, such as AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropionate]-rapamycin (also known as CC1779); 40-epio-(tetrazole)-rapamycin (also known as ABT578); 32-deoxyrapamycin; 16-pentyneoxy-32-( S )-Dihydrorapamycin; derivatives disclosed in WO05 / 005434; U.S. Patents 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842 and 5,256,790, and WO94 / 090101, WO92 / 051 79. Derivatives disclosed in 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 embodiments, the mTOR inhibitor is a bisteric inhibitor (see, for example, WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552.

[0233] BRAF inhibitors that can be used in combination with the compounds of the present invention include, for example, vemurafenib, dabrafenib, and encorafenib. BRAF may contain type 3 BRAF mutations. In some embodiments, the type 3 BRAF mutation is 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.

[0234] MCL-1 inhibitors include, but are not limited to, 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 closely associated with tumor progression and resistance to targeted therapies, not only conventional chemotherapy but also BCL-2 inhibitors such as ABT-263.

[0235] In some implementations, the additional therapeutic agent is an SHP2 inhibitor. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which facilitates a variety of cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in a stable, inactive, self-inhibiting conformation through a binding network involving residues from the N-SH2 and PTP domains. Stimulation with cytokines or growth factors, such as those acting via receptor tyrosine kinases (RTKs), exposes the catalytic site, leading to enzymatic activation of SHP2.

[0236] SHP2 is involved in signal transduction via the RAS-mitogen-activated protein kinase (MAPK) pathway, namely the JAK-STAT or phosphoinositol 3-kinase-AKT pathway. Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human developmental disorders, such as Noonan Syndrome and Leopard Syndrome, and human cancers, such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancers. Some of these mutations destabilize the autoinhibitory conformation of SHP2 and promote autoactivation or enhanced growth factor-driven activation of SHP2. Therefore, SHP2 represents a target of particular interest for developing novel therapies for treating a variety of diseases, including cancer. It has been shown that combinations of SHP2 inhibitors (e.g., RMC-4550 or SHP099) with RAS pathway inhibitors (e.g., MEK inhibitors) can inhibit the proliferation of various cancer cell lines (e.g., pancreatic, lung, ovarian, and breast cancer) in vitro. Therefore, combination therapy involving SHP2 inhibitors and RAS pathway inhibitors can be a general strategy for preventing tumor resistance in a variety of malignancies.

[0237] Non-limiting examples of such SHP2 inhibitors known in the art include: Chen et al., Mol Pharmacol 2006, 70 , 562; Sarver et al., J. Med. Chem. 2017, 62, 1793; Xie et al., J. Med.Chem. 2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734; and PCT applications: WO2015107493; WO2015107494; WO201507495; WO2016203404; WO2016203405; WO2016203406; WO2011022440; WO2017156397; WO2017079723; WO20172113 03; WO2012041524; WO2017211303; WO2019051084; WO2017211303; US20160030594; U S20110281942; WO2010011666; WO2014113584; WO2014176488; WO2017100279; WO201 9051469; US8637684; WO2007117699; WO2015003094; WO2005094314; WO2008124815; WO2009049098; WO2009135000; WO2016191328; WO2016196591; WO2017078499; WO201 7210134; WO2018013597; WO2018129402; WO2018130928; WO20181309928; WO2018136264; WO2018136265; WO2018160731; WO2018172984; and WO2010121212 are each incorporated herein by reference.

[0238] In some embodiments, the SHP2 inhibitor binds to the active site. In some embodiments, the SHP2 inhibitor is a mixed irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, such as a non-covalent allosteric inhibitor. In some embodiments, the SHP2 inhibitor is a covalent SHP2 inhibitor, such as an inhibitor targeting a cysteine ​​residue (C333) located outside the active site of the phosphatase. In some embodiments, the SHP2 inhibitor is a reversible inhibitor. In some embodiments, the SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP2 inhibitor is SHP099. In some embodiments, the SHP2 inhibitor is TNO155. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor is RMC-4630. In some embodiments, the SHP2 inhibitor is JAB-3068. In some embodiments, the SHP2 inhibitor is RLY-1971.

[0239] In some embodiments, the additional therapeutic agent is selected from the group consisting of: MEK inhibitors, HER2 inhibitors, SHP2 inhibitors, CDK4 / 6 inhibitors, mTOR inhibitors, SOS1 inhibitors, and PD-L1 inhibitors. In some embodiments, the additional therapeutic agent is selected from the group consisting of: MEK inhibitors, SHP2 inhibitors, and PD-L1 inhibitors. See, for example, Hallin et al., Cancer Discovery, DOI: 10.1158 / 2159-8290 (October 28, 2019), and Canon et al., Nature, 575:217 (2019). In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PDL-1 inhibitor and an SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PDL-1 inhibitor and an SHP2 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SHP2 inhibitor. In some implementations, the cancer is colorectal cancer, and the treatment comprises administering a combination of the Ras inhibitor of the present invention with a second or third therapeutic agent.

