RAS inhibitors

Abstract

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

Description

[0001] This application is a divisional application of the invention patent application filed on July 22, 2022, with application number 202080076129.4 and invention title "RAS Inhibitor".

[0002] Cross-reference to related applications This application claims priority to U.S. Application No. 62 / 930,355, filed November 4, 2019; U.S. Application No. 62 / 951,652, filed December 20, 2019; U.S. Application No. 63 / 000,357, filed March 26, 2020; U.S. Application No. 63 / 011,636, filed April 17, 2020; and U.S. Application No. 63 / 043,588, filed June 24, 2020, all of which are hereby incorporated by reference 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 known as statins bind to the active site of HMG-CoA reductase, preventing the enzyme from binding to its substrate. The fact that many such drug / target interactions are known might mislead some into believing that small molecule regulators targeting most (if not all) proteins can be discovered, providing a reasonable amount of time, effort, and resources. But this is far from the case. Currently, it is estimated that only about 10% of all human proteins are targetable by small molecules. (Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019)). The other 90% are currently considered incurable or intractable for small molecule drug discovery. These targets are often referred to as “undruggable.” These undruggable targets comprise a vast and largely unexplored reservoir of medically important human proteins. Therefore, there is great interest in discovering new 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 a variety of human cancers and are therefore suitable targets for anticancer therapies. In fact, approximately 30% of all human cancers in the United States are caused by Ras protein mutations, many of which are fatal. Dysregulation of Ras proteins through activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations in 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, and it can be activated even in the presence of such low nucleotide concentrations. Mutations at codon 13 (e.g., G13D) and codon 61 (e.g., Q61K) in Ras also cause 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 drugs 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: a target protein (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 formed therewith, exert an 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 provides a compound of structural formula I or a pharmaceutically acceptable salt thereof: 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heteroarylene; B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9' or >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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; 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 is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, acetal, haloacetal or acetal sulfone; X 1 It is optionally substituted with a 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 ynyl, 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 Y3 Y 4 and Y 7 It can be either C or N independently; 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, optionally substituted C1-C6 alkyl group, optionally substituted C1-C6 heteroalkyl group, optionally substituted 3- to 6-membered cycloalkyl group, optionally substituted 3- to 6-membered cycloalkenyl group, optionally substituted 3- to 6-membered heterocycloalkyl group, optionally substituted 6- to 10-membered aryl group, or optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 Together with the atoms to which they are attached, they form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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, a halogen, an optionally substituted C1-C3 alkyl group, 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 H, 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 optionally substituted C1-C6 alkyl; or R 9 and R 9' It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R 10a It is hydrogen or a halogen group; R 11 It is hydrogen or C1-C3 alkyl; and R 21 It is hydrogen or a C1-C3 alkyl group (e.g., methyl).

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

[0009] A further provided conjugate or 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: 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-membered heteroarylene; B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9' or >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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; 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 1It is optionally substituted with a 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 ynyl, 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 It can be either C or N independently; 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, optionally substituted C1-C6 alkyl group, optionally substituted C1-C6 heteroalkyl group, optionally substituted 3- to 6-membered cycloalkyl group, optionally substituted 3- to 6-membered cycloalkenyl group, optionally substituted 3- to 6-membered heterocycloalkyl group, optionally substituted 6- to 10-membered aryl group, or optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 Together with the atoms to which they are attached, they form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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, a halogen, an optionally substituted C1-C3 alkyl group, 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 H, 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 optionally substituted C1-C6 alkyl; or R 9 and R 9' It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R 10a It is hydrogen or a halogen group; R 11 It is hydrogen or C1-C3 alkyl; and R 21 It is an H or C1-C3 alkyl group.

[0010] A method for treating cancer in a subject in need is also provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt 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 further 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, any limitations set forth with respect to one embodiment of the invention may be applied to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or utilize any compound or composition of the invention. Attached Figure Description

[0014] Figure 1A and Figure 1B These figures illustrate that H was (in two different cell-based assays) SPaired analysis of the potency of certain inventive compounds (formula BB) (top right) and corresponding compounds (top left) of formula AA, substituted by Me. The y-axis represents pERK EC50 as measured in the H358 cell line. Figure 1A ) or CTG IC50 ( Figure 1B ).

[0015] Figure 2A and Figure 2B In an NSCLC (KRAS G12C) xenograft model, the compound of this invention, compound A, induced significant regression in vivo. Some animals exhibited a complete response (CR) of 3 consecutive tumor measurements ≤ 30 mm3. Figure 2A This study demonstrates that daily oral administration of 100 mg / kg of compound A via tube feeding induced tumor regression in the NCI-H358 KRASG12C xenograft model, a model sensitive to KRASG12C inhibition alone. A spaghetti titer plot showing individual tumor growth is also included. Figure 2B ) shown in the tumor volume map ( Figure 2A )back.

[0016] Figure 3A and Figure 3B In the NSCLC (KRAS G12C) model, the combination of the compound of the present invention, namely compound B, with the MEK inhibitor cobimetinib caused tumor xenograft regression. Figure 3A The study showed that intermittent intravenous administration of compound B combined with daily oral administration of 2.5 mg / kg cobimetinib induced tumor regression, while each single agent induced tumor growth inhibition. The study ended with a waterfall plot (…). Figure 3B The figure shows that 6 out of 10 mice in the combination group experienced tumor regression, while no tumor regression was recorded in any of the single-drug groups.