[0240] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0241] Immunotherapy includes, but is not limited to, monoclonal antibodies, immunomodulatory imides (IMiD), GITR agonists, genetically engineered T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTE), and anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA4 agents, anti-LAG1 agents, and anti-OX40 agents.

[0242] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs containing imide groups (drugs that regulate immune responses). IMiD drugs include thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0243] Exemplary anti-PD-1 antibodies and their methods of use are described in Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168A1), and are also described elsewhere in this article.

[0244] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Patent Nos. 6,111,090, 8,586,023, WO2010 / 003118, and WO2011 / 090754; or, for example, U.S. Patent Nos. 7,025,962, EP The anti-GITR antibodies described in U.S. Patent Nos. 1947183, 7,812,135, 8,388,967, 8,591,886, 7,618,632, EP1866339, WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0245] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions synthesized in vitro, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally can be used to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), thereby promoting cell death or arresting cell growth. In some embodiments, one or more additional therapies include an anti-angiogenic agent.

[0246] Anti-angiogenic agents can be MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of anti-angiogenic agents include rapamycin, tesiromixol (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578 and US20090012085, as well as U.S. Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are inhibitors with very low or no MMP-1 inhibitory activity. More preferably, they are inhibitors that selectively inhibit MMP-2 or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors include AG-3340, RO 32-3555, and RS 13-0830.

[0247] Other exemplary anti-angiogenic agents include kinase domain KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding domains that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen-binding domains that specifically bind to VEGF (e.g., bevacizumab) or soluble VEGF receptors or their ligand-binding domains), such as VEGF-TRAP™, as well as anti-VEGF receptor agents (e.g., antibodies or antigen-binding domains that specifically bind to VEGF receptors), EGFR inhibitors (e.g., antibodies or antigen-binding domains that specifically bind to EGFR), such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Ang1 agents and anti-Ang2 agents (e.g., antibodies or antigen-binding domains that specifically bind to Angle and Ang2 or their receptors, such as Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding domains that specifically bind to Tie2 kinase). Other anti-angiogenic agents include Camppath, IL-8, β-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen-binding domains, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM unintegrin domains that antagonize the binding of integrins to their ligands (US2002 / 0042368), and specifically binding anti-eph receptor or anti-pterygium antibodies or anti- The original binding region (US Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124 and members of their patent families), and anti-PDGF-BB antagonists (e.g., specifically bound antibody or antigen-binding regions), and antibody or antigen-binding regions specifically bound to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibody or antigen-binding regions specifically bound to PDGFR kinases). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptaniboctasodium (Gilead Sciences, USA); alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); ilomastat (Arriva, USA, US5892112); and emaxanib (Pfizer, USA, US 5792783).Vatalanib (Novartis, Switzerland); 2-Methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); Anecortave acetate (Alcon, USA); α-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); Anti-Vn Mab (Crucell, Netherlands), DAC anti-angiogenic agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (KyowaHakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); Fibrinogen-E fragment (BioActa, UK); Angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); Maspin (Sosei, Japan); 2-Methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (LaneLabs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02233610); Platelet-4 (RepliGen, USA, EP 407122); Vascular endothelial growth factor antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA);Second-generation α5β3 integrin MAb (Applied Molecular Evolution, USA and Medlmmune, USA); enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived anti-angiogenic agents (XOMA, USA); PI 88 (Progen, Australia); silengitide (MerckKGaA, Germany; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (Boston Children's Hospital, USA); ATN 161 (Attenuon, USA); 2-Methoxyestradiol (Boston Children's Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD2171 (AstraZeneca, UK); Vatalani (pINN) (Novartis, Switzerland and Schering AG, Germany); Tissue Factor Pathway Inhibitor (EntreMed, USA); Pinn (Gilead Sciences, USA); Xanthorrhizol (Yonsei University, South Korea); Gene-based VEGF-2 Vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada);SDX 103 (University of California, San Diego, USA); PX 478 (ProlX, USA); METASTATIN (EntreMed, USA); Troponin I (Harvard University, USA); SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, UK); atipremod (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); angiogenesis vaccine (EntreMed, USA); urokinase plasminogen activator inhibitor (Dendreon, USA). USA); oglufanide (pINN) (Melmotte, USA); HIF-lα inhibitor (Xenova, UK); CEP5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); Angusidin (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); Drug delivery system, intraocular 2-methoxyestradiol; Angnex (Maastricht University, Netherlands, and Minnesota University, USA);ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor necrosis factor-alpha inhibitor; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, α5β (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan); Cobretastatin A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); Irsogladine (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); Squalamine (Genaera, USA); RPI 4610 (Sirna, USA); Heparinase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); and Honokiol (Emory University, USA);ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VE-cadherin-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck&Co, USA); Tie-2 ligand (Regeneron, USA); and thrombin-1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0248] Other examples of therapeutic agents that can be used in combination with the compounds of the present invention include agents that specifically bind to and inhibit the activity of growth factors (e.g., antibodies, antigen-binding domains, or soluble receptors), such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen-binding domains that specifically bind to the receptor c-Met.