[0017] Figure 4A and Figure 4B In an NSCLC (KRAS G12C) model, weekly administration of the compound of this invention, compound C, and daily administration of the SHP2 inhibitor RMC-4550 induced xenograft regression. Figure 4A The study demonstrated the combined activity of weekly intravenous administration of 60 mg / kg compound C plus daily oral administration of 30 mg / kg SHP2 inhibitor. The end-of-life response in individual tumor studies was measured using a waterfall plot. Figure 4B Draw it out.

[0018] Figure 5In a long-term cell growth NSCLC (KRAS G12C) model, the combination of the compound of the present invention, namely compound D, with the MEK inhibitor trametinib, persistently inhibited in vitro growth.

[0019] Definitions and chemical terms In this application, unless the context clearly indicates otherwise, (i) the term “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 that is 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.

[0020] As used herein, the term "about" is used to indicate that a value includes the standard deviation of the error of the apparatus or method used to determine the 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).

[0021] As used in this article, in the context of describing adjacent atoms, the term "adjacent" refers to divalent atoms directly connected by covalent bonds.

[0022] As used herein, “compounds of the 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 in Tables 1 and 2, and their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including transisomers) and tautomers.

[0023] 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).

[0024] Those skilled in the art will understand that certain compounds described herein may exist in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, transisomers, tautomers) or isotopic forms (e.g., one or more atoms are substituted with different isotopes of said atoms, such as hydrogen being substituted with deuterium). Unless otherwise indicated or clearly apparent from the context, the depicted structures are to be understood as representing any such isomeric or isotopic forms, individually or in combination.

[0025] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are covered. Compounds of this disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are 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.

[0026] 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 exchanging 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 proton-transfer tautomerism include keto-enol pairs, amide-imine pairs, lactam-lactamimide pairs, amide-imine pairs, enamine-imine pairs, and cyclic forms, in which the proton may occupy two or more positions in the heterocyclic system, such as 1H-imidazolium and 3H-imidazolium, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. In some embodiments, the tautomerism may be in equilibrium or spatially locked into one form through appropriate substitution. In some embodiments, the tautomerism is obtained from the interconversion of acetals.

[0027] 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, for example...2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P, 33 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. 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 due to their ease of preparation and detectability. Additionally, heavier isotopes, such as deuterium (i.e.,...), are also 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 is replaced, or one or more carbon atoms are replaced. 13 C or 14 Carbon enrichment is replaced by C-rich carbon. Positron-emitting isotopes, for example... 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.

[0028] 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.

[0029] Throughout this specification, substituents of the compounds disclosed herein are disclosed in groups or ranges. Specifically, this disclosure is intended to cover each individual combination of members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended 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 in groups or ranges at said 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.

[0030] The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein the alkyl is optionally substituted”). It is not intended to imply that the characteristic “X” (e.g., alkyl) itself is optional. As described herein, certain target compounds 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 suitable substituents, such as any of the substituents or groups described herein. Unless otherwise indicated, the “optionally substituted” group may have suitable substituents at each substituted position of said group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the specified group. For example, in the term “optionally substituted C1-C6 alkyl-C2-C9 heteroaryl,” the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. The 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 it to be generated, detected, and, in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0031] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group can independently be deuterium; halogen; -(CH2). 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R°;-O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°;-(CH2) 0-4 Ph, which can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2) 0-4 O(CH2) 0-1 -Pyridyl, which may be R° substituted; 4-8 membered saturated or unsaturated heterocyclic alkyl (e.g., pyridyl); 3-8 membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(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) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 -C(O)-N(R°)2;-(CH2) 0-4 -C(O)-N(R°)-S(O)2-R°; -C(NCN)NR°2; -(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-(CH2) 0-4 OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)₂OR°;-(CH₂) 0-4 OS(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; -(C 1-4 (linear or branched alkylene)ON(R°)2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, -C1-6 aliphatic group, -CH2Ph, -O(CH2). 0-1 Ph, -CH2- (5-6 membered heteroaryl ring), or 3-6 membered saturated, partially unsaturated or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, or, despite the above definition, two independent R° together with their inserted atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0032] Suitable monovalent substituents on R° (or a ring formed by two independently existing R° and their inserted atoms) can be halogens, -(CH2)O-2R, or -(CH2)O-2R. ● -(halogenated R) ● -(CH2)O-2OH, -(CH2)O-2OR ● -(CH2)0-2CH(OR) ● )2、-O(halogenated R) ● ), -CN, -N3, -(CH2)0-2C(O)R ● , -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR ● -(CH2)O-2SR ● , -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR ● -(CH2)0-2NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● -(C 1-4 (straight-chain or branched alkylene)C(O)OR ● or -SSR ● , where each R ● It is either unsubstituted or, in the case of a prefix "halogen group", substituted with one or more halogens, and independently selected from C.1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member 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.

[0033] 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 C1-6 aliphatic group, which may be substituted as defined below; or an unsubstituted 5-6 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 C1-6 aliphatic group that may be substituted as defined below; or an unsubstituted 5-6 saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0034] R * Suitable substituents on aliphatic groups include halogens, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a prefix of "halogen," substituted with only one or more halogens, and is independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] 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, it is hydrogen; a C1-6 aliphatic group, which may be substituted as defined below; an unsubstituted -OPh; or an unsubstituted 3-6 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 groups. † Together with the inserted atoms, they form 3-12 saturated, partially unsaturated, or aryl monocyclic or bicyclic rings with 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0036] R † Suitable substituents on the aliphatic group are independently halogens, -R ● -(halogenated R) ● -OH, -OR ● -O(halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of a prefix of "halogen," substituted with only one or more halogens, and is independently C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 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.