[0249] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an autophagy inhibitor. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), 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 RNA or siRNA that inhibits protein expression, including but not limited to ATG5 (involved in autophagy), may also be used. In some embodiments, one or more of the additional therapies include an autophagy inhibitor.

[0250] Another example of a therapeutic agent that can be used in combination with the compounds of the present invention is an antitumor agent. In some embodiments, the one or more additional therapies include an antitumor agent. Non-limiting examples of antitumor agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, aifostine, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, and DA. 3030 (Dong-A), daclizumab, and denileukin Diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, diclofenac (HIT), interferon-alpha, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetinbeta, etoposide phosphate Phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphatephosphate), formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin, imiquimod, interferon α, natural interferon α, interferon α-2, interferon α-2a, interferon α-2b, interferon α-Nl, interferon α-n3, compound interferon-1, natural interferon α, interferon β, interferon β-la, interferon β-lb, interferon γ, natural interferon γ-la, interferon γ-lb), interleukin-1 β, iobenguane, irinotecan, isoladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + Fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoxohydrazone, dibromoceroxyl, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, niluamide, noscapine, novel erythropoietin, NSC631570 Octreotide, Oprelvekin, Osaterone, Oxaliplatin, Pacific Paclitaxel, Pamidronicacid, Pegaspargase, Pegylated Interferon Alpha-2b, Pentosan Polysulfate Sodium, Pentostatin, Picibanil, Birubicin, Rabbit Anti-thymocyte Multiclonal Antibody, Pegylated Interferon Alpha-2a, Porfimer Sodium, Raloxifene, Raltitrexed, Rasburi Embdiment, Rhenium Ethidate Re 186, RII Isotretinoin, Rituximab, Romotide, Lecithin (153) Sm)(samarium lexidronam), sargramostim, sizofiran, sobuzoxane, sonermin, strontium chloride-89, suramin, tasonermin, tazarotene, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131) Trastuzumab, treosulfan, retinoic acid, trilostane, trimetrexate, triptorelin, natural tumor necrosis factor α, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysis product vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC8015 (Dendreon), Decitabine, Dexaminoglutethimide, Diaziquone, EL 532 (Elan), EM 800 (Endorecherche), Eniluracil, Etanidazole, Fenretinide, Filgrastim, SD01 (Amgen), Fulvestrant, Galocitabine, Gastrin-17 Immunogen, HLA-B7 Gene Therapy (Vical), Granulocyte Macrophage Colony Stimulating Factor, Histamine Dihydrochloride, Ibrimomab Tiuxetan, Ilomastat, IM 862 (Cytran), Interleukin-2, Iproxifene, LDI 200 (Milkhaus), Leridistim, Lintuzumab, CA 125 MAb (Biomira), Cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), Idiotype 105AD7 MAb (CRC Technology), Idiotype CEA MAb (Trilex), LYM-1-Iodine-131 MAb (Techni clone), Polymorphic Epithelial Mucin-Yttrium-90 MAb (Antisoma), Marimastat, Menogaril, Mitumomab, Motexafin Gadolinium, MX 6 (Galderma), Nelarabine, Nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL172 (SR Pharma), SU 5416 (SUGEN), TA 077(Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyletiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysis product vaccine (New York Medical College), viral melanoma cell lysis product vaccine (Royal Newcastle Hospital), or valspodar.

[0251] Additional examples of therapeutic agents that can be used in combination with the compounds of the present invention include ipilimumab (Yervoy®); trimemumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; and anti-OX40 (Providence Health). Services); huMAbOX40L; atacivib; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP 224; adalimumab (Humira®); ado-trastuzumab emtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); Baliximab (Simulect®); Belimumab (Benlysta®); Brentuximab vedotin (Adcetris®); Canakinumab (Ilaris®); Certolizumab pegol (Cimzia®); Zenapax®; Daratumumab (Darzalex®); Denosumab (Prolia®); Eculizumab (Soliris®); Efalizumab (Raptiva®); Gemtuzumab ozogamicin (Mylotarg®); Golimumab (Simponi®);Ibrimomab tiuxetan (Zevalin®); infliximab (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); ofatumumab (Arzerra®); omalizumab (Xolair®); palivizumab (Synagis®); pertuzumab (Perjeta®); pertuzumab (Perjeta®); ranibizumab (Lucentis®); raxibacumab (Abthrax®); Tocilizumab (Actemra®); Tositumomab; Tositumomab-i-131; Tositumomab and Tositumomab-i-131 (Bexxar®); Utekinumab (Stelara®); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0252] Depending on the condition being treated, the compounds described herein may be used in combination with the pharmaceutical agents disclosed herein or other suitable pharmaceutical agents. Therefore, in some embodiments, one or more compounds of this disclosure will be administered co-administered with other therapies described herein. When used in combination therapy, the compounds described herein may be administered simultaneously or separately with a second pharmaceutical agent. This combination administration may include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein may be formulated together with any pharmaceutical agent described herein into the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention may be administered simultaneously with any therapy described herein, wherein the two agents are present in separate formulations. In another alternative, the compounds of this disclosure may be administered first, followed by any therapy described herein, or vice versa. In some embodiments of the separate administration regimen, the compounds of the present invention and any therapy described herein are administered at intervals of minutes, hours, or days.