[0037] As used in this article, the term "acetyl" refers to the group -C(O)CH3.

[0038] As used in this article, the term "alkoxy" refers to -O-C1-C 20 Alkyl group, wherein the alkoxy group is attached to the remainder of the compound via an oxygen atom.

[0039] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms (e.g., 1 to 10 or 1 to 6). In some embodiments, the alkyl group is unbranched (i.e., straight-chain); in other 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.

[0040] 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, and isopropylene. The term "C"... x -C y "alkylene" refers to an alkylene group having between x and y carbons. Exemplary values ​​for x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C...). 10 C2-C 20 C2-C6, C2-C 10 Or C2-C 20 Alkylene). In some embodiments, the alkylene may be further substituted with 1, 2, 3 or 4 substituents as defined herein.

[0041] Unless otherwise specified, the term "alkenyl" as used herein 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 of such groups are vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl groups include cis and trans isomers. Unless otherwise specified, the term "alkenylene" as used herein 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.

[0042] As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched group containing carbon-carbon linkages and having 2 to 20 carbons (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons), and examples of such groups are ethynyl and 1-propynyl.

[0043] As used herein, the term "alkynyl sulfone" indicates a structure containing The group, wherein R is any chemically feasible substituent described herein.

[0044] As used in this article, the term "amino" represents -N(R) † )2, for example -NH2 and -N(CH3)2.

[0045] 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.

[0046] As described herein, the term "amino acid" refers to a molecule having a side chain, an amino group, and an acid group (e.g., -CO2H or -SO3H), wherein the amino acid is linked to a parent molecule group via the side chain, amino group, or acid group (e.g., side chain). As used herein, the term "amino acid" in its broadest sense refers to any compound or substance that can be incorporated into a polypeptide chain, for example, by forming one or more peptide bonds. In some embodiments, the amino acid has the universal structure H2N-C(H)(R)-COOH. In some embodiments, the amino acid is a naturally occurring amino acid. In some embodiments, the amino acid is a synthetic amino acid; in some embodiments, the amino acid is a D-amino acid; in some embodiments, the amino acid is an L-amino acid. "Standard amino acid" refers to any one of the twenty standard L-amino acids commonly found in naturally occurring peptides. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxyvaline, isoleucine, leucine, lysine, methionine, valine, ornithine, phenylalanine, proline, pyrrolidone, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0047] 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 are 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.

[0048] 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)-, which is also represented as -N(C(O)-H)-.

[0049] As used herein, the terms "carbocyclic" and "carbocyclic group" refer to monovalent, optionally substituted C3-C groups. 12A monocyclic, bicyclic, or tricyclic structure, which can 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 are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, dihydroindenyl, decahydronaphthyl, etc. The carbocyclic ring may be attached to its side group at any ring atom that produces a stable structure, and unless otherwise specified, any ring atom may optionally be substituted.

[0050] As used in this article, the term "carbonyl" refers to a C(O) group, which can also be represented as C=O.

[0051] As used in this article, the term "carboxyl" refers to -CO2H, (C=O)(OH), COOH, or C(O)OH, or its unprotonated counterpart.

[0052] As used in this article, the term "cyano" refers to the -CN group.

[0053] 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 of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0054] 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.

[0055] As used in this article, “diastereomers” refers to stereoisomers that are not mirror images of each other and cannot be superimposed on each other.

[0056] 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 enantiomeric excess (as determined by standard methods in the art).

[0057] The term "guanidinyl" refers to a group having the following structure: , where each R is independently any chemically feasible substituent described herein.

[0058] 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.

[0059] As used in this article, the term "haloacetyl" refers to an acetyl group in which at least one hydrogen atom is replaced by a halogen.

[0060] 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.

[0061] As used in this article, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0062] As used herein, the term "heteroalkyl" refers to an alkyl group 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.

[0063] As used herein, the term "heteroaryl" refers to a monovalent, monocyclic, or polycyclic structure containing at least one fully aromatic ring: that is, they contain 4... n +2 π electrons and containing at least one cyclic heteroatom selected from N, O, or S in the aromatic ring. Exemplary unsubstituted heteroaryl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heteroaryl" includes any of the aforementioned heteroaryl rings fused to one or more aromatic or carbocyclic rings (e.g., phenyl or cyclohexane rings) in bicyclic, tricyclic, and tetracyclic groups. 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 specifically stated. In some embodiments, the heteroaryl group is substituted with 1, 2, 3, or 4 substituents.

[0064] As used herein, the term "heterocyclic alkyl" refers to a monovalent, monocyclic, bicyclic, or polycyclic system in which at least one ring is a non-aromatic ring and said non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. This system may be a bridging ring, a fused ring, or a spirocyclic ring. Five-membered rings have zero to two double bonds, and six- and seven-membered rings have zero to three double bonds. Exemplary unsubstituted heterocyclic alkyl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heterocyclic alkyl" also refers to a heterocyclic compound having a bridging polycyclic structure, wherein one or more carbons or heteroatoms bridge non-adjacent members of a monocyclic ring, such as a quinine cycloyl group. The term "heterocyclic alkyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the aforementioned heterocycles is fused with 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 are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphthidyl. Heterocyclic alkyl rings may be attached to their side groups at any ring atom that produces a stable structure, and unless otherwise specifically stated, any ring atom may optionally be substituted.

[0065] As used in this article, the term "hydroxyl group" refers to the -OH group.

[0066] 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.

[0067] As used herein, the term "isomer" means any tautomer, stereoisomer, transisomer, enantiomer, or diastereomer of any compound of the present invention. It should be understood that the compounds of the present invention may have one or more chiral centers or double bonds, and therefore exist in stereoisomeric form, such as double-bonded isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the present invention, the chemical structures described herein and therefore the compounds of the present invention encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms, as well as mixtures of enantiomers and stereoisomers, such as racemates. The enantiomers and stereoisomers of the compounds of this invention can 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 by well-known asymmetric synthetic methods from stereoisomerically pure or enantiomerically pure intermediates, reagents, and catalysts.

[0068] As used herein, the term "connector" refers to linking part B of a compound of formula I to part W, such that the resulting compound can obtain a divalent organic moiety with an IC50 of 2 μM or lower in the examples provided below and in the Ras-RAF destruction assays provided herein: The purpose of this biochemical assay is to measure the ability of the test compound to promote the formation of a ternary complex between a nucleotide-loaded Ras isoform and cyclic protein A; the resulting ternary complex is disrupted by BRAF. RBD The binding of the constructs inhibits Ras signal transduction via the RAF effector.

[0069] 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. RBD Compounds were combined in 384-well assay plates at final concentrations of 25 µM, 12.5 nM, and 50 nM, respectively. The compounds present in the wells were initially at a final concentration of 30 µM, followed by 10-point, 3-fold serial dilutions. After incubation at 25 °C for 3 hours, a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was added to the assay wells to final concentrations of 10 nM and 50 nM, respectively, and the reaction was incubated for another 1.5 hours. TR-FRET signals were read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds promoting the destruction of the Ras:RAF complex were identified as those causing a decrease in the TR-FRET ratio relative to the DMSO control wells.

[0070] In some embodiments, the linker contains 20 or fewer linear atoms. In some embodiments, the linker contains 15 or fewer linear atoms. In some embodiments, the linker contains 10 or fewer linear atoms. In some embodiments, the molecular weight of the linker is less than 500 g / mol. In some embodiments, the molecular weight of the linker is less than 400 g / mol. In some embodiments, the molecular weight of the linker is less than 300 g / mol. In some embodiments, the molecular weight of the linker is less than 200 g / mol. In some embodiments, the molecular weight of the linker is less than 100 g / mol. In some embodiments, the molecular weight of the linker is less than 50 g / mol.

[0071] 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.

[0072] As used herein, the term "stereoisomer" means that a compound (e.g., any compound of the formula described herein) may have all possible different isomers and conformations, particularly all possible stereochemical and conformational isomers of the basic molecular structure, all diastereomers, enantiomers, or conformations, 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.

[0073] As used in this article, the term "sulfonyl" refers to the -S(O)2- group.

[0074] As used in this article, the term "thiocarbonyl" refers to the -C(S)- group.

[0075] As used herein, the term "vinyl ketone" refers to a group containing a carbonyl group directly attached to a carbon-carbon double bond.

[0076] As used herein, the term "vinyl sulfone" refers to a group containing a sulfonyl group directly attached to a carbon-carbon double bond.

[0077] As used in this article, the term "acetylenoid" refers to a structure containing The group, wherein R is any chemically feasible substituent described herein.

[0078] 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 forms, protected forms, prodrug forms, ester forms, isomer forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may refer to a particular form of the compound. In some embodiments, reference to a particular compound may refer to the compound in any form. In some embodiments, for example, a formulation of a single stereoisomer of a compound may be considered a different form of the compound rather than a racemic mixture of the compound; a particular salt of a compound may be considered a different form from another salt of the compound; a formulation of a conformational isomer ((Z) or (E)) containing a double bond may be considered a different form from a formulation of another conformational isomer ((E) or (Z)) containing the double bond; a formulation in which one or more atoms have isotopes different from those present in a reference formulation may be considered a different form. Detailed Implementation

[0079] compound 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: a target protein (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 between the Ras protein and the widely expressed cytosolic chaperone protein cyclophilin A (CYPA). Without being bound by theory, the inventors believe that one way the compounds of the present invention, and the complexes or conjugates thereto, exert an inhibitory effect on Ras is by spatially blocking the interaction sites between Ras and downstream effector molecules such as RAF required for the propagation of oncogenic signals.

[0080] 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., cyclophilic protein A) can facilitate 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 thioglycolic side chain of cysteine ​​at position 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 facilitate the ability of the compounds of this invention to form complexes and act as Ras inhibitors. Thus, the compounds of this invention can inhibit a variety of Ras proteins (e.g., K-Ras, N-Ras, H-Ras, and mutants thereof with mutations at positions 12, 13, and 61, such as G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, as well as other mutants described herein).

[0081] 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, such as a determination performed under these conditions ( Note: The following scheme description is for monitoring K-Ras The procedure for crosslinking G12C (GMP-PNP) with the compounds of this invention. This method can also replace other Ras proteins or nucleotides. (To be implemented).