[0253] In some embodiments of any of the methods described herein, a first therapy (e.g., the compound of the present invention) and one or more additional therapies are administered simultaneously or sequentially in any order. The first therapeutic agent may be administered immediately before or after the administration of the one or more additional therapies, for up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7 days, 1-14 days, 1-21 days, or 1-30 days.

[0254] The invention is further characterized by a kit comprising (a) a pharmaceutical composition comprising the agents described herein (e.g., compounds of the present invention) and (b) a packaging insert with instructions on performing any of the methods described herein. In some embodiments, the kit comprises (a) a pharmaceutical composition comprising the agents described herein (e.g., compounds of the present invention), (b) one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents), and (c) a packaging insert with instructions on performing any of the methods described herein.

[0255] Since one aspect of the invention covers the treatment of diseases or their related symptoms with combinations of separately administerable pharmaceutically active compounds, the invention also relates to the combination of independent pharmaceutical compositions in the form of a kit. The kit may contain two independent pharmaceutical compositions: the compound of the invention and one or more additional therapies. The kit may include a container for containing the independent compositions, such as a dispensing vial or a dispenser foil package. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit may include instructions on the use of the independent components. The kit format is particularly advantageous when the independent components are preferably administered in different dosage forms (e.g., oral or parenteral), at different dose intervals, or when the prescribing healthcare professional wishes to adjust the individual components in the combination.

[0256] Implementation plan with numbering [1] A compound or a pharmaceutically acceptable salt thereof having the structure of formula I: Formula I The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heteroarylene; B is -CH(R) 9 - or > C = CR 9 R 9’ In which carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R) 6 )-, where C binds to -C(R) 7 R 8 )-;-C(O)NH-CH(R 6 )-, where C binds to -C(R) 7 R 8 )-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2Y 3 Y 4 and Y 7 Independently C or N; Y 5 It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 1 It is a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 6-membered cycloalkenyl group, an optionally substituted 3- to 6-membered heterocycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 It combines with the atoms it is attached to to form optional substituted 3- to 14-membered heterocyclic alkyl groups; R 2 It is absent, hydrogen, optionally substituted C1-C6 alkyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3 to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optional substituted C1-C6 alkyl group; R 10 It is hydrogen, halogenated, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R 10a It is hydrogen or halogenated; R 11 It is hydrogen or C1-C3 alkyl; and R 34It is hydrogen or C1-C3 alkyl.

[0257] [2] The compound as described in paragraph [1] or a pharmaceutically acceptable salt thereof, wherein G is an optionally substituted C1-C4 heteroalkylene.

[0258] [3] The compound or a pharmaceutically acceptable salt thereof as described in paragraph [1] or [2], wherein the compound has the structure of formula Ia: Formula Ia The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 )-, where carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y4 and Y 7 Independently C or N; Y 5 and Y 6 Independently CH or N; R 1 It is cyano, 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. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl. R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R 11 It is hydrogen or C1-C3 alkyl.

[0259] [4] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [3], wherein X 2 It is NH.

[0260] [5] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [4], wherein X 3 It is CH.

[0261] [6] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [5], wherein R 11 It is hydrogen.

[0262] [7] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [5], wherein R 11 It is a C1-C3 alkyl group.

[0263] [8] The compound or a pharmaceutically acceptable salt thereof as described in paragraph [7], wherein R 11 It is a methyl group.

[0264] [9] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [6], wherein the compound has the structure of formula Ib: Formula Ib The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5 and Y 6 Independently CH or N; R 1 It is cyano, 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. R 2It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; and R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl.

[0265]

[10] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] through [9], wherein X 1 It is an optional substituted C1-C2 alkylene group.

[0266]

[11] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[10] , wherein X 1 It is methylene.

[0267]

[12] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[11] , wherein R 5 It is hydrogen.

[0268]

[13] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[11] , wherein R 5 It is a C1-C4 alkyl group that can be optionally substituted with a halogen.

[0269]

[14] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[13] , wherein R 5 It is a methyl group.

[0270]

[15] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[14] , wherein Y 4 It's C.

[0271]

[16] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[15] , wherein R 4 It is hydrogen.

[0272]

[17] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] through

[16] , wherein Y 5 It is CH.

[0273]

[18] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] through

[17] , wherein Y 6 It is CH.

[0274]

[19] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] through

[18] , wherein Y 1 It's C.

[0275]

[20] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] through

[19] , wherein Y 2 It's C.

[0276]

[21] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] through

[20] , wherein Y 3 It is N.

[0277]

[22] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[21] , wherein R 3 It does not exist.

[0278]

[23] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[22] , wherein Y 7 It's C.