[0082] The purpose of this biochemical assay is to measure the covalently labeled components of the test compound. Nucleotides The ability of K-Ras isoforms to be determined. A stock solution of 5 µM K-Ras (1-169) G12C loaded with GMP-PNP was diluted 10-fold to a final concentration of 0.5 µM in 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; the final sample volume was 100 µL.

[0083] 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 with an increasing acetonitrile gradient in the mobile phase to a mass spectrometer. Analysis of the raw data was performed using Waters MassLynxMS software, where the binding percentage was calculated from the deconvolution of labeled and unlabeled K-Ras protein peaks.

[0084] Therefore, this article provides a compound having the structure of Formula I or a pharmaceutically acceptable salt thereof: 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heteroarylene; B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9' or >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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; 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 is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, acetal, haloacetal or acetal sulfone; X 1 It is optionally substituted with a 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 ynyl, 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' is 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 It can be either C or N independently; 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, optionally substituted C1-C6 alkyl group, optionally substituted C1-C6 heteroalkyl group, optionally substituted 3- to 6-membered cycloalkyl group, optionally substituted 3- to 6-membered cycloalkenyl group, optionally substituted 3- to 6-membered heterocycloalkyl group, optionally substituted 6- to 10-membered aryl group, or optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 Together with the atoms to which they are attached, they form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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, a halogen, an optionally substituted C1-C3 alkyl group, 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 H, 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 optionally substituted C1-C6 alkyl; or R 9 and R 9' It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R 10a It is hydrogen or a halogen group; R 11 It is hydrogen or C1-C3 alkyl; and R 21 It is hydrogen or a C1-C3 alkyl group (e.g., methyl).

[0085] In some implementation schemes, R 9 It is H, 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.

[0086] In some implementation schemes, R 21 It is hydrogen.

[0087] In some embodiments, this document provides a compound having the structure of formula Ia, or a pharmaceutically acceptable salt thereof: 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; 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 is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, acetal, haloacetal or acetal sulfone; X 1 It is optionally substituted with a 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 ynyl, 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 It can be either C or N independently; 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, optionally substituted C1-C6 alkyl group, optionally substituted C1-C6 heteroalkyl group, optionally substituted 3- to 6-membered cycloalkyl group, optionally substituted 3- to 6-membered cycloalkenyl group, optionally substituted 3- to 6-membered heterocycloalkyl group, optionally substituted 6- to 10-membered aryl group, or optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 Together with the atoms to which they are attached, they form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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, a halogen, an optionally substituted C1-C3 alkyl group, 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 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 optionally substituted C1-C6 alkyl; R 10 It is hydrogen, halogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R 10a It is hydrogen or a halide group; and R 11 It is hydrogen or C1-C3 alkyl.

[0088] In some embodiments, this disclosure provides a compound having structural formula Ib, or a pharmaceutically acceptable salt thereof: 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-membered heteroarylene; 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; 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 is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, acetal, haloacetal or acetal sulfone; X1 It is optionally substituted with a 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 ynyl, 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 It can be either C or N independently; Y 5 and Y 6 It can be CH or N independently; R 1 It is a 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; R 6 It is hydrogen or methyl; R7 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 a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted. R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R 11 It is hydrogen or C1-C3 alkyl.

[0089] In some embodiments of the compounds of the present invention, G is optionally a substituted C1-C4 heteroalkylene group.

[0090] In some embodiments, a compound having the structure of formula Ic, or a pharmaceutically acceptable salt thereof, is provided: 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-membered heteroarylene; 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; L is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; 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 ynyl, 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 It can be either C or N independently; Y 5 and Y 6 It can be CH or N independently; R 1 It is a 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. R2 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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 a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted. R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R 11 It is hydrogen or C1-C3 alkyl.

[0091] In some embodiments of the compounds of the present invention, X 2 It is NH. In some implementations, X 3 It is CH. In some implementations, R 11 It is hydrogen. In some implementations, R 11 It is a C1-C3 alkyl group. In some embodiments, R 11 It is a methyl group.

[0092] In some embodiments, the compounds of the present invention have the structure of formula Id, or a pharmaceutically acceptable salt thereof: 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, 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 It can be either C or N independently; Y 5 and Y 6 It can be CH or N independently; R 1 It is a 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; R 6 It is hydrogen or methyl; R 7 It is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7It 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.

[0093] In some embodiments of the compounds of the present invention, X 1 It is an optionally substituted C1-C2 alkylene group. In some embodiments, X 1 It is methylene. In some embodiments, X 1 It is a methylene group substituted with a C1-C6 alkyl group or a halogen. In some embodiments, X 1 It is -CH(Br)-. In some implementations, X 1It is -CH(CH3)-. In some implementations, R 5 It is hydrogen. In some implementations, R 5 It is a C1-C4 alkyl group optionally substituted with a halogen. In some embodiments, R 5 It is a methyl group. In some embodiments, Y... 4 It is C. In some implementations, R 4 It is hydrogen. In some implementations, Y 5 It is CH.

[0094] In some implementation schemes, 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.

[0095] In some embodiments, the compounds of the present invention have the structure of formula Ie, or a pharmaceutically acceptable salt thereof: 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; R 1 It is a 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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.

[0096] In some embodiments of the compounds of the present invention, R 6 It is hydrogen. In some implementations, 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 optionally substituted C1-C6 alkyl group. In some embodiments, R2 is a fluoroalkyl group. In some embodiments, R... 2 It is an ethyl group. In some embodiments, R2 is -CH2CF3. In some embodiments, R2 is a C2-C6 ynyl group. In some embodiments, R2 is -CHC≡CH. In some embodiments, R2 is -CH2C≡CCH3. In some embodiments, R... 7 It is an optionally substituted C1-C3 alkyl group. In some embodiments, R 7 It is a C1-C3 alkyl group. In some embodiments, R 8 It is an optionally substituted C1-C3 alkyl group. In some embodiments, R 8 It is a C1-C3 alkyl group.

[0097] In some embodiments, the compounds of the present invention have the structure of formula If, or a pharmaceutically acceptable salt thereof: 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; R 1 It is a 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 a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted.

[0098] In some embodiments of the compounds of the present invention, R 1 It is optionally a substituted 6- to 10-membered aryl group, optionally a substituted 3- to 6-membered cycloalkenyl group, or optionally a substituted 5- to 10-membered heteroaryl group. In some embodiments, R 1 It is a 6-membered aryl group that is optionally substituted, a 6-membered cycloalkenyl group that is optionally substituted, or a 6-membered heteroaryl group that is optionally substituted.

[0099] In some embodiments of the compounds of the present invention, R1 is , , , , , , , or R1, or its stereoisomers (e.g., reversible isomers). In some embodiments of the compounds of the present invention, R1 is... Or its stereoisomers (e.g., transisomers). In some embodiments of the compounds of the present invention, R1 is... .

[0100] In some embodiments, the compounds of the present invention have the structure of formula Ig, or a pharmaceutically acceptable salt thereof: Where 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; R 2 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, 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 a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted. X e and X f It is either N or CH independently; and R 12 It is a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, or a 3- to 6-membered heterocyclic alkyl group that is optionally substituted.

[0101] 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.

[0102] In some embodiments of the compounds of the present invention, R 12 It is an optionally 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 VI, or a pharmaceutically acceptable salt thereof: 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 does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9' or >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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; 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 is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, acetal, haloacetal or acetal sulfone; X 1 It is optionally substituted with a 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 ynyl, 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 It can be either C or N independently; Y 5 It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 2 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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, a halogen, an optionally substituted C1-C3 alkyl group, 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 H, 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 optionally substituted C1-C6 alkyl; or R 9 and R 9' It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R 10a It is hydrogen or a halogen group; R 11 It is hydrogen or C1-C3 alkyl; R 21 It is hydrogen or a C1-C3 alkyl group (e.g., methyl); and X e and X f It can be either N or CH on its own.

[0104] In some embodiments, the compounds of the present invention have the structure of formula VIa, or a pharmaceutically acceptable salt thereof: Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered aryl (e.g., phenyl or phenol) or a substituted 5- to 6-membered heteroaryl. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; X 1 It is optionally substituted with a 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 ynyl, 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, C1-C6 fluoroalkyl, 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 a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted. X e and X f It can be either N or CH independently; R 11 It is hydrogen or C1-C3 alkyl; and R 21 It is hydrogen or C1-C3 alkyl.

[0105] In some embodiments of the compounds of the present invention, Xe It is N and X f It is CH. In some implementations, X e It is CH and X f It is N.

[0106] In some embodiments, the compounds of the present invention have the structure of formula VIb, or a pharmaceutically acceptable salt thereof: Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered aryl (e.g., phenyl or phenol) or a substituted 5- to 6-membered heteroaryl. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; R 9 It is a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted. L either does not exist or is a connector; and W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynyl ketone, or alkynyl sulfone. In some embodiments of the compounds of the present invention, A is an optionally substituted 6-membered aryl group.

[0107] In some embodiments, the compounds of the present invention have the formula VIc (corresponding to...) Figure 1A and Figure 1B The structure of (BB) or its pharmaceutically acceptable salt: 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 does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9' or >CR 9 R 9' In which carbon is bonded to -N(R) 11The carbonyl carbon of C(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; 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 is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, acetal, haloacetal or acetal sulfone; X 1 It is optionally substituted with a 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 ynyl, 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 It can be either C or N independently; Y 5 It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 2Absent, 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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, a halogen, an optionally substituted C1-C3 alkyl group, 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 H, 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 optionally substituted C1-C6 alkyl; or R 9 and R 9' It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R 10a It is hydrogen or a halogen group; R 11 It is hydrogen or C1-C3 alkyl; and R 21 It is hydrogen or a C1-C3 alkyl group (e.g., methyl).

[0108] In some implementations, A has the following structure: Where R 13 It is hydrogen, a halogen group, a hydroxyl group, an amino group, an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C6 heteroalkyl group; and R 13a It is either hydrogen or a halogen group. In some implementations, R 13 It is hydrogen. In some implementations, R 13 and R 13a Each is hydrogen. In some implementations, R 13 It is hydroxyl, methyl, fluorine or difluoromethyl.

[0109] In some embodiments, A is an optionally substituted 5- to 6-membered heteroaryl group. In some embodiments, A is: .

[0110] In some embodiments, A is an optionally substituted C1-C4 heteroalkylene group. In some embodiments, A is: In some embodiments, A is an optionally substituted 3- to 6-membered heterocyclic alkyl group. In some embodiments, A is: , or In some implementations, A is... .

[0111] In some embodiments of the compounds of the present invention, B is -CHR. 9 -. In some implementations, R 9 It is H, 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. In some embodiments, R 9 yes: In some implementations, R 9 yes: In some implementations, R 9 It is H, 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.