[0279]

[24] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to [6] or [9] to

[23] , wherein the compound has the structure of formula Ic: Formula Ic Where A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; R 1It is cyano, 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. R 2 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; and R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl.

[0280]

[25] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[24] , wherein R 6 It is hydrogen.

[0281]

[26] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[25] , wherein R 2 It is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl.

[0282]

[27] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[26] , wherein R 2 It is an optional substituted C1-C6 alkyl group.

[0283]

[28] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[27] , wherein R 2 It is an ethyl group.

[0284]

[29] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] through

[28] , wherein R 7 It is an optional substituted C1-C3 alkyl group.

[0285]

[30] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[29] , wherein R 7 It is a C1-C3 alkyl group.

[0286]

[31] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] through

[30] , wherein R 8 It is an optional substituted C1-C3 alkyl group.

[0287]

[32] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[31] , wherein R 8 It is a C1-C3 alkyl group.

[0288]

[33] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[32] , wherein the compound has the structure of formula Id: FormulaId Where A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; R 1 It is cyano, 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. R 2 It is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; and R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl.

[0289]

[34] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[33] , wherein R 1 It consists of 5 to 10 heteroaryl compounds.

[0290]

[35] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[34] , wherein R 1 It is either a 6-membered aryl group that is optionally substituted or a 6-membered heteroaryl group that is optionally substituted.

[0291]

[36] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[35] , wherein the compound has the structure of formula Ie: Formula Ie Where A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; R 2 It is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; and R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl. X e and X f Independently N or CH; and R 12It is an optional substituted C1-C6 alkyl or optional substituted C1-C6 heteroalkyl, or an optional substituted 3- to 7-membered heterocyclic alkyl.

[0292]

[37] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[36] , wherein X e It is N, and X f It is CH.

[0293]

[38] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[36] , wherein X e It is CH, and X f It is N.

[0294]

[39] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[36] to

[38] , wherein R 12 It is an optional substituted C1-C6 heteroalkyl group.

[0295]

[40] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs

[36] to

[39] , wherein R 12 yes , or .

[0296]

[41] The compound or a pharmaceutically acceptable salt thereof as described in paragraph [1] or [2], wherein the compound has the structure of formula VI: Style VI The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 3 to 6-membered heterocyclic alkyl; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heteroarylene; B is -CH(R) 9 - or > C = CR 9 R 9’ In which carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R) 6 )-, where C binds to -C(R) 7R 8 )-;-C(O)NH-CH(R 6 )-, where C binds to -C(R) 7 R 8 )-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5 It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 2 It is absent, hydrogen, optionally substituted C1-C6 alkyl, 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; R 3 Does not exist, or R 2 and R 3It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR 7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3 to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optional substituted C1-C6 alkyl group; R 10 It is hydrogen, halogenated, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; R 10a It is hydrogen or halogenated; R 11 It is hydrogen or C1-C3 alkyl; R 34 It is hydrogen or C1-C3 alkyl; and X e and X f It can be either N or CH.

[0297]

[42] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[41] , wherein the compound has the structure of formula VIa: VIA Wherein A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W represents a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, and borate esters. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; R 2 It is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; and R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl. X e and X f Independently N or CH; R 11 It is hydrogen or C1-C3 alkyl; and R 21 It is hydrogen or C1-C3 alkyl.

[0298]

[43] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[41] or

[42] , wherein the compound has the structure of formula VIb: Formula VIb Wherein A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W represents a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, and borate esters. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; R9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; and X e and X f It can be either N or CH.

[0299]

[44] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[43] , wherein A is an optionally substituted 6-membered aryl group.

[0300]

[45] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[44] , wherein A has the following structure: Where R 13 It is hydrogen, hydroxyl, amino, optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl.

[0301]

[46] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[45] , wherein R 13 It is hydrogen.

[0302]

[47] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[45] , wherein R 13 It is a hydroxyl group.

[0303]

[48] ​​The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] through

[47] , wherein B is -CHR 9 -

[0304]

[49] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[48] , wherein R 9 It is an optional substituted C1-C6 alkyl or an optional substituted 3- to 6-membered cycloalkyl.

[0305]

[50] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[49] , wherein R 9 yes .

[0306]

[51] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[50] , wherein R 9 yes .

[0307]

[52] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[47] , wherein B is an optionally substituted 6-membered aryl group.

[0308]

[53] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[52] , wherein B is a 6-membered aryl group.

[0309]

[54] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[53] , wherein B is: .

[0310]

[55] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[54] , wherein R 7 It is a methyl group.

[0311]

[56] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[55] , wherein R 8 It is a methyl group.

[0312]

[57] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[56] , wherein the linker is a structure of formula II: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Formula II Where A 1 It is the key between the connector and B; A 2 It is the key between W and the connector; B 1 B 2 B 3 and B 4 Each is independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NR. N ;R N It is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl; C 1 and C 2 Each is independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl groups; f, g, h, i, j, and k are each independently 0 or 1; and D 1The C1-C that can be arbitrarily replaced. 10 Alkylene, optionally substituted C2-C 10 alkenyl groups, optionally substituted C2-C 10 Alynyl group, optionally substituted 3- to 14-membered heterocyclic alkyl group, optionally substituted 5- to 10-membered heteroaryl group, optionally substituted 3- to 8-membered heterocyclic alkyl group, optionally substituted 6- to 10-membered aryl group, optionally substituted C2-C group 10 Polyethylene glycol or optionally substituted C1-C 10 Heteroalkyl, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -Connected to -(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 Chemical bonds.

[0313]

[58] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[57] , wherein the linker is acyclic.

[0314]

[59] The compound as described in paragraph

[58] or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of formula IIa: Formula IIa Where X a It either does not exist or is N; R 14 It is a C1-C6 alkyl group that is absent, contains hydrogen, or is optionally substituted; and L 2 It is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene. Where X a R 14 or L 2 At least one of them does not exist.

[0315]

[60] The compound as described in paragraph

[59] or a pharmaceutically acceptable salt thereof, wherein the linker has the following structure: .

[0316]

[61] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[57] , wherein the linker is or comprises a cyclic group.

[0317]

[62] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[57] or

[61] , wherein the linker has the structure of formula IIb: Formula IIb Where o is 0 or 1; R 15 It is hydrogen or an optional substituted C1-C6 alkyl group; Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heteroalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroalkylene; and L 3 It is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene.

[0318]

[63] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[62] , wherein the linker has the following structure: .

[0319]

[64] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[63] , wherein W comprises carbodiimide.

[0320]

[65] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[64] , wherein W has the structure of formula IIIa: Formula IIIa Where R 14It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 8-membered cycloalkyl, an optional substituted 6- to 10-membered aryl, an optional substituted 3- to 14-membered heterocycloalkyl, or an optional substituted 5- to 10-membered heteroaryl.

[0321]

[66] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[65] , wherein W has the following structure: .

[0322]

[67] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[63] , wherein W comprises oxazoline or thiazoline.

[0323]

[68] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[67] , wherein W has the structure of formula IIIb: Formula IIb Where X 1 Is it O or S? X 2 Does not exist or NR 19 ; R 15 R 16 R 17 and R 18 Independently hydrogen or optionally substituted C1-C6 alkyl; and R 19 It is hydrogen, C(O) (optionally substituted C1-C6 alkyl), optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocyclic alkyl, or optionally substituted 5- to 10-membered heteroaryl.

[0324]

[69] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[68] , wherein W is .

[0325]

[70] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[63] , wherein W comprises chloroethylurea, chloroethylthiourea, chloroethyl carbamate or chloroethyl thiocarbamate.

[0326]

[71] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[70] , wherein W has the structure of formula IIIc: Formula IIIc Where X 3 Is it O or S? X 4 It is O, S, NR 26 ; R 21 R 22 R 23 R 24 and R 26 Independently hydrogen or optionally substituted C1-C6 alkyl; and R 25 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocyclic alkyl, or optionally substituted 5- to 10-membered heteroaryl.

[0327]

[72] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[71] , wherein W is .

[0328]

[73] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[63] , wherein W comprises aziridine.

[0329]

[74] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[73] , wherein W has the structure of formula IIId1, IIId2, IIId3 or IIId4: Where X 5 Does not exist or NR 30 ; Y is absent or is C(O), C(S), S(O), SO2 or optionally substituted C1-C3 alkylene groups; R 27 It is hydrogen, -C(O)R 32 -C(O)OR 32 -SO2R 33 -SOR 33 Optionally substituted C1-C6 alkyl, Optionally substituted 6- to 10-membered aryl, Optionally substituted 3- to 14-membered heterocyclic alkyl or Optionally substituted 5- to 10-membered heteroaryl; R 28 and R 29 Independently hydrogen, CN, C(O)R 31 CO2R 31 C(O)R 31 R 31Optionally substituted C1-C6 alkyl, Optionally substituted 3- to 10-membered cycloalkyl, Optionally substituted 6- to 10-membered aryl, Optionally substituted 3- to 14-membered heterocycloalkyl or Optionally substituted 5- to 10-membered heteroaryl; Each R 31 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocyclic alkyl, or optionally substituted 5- to 10-membered heteroaryl; R 30 It is hydrogen or an optionally substituted C1-C6 alkyl group; and R 32 and R 33 Independently, it is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 14-membered heterocyclic alkyl, or optionally substituted 5- to 10-membered heteroaryl.

[0330]

[75] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[73] or

[74] , wherein W is: .

[0331]

[76] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[63] , wherein W comprises an epoxide.

[0332]

[77] The compound or a pharmaceutically acceptable salt thereof as described in paragraph

[76] , wherein W is .

[0333]

[78] A compound from Table 1 or Table 2 or a pharmaceutically acceptable salt thereof.