[0112] In some embodiments of the compounds of the present invention, B is an optionally substituted 6-membered arylene. In some embodiments, B is a 6-membered arylene. 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 21 It is hydrogen.

[0116] In some embodiments of the compounds of the present invention, the connector has the structure of Formula II: Where A 1 It is the key between the connector and B; A 2 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 groups, optionally substituted C1-C3 heteroalkylene groups, O, S, and NR. N ;R N It is hydrogen, with C optionally substituted. 1-4 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- to 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 C1-C is arbitrarily replaced 10 Alkylene, optionally substituted C2-C 10 alkenyl, 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, the connector is acyclic. In some embodiments, the connector has the structure of formula IIa: Where X a It either does not exist or is N; R14 It does not contain, is hydrogen or optionally substituted C1-C6 alkyl groups; and L 2 The C1-C4 alkylene group is absent, is -SO2-, optionally substituted, or optionally substituted, wherein X a R 14 or L 2 At least one of the following is present. In some embodiments, the connector has the following structure: .

[0117] In some embodiments, the joint is or includes an annular portion. In some embodiments, the joint has a structure of formula IIb: Where o is 0 or 1; R 15 It is hydrogen or optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; X 4 It is absent, or is optionally substituted C1-C4 alkylene, O, NCH3, or optionally substituted C1-C4 heteroalkylene; Cy is a optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heteroalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroalkylene; and L 3 It is absent, is -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene.

[0118] In some implementations, the connector has the structure of formula IIb-1: Where o is 0 or 1; R 15 It is hydrogen or optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene or optionally substituted 3- to 8-membered heteroalkylene; Cy is a optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heteroalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroalkylene; and L 3 It is absent, is -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene.

[0119] In some implementations, the connector has a structure of type IIc: Where R 15 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heteroalkylene; and R 15a R 15b R 15c R 15d R 15e R 15f and R 15g Independently, it is hydrogen, halogen, hydroxyl, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or R 15b and R 15d It combines with the carbon to which it is attached to form optionally substituted 3 to 8-membered cycloalkylene or optionally substituted 3 to 8-membered heteroalkylene.

[0120] In some implementations, the connector has the following structure: .

[0121] In some implementations, the connector has the following structure: .

[0122] In some implementations, the joint has a structure .

[0123] In some implementations, the joint has a structure In some embodiments of the compounds of the present invention, W is a crosslinking group comprising a vinyl ketone. In some embodiments, W has the structure of formula IIIa: Where R 16a R 16b and R 16c Independently, it is hydrogen; -CN; halogen; or a -C1-C3 alkyl group optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or a 4- to 7-membered saturated heterocyclic alkyl group. In some embodiments, W is: In some embodiments, W is a crosslinking group containing an acetylacetonate. In some embodiments, W has the structure of formula IIIb: Where R 17 It is hydrogen; a -C1-C3 alkyl group optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or a 4- to 7-membered saturated heterocyclic alkyl group; or a 4- to 7-membered saturated heterocyclic alkyl group. In some embodiments, W is: In some implementations, W is... .

[0124] In some embodiments, W is a crosslinking group comprising vinyl sulfone. In some embodiments, W has the structure of formula IIIc: Where R 18a R 18b and R 18c Independently, it is hydrogen; -CN; or a -C1-C3 alkyl group optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or a 4- to 7-membered saturated heterocyclic alkyl group. In some embodiments, W is: or In some embodiments, W is a crosslinking group comprising an alkynyl sulfone. In some embodiments, W has the structure of formula IIId: Where R 19 It is hydrogen; a -C1-C3 alkyl group optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or a 4- to 7-membered saturated heterocyclic alkyl group; or a 4- to 7-membered saturated heterocyclic alkyl group. In some embodiments, W is: or In some implementations, W has the structure of formula IIIe: Where X e It is halogen; and R 20 W is hydrogen; optionally substituted with one or more substituents, said substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or 4 to 7-membered saturated heterocyclic alkyl. In some embodiments, W is a haloacetal. In some embodiments, W is not a haloacetal.

[0125] In some embodiments, the compounds of the present invention are selected from Table 1, or pharmaceutically acceptable salts or stereoisomers thereof.

[0126] Table 1: Some compounds of the present invention 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.

[0127] Parentheses should be ignored.

[0128] The reactivity of this stereoisomer can actually be attributed to -NC(O)- C The presence of a small number of stereoisomers in the (S) configuration at the H(CH3)2-N(CH3)- position.

[0129] 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.

[0130] Table 2: Some compounds of the present invention .

[0131] 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.

[0132] In some embodiments, the compounds of the present invention are or are used as prodrugs, for example for administration to cells or to a subject in need.

[0133] Pharmaceutical compositions comprising the compounds of the present invention or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients are also provided.

[0134] A further provided conjugate or salt thereof, comprising the structure of formula IV: Where L is the connector; P is the monovalent organic fraction; and M has the structure of 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) 10 The carbon atom of )-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-membered heteroarylene; B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9' or >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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; 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 is optionally substituted with a 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 ynyl, 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 Y7 It can be either C or N independently; 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, optionally substituted C1-C6 alkyl group, optionally substituted C1-C6 heteroalkyl group, optionally substituted 3- to 6-membered cycloalkyl group, optionally substituted 3- to 6-membered cycloalkenyl group, optionally substituted 3- to 6-membered heterocycloalkyl group, optionally substituted 6- to 10-membered aryl group, or optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 Together with the atoms to which they are attached, they form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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, a halogen, an optionally substituted C1-C3 alkyl group, 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 H, 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 optionally substituted C1-C6 alkyl; or R 9 and R 9' It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R 10a It is hydrogen or a halide group; and R 11 It is hydrogen or C1-C3 alkyl.