[0334]

[79] A pharmaceutical composition comprising a compound as described in any one of paragraphs [1] to

[78] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0335]

[80] A conjugate or a salt thereof, comprising the structure of formula IV: MLP Formula IV Where L is the connector; P is the monovalent organic fraction; and M has the structure of formula V: Formula V The dashed lines represent zero, one, two, three, or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, in which the amino nitrogen is bound to -CH(R) 10 The carbon atom of )-; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 3 to 6-membered heterocyclic alkyl group; optionally substituted 6-membered arylene group; or optionally substituted 5 to 6-membered heteroarylene group; B is -CH(R) 9 - or > C = CR 9 R 9’ In which carbon is bonded to -N(R) 11 The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 3- to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; G is an optionally substituted C1-C4 alkylene group; an optionally substituted C1-C4 alkenyl group; an optionally substituted C1-C4 heteroalkylene group; -C(O)O-CH(R) 6 )-, where C binds to -C(R) 7 R 8 )-;-C(O)NH-CH(R 6 )-, where C binds to -C(R) 7 R 8 )-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; X 3 It is N or CH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; Y 1 It is C, CH, or N; Y 2 Y 3 Y 4 and Y 7 Independently C or N; Y 5It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 1 It is a cyano group, an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, an optionally substituted 3- to 6-membered cycloalkenyl group, an optionally substituted 3- to 6-membered heterocycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 It combines with the atoms it is attached to to form optional substituted 3- to 14-membered heterocyclic alkyl groups; R 2 It is absent, hydrogen, optionally substituted C1-C6 alkyl, 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; R 3 Does not exist, or R 2 and R 3 It combines with the atoms to which it is attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; R 4 It is a methyl group that is absent, hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, C1-C4 alkyl, cyano, hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 8 It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7 and R 8 It combines with the carbon atom it is attached to to form C=CR7’ R 8’ C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3- to 6-membered cycloalkyl; or optionally substituted 3- to 7-membered heterocycloalkyl; R 7a and R 8a It is independently hydrogen, halogenated, optionally substituted C1-C3 alkyl, or combined with the carbon to which it is attached to form a carbonyl group; R 7’ It is hydrogen, halogen, or optionally substituted C1-C3 alkyl; R 8’ It is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R 7’ and R 8’ It combines with the carbon atoms to which it is attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl; R 9 It is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heteroalkyl, or R 9 L and the atoms to which they are attached combine to form optionally substituted 3 to 14-membered heterocyclic alkyl groups; R 9’ It is hydrogen or an optional substituted C1-C6 alkyl group; R 10a It is hydrogen or halogenated; R 11 It is hydrogen or C1-C3 alkyl; and R 34 It is hydrogen or C1-C3 alkyl.

[0336]

[81] The conjugate or its salt as described in paragraph

[80] , wherein M has the structure of formula Vc: Vc Wherein A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene. B is -CH(R) 9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; X 1 It can be an optional C1-C2 alkylene group, NR, O, or S(O). n ; X 2 It is O or NH; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; Each R ’ Independently H or optionally substituted C1-C4 alkyl; X e and X f Independently N or CH; R 2 It is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R 7 It is a C1-C3 alkyl group; R 8 It is a C1-C3 alkyl group; and R 9 It is an optional substituted C1-C6 alkyl, an optional substituted C1-C6 heteroalkyl, an optional substituted 3- to 6-membered cycloalkyl, or an optional substituted 3- to 7-membered heteroalkyl. R 11 It is hydrogen or C1-C3 alkyl; and R 34 It is hydrogen or C1-C3 alkyl.

[0337] In some embodiments of the compounds of the present invention, X e It is N, and X f It is CH. In some implementations, X e It is CH, and X f It is N.

[0338]

[82] Conjugates or salts thereof as described in paragraphs

[80] or

[81] , wherein M has the structure of formula Vd: Vd Wherein A is an optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 3 to 6-membered heterocyclic alkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L either does not exist or is a connector; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, azacyclopropane, trifluoromethyl ketone, boric acid, borate esters, etc. N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enoses; R 9 It is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heteroalkyl; and X e and X f It can be either N or CH.

[0339]

[83] The conjugate or salt thereof as described in any one of paragraphs

[80] to

[82] , wherein the linker has the structure of Formula II: A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Formula II Where A 1 It is the key between the connector and B; A 2 It is the bond between P and the connector; B 1 B 2 B 3 and B 4 Each is independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NR. N ;R NIt is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, optionally substituted 3- to 14-membered heterocyclic alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl; C 1 and C 2 Each is independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl groups; f, g, h, i, j, and k are each independently 0 or 1; and D 1 The C1-C that can be arbitrarily replaced. 10 Alkylene, optionally substituted C2-C 10 alkenyl groups, optionally substituted C2-C 10 Alynyl group, optionally substituted 3- to 14-membered heterocyclic alkyl group, optionally substituted 5- to 10-membered heteroaryl group, optionally substituted 3- to 8-membered heterocyclic alkyl group, optionally substituted 6- to 10-membered aryl group, optionally substituted C2-C group 10 Polyethylene glycol or optionally substituted C1-C 10 Heteroalkyl, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -Connected to -(B 3 ) i -(C 2 ) j -(B 4 ) k –A 2 Chemical bonds.

[0340]

[84] The conjugate or salt thereof as described in any one of paragraphs

[80] to

[83] , wherein the monovalent organic portion is a protein.

[0341]

[85] The conjugate or its salt as described in paragraph

[84] , wherein the protein is Ras protein.

[0342]

[86] The conjugate or its salt as described in paragraph

[85] , wherein the Ras protein is K-Ras G12D or K-Ras G13D.

[0343]

[87] A conjugate or salt thereof as described in any one of paragraphs

[80] to

[86] , wherein the linker is bonded to the monovalent organic moiety by a bond to the carboxyl group of an amino acid residue of the monovalent organic moiety.

[0344]

[88] A method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, as described in any one of paragraphs [1] to

[78] , or a pharmaceutical composition as described in paragraph

[79] .

[0345]

[89] The method described in paragraph

[88] , wherein the cancer is pancreatic cancer, non-small cell lung cancer, colorectal cancer or endometrial cancer.

[0346]

[90] The method described in paragraphs

[88] or

[89] , wherein the cancer contains a Ras mutation.

[0347]

[91] The method as described in paragraph

[90] , wherein the Ras mutation is K-Ras G12D or K-Ras G13D.

[0348]

[92] A method of treating a subject with Ras protein-related disease, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to

[78] or a pharmaceutical composition as described in paragraph

[79] .

[0349]

[93] A method for inhibiting Ras protein in cells, the method comprising contacting the cells with an effective amount of a compound as described in any one of paragraphs [1] to

[78] or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in paragraph

[79] .

[0350]

[94] The method as described in paragraph

[92] or

[93] , wherein the Ras protein is K-Ras G12D or K-Ras G13D.

[0351]

[95] The method described in paragraphs

[93] or

[94] , wherein the cell is a cancer cell.

[0352]

[96] The method described in paragraph

[95] wherein the cancer cells are pancreatic cancer cells, non-small cell lung cancer cells, colorectal cancer cells or endometrial cells.

[0353]

[97] The method or use as described in any one of paragraphs

[88] to

[96] , wherein the method further includes the administration of additional anticancer therapy.

[0354]

[98] The method described in paragraph

[97] , wherein the additional anticancer 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.

[0355]

[99] The method described in paragraph

[97] or

[98] , wherein the additional anticancer therapy is an SHP2 inhibitor. Example

[0356] This disclosure will be further illustrated by the following examples and synthetic embodiments, which should not be construed as limiting the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the provided embodiments are intended to illustrate certain implementations and are not intended to limit the scope of this disclosure. It should also be understood that various other implementations, modifications, and equivalents conceived by those skilled in the art may also be invoked without departing from the spirit of this disclosure or the scope of the appended claims.

[0357] Chemical synthesis The following examples and definitions used elsewhere in this document are as follows: instrument Mass spectrometry data acquisition was performed using a Shimadzu LCMS-2020 or Waters Acquity UPLC equipped with a QDa detector or SQ detector 2. Samples were injected into a C-18 reversed-phase column to remove the assay buffer and prepare samples for mass spectrometry. Compounds were eluted from the column using an acetonitrile gradient and fed into the mass analyzer. Initial data analysis was performed using a Shimadzu LabSolutions or Waters MassLynx. NMR data were collected using a Bruker AVANCE IIIHD 400MHz or Bruker Ascend 500MHz instrument, and raw data were analyzed using TopSpin or MestrelabMnova.

[0358] Synthetic intermediates Intermediate 1. Synthesis of 3-(5-bromo-1-ethyl-2-[2-[(1 S [1-Methoxyethyl]pyridin-3-yl]indol-3-yl)-2,2-dimethylprop-1-ol Step 1: Synthesis of 1-(5-bromo-1H -indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylprop-1-one Under a nitrogen atmosphere, at 0°C, a 1M SnCl4 solution (137 mL, 137 mmol) was slowly added to a mixture of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionyl chloride (65 g, 137 mmol, crude) in DCM (120 mL). The mixture was stirred at 0°C for 30 minutes, followed by dropwise addition of 5-bromo-1-dimethylpropionyl chloride. H A solution of 1-(5-bromo-1-indole) (26.8 g, 137 mmol) in DCM (40 mL) was prepared. The mixture was stirred at 0 °C for 45 min, then diluted with EtOAc (300 mL), washed with brine (4 × 100 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1-(5-bromo-1-indole). H (-Indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylprop-1-one ...

Claims

1. A compound selected from: 。 2. The compound of claim 1, wherein the compound has the following structure: 。 3. The compound of claim 1, wherein the compound has the following structure: 。 4. The compound of claim 1, wherein the compound has the following structure: 。 5. The compound of claim 1, wherein the compound has the following structure: 。 6. The compound of claim 1, wherein the compound has the following structure: 。 7. The compound of claim 1, wherein the compound has the following structure: 。

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