[0135] In some embodiments, the conjugate or its salt comprises a structure of formula IV: Where L is the connector; P is the monovalent organic fraction; and M has the structure of 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; 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 is optionally substituted with a 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 ynyl, 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 It can be either C or N independently; 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, optionally substituted C1-C6 alkyl group, optionally substituted C1-C6 heteroalkyl group, optionally substituted 3- to 6-membered cycloalkyl group, optionally substituted 3- to 6-membered cycloalkenyl group, optionally substituted 3- to 6-membered heterocycloalkyl group, optionally substituted 6- to 10-membered aryl group, or optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 Together with the atoms to which they are attached, they form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; R 6 It is hydrogen or methyl; R 7It 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, a halogen, an optionally substituted C1-C3 alkyl group, 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 optionally substituted C1-C6 alkyl; R 10 It is hydrogen, halogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R 10a It is hydrogen or a halide group; and R 11 It is hydrogen or C1-C3 alkyl.

[0136] In some embodiments, the conjugate has the structure of formula IV: Where L is the connector; P is the monovalent organic fraction; and M has the structure of Vc: 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-membered heteroarylene; 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; 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 is optionally substituted with a 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 ynyl, 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 It can be either C or N independently; Y 5 and Y 6 It can be CH or N independently; R 1 It is a 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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 a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted. R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R 11 It is hydrogen or C1-C3 alkyl.

[0137] In some embodiments, the compounds of the present invention have the structure of formula IV: Where L is the connector; P is the monovalent organic fraction; and M has the structure of Vd: Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered aryl (e.g., phenyl or phenol) or a substituted 5- to 6-membered heteroaryl. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6-membered cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; X 1 It is optionally substituted with a 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 ynyl, 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, C1-C6 fluoroalkyl, 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 a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted. X e and X f It can be either N or CH independently; R 11 It is hydrogen or C1-C3 alkyl; and R 21 It is hydrogen or C1-C3 alkyl.

[0138] 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.

[0139] In some embodiments, the compounds of the present invention have the structure of formula IV: Where L is the connector; P is the monovalent organic fraction; and M has the structure of Ve: Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered aryl (e.g., phenyl or phenol) or a substituted 5- to 6-membered heteroaryl. B is -CH(R) 9 )-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3- to 6-membered cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroarylene; and R 9 It is a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted.

[0140] In some embodiments of the conjugate of the present invention, the connector has a structure of Formula II: Where A 1 It is the key between the connector and B; A 2 The key between P and the connector; B 1 B 2 B 3 and B 4 Each is independently selected from optionally substituted C1-C2 alkylene groups, optionally substituted C1-C3 heteroalkylene groups, 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 C1-C is arbitrarily replaced 10 Alkylene, optionally substituted C2-C 10 alkenyl, 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 Chemical bonds.

[0141] In some embodiments of the conjugates of the present invention, the monovalent organic moiety is a protein, such as a Ras protein. In some embodiments, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras proteins are described herein. In some embodiments, the linker is attached to the monovalent organic moiety via a bond to a sulfhydryl group of an amino acid residue. In some embodiments, the linker is attached to the monovalent organic moiety via a bond to a carboxyl group of an amino acid residue.

[0142] A further method of treating a subject with cancer is provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof. The cancer may be, for example, pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or squamous cell lung cancer. In some embodiments, the cancer comprises a Ras mutation, such as K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras mutations are described herein.

[0143] A further method is provided for treating Ras protein-related conditions in a subject of need, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0144] A further method for inhibiting Ras proteins in cells is provided, the method comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras proteins are 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 described herein. The cells may be in vivo or in vitro.

[0145] For the compounds of the present 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.

[0146] In some embodiments, the methods or uses described herein also include administering additional anticancer therapies. In some embodiments, the additional anticancer therapy is a HER2 inhibitor, EGFR inhibitor, second Ras inhibitor, SHP2 inhibitor, SOS1 inhibitor, Raf inhibitor, MEK inhibitor, ERK inhibitor, PI3K inhibitor, PTEN inhibitor, AKT inhibitor, mTORC1 inhibitor, BRAF inhibitor, PD-L1 inhibitor, PD-1 inhibitor, CDK4 / 6 inhibitor, or a combination thereof. In some embodiments, the additional anticancer therapy is an SHP2 inhibitor. Other additional anticancer therapies are described herein.

[0147] Synthesis method The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic processes.

[0148] The compounds of the present 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 the present invention can be synthesized using the methods described in the following embodiments, as well as synthetic methods known in the field of synthetic organic chemistry or modifications thereof as understood by those skilled in the art. These methods include, but are not limited to, the methods described in the following embodiments.

[0149] Scheme 1. General Synthesis of Macrocyclic Esters Scheme 1 outlines the general synthesis of macrocyclic esters. Appropriately substituted aryl-3-(5-bromo-1-ethyl-1-yl) H-Indol-3-yl)-2,2-dimethylprop-1-ol(1) can be protected by 3-(5-bromo-2-iodo-1-yl) H Starting with indol-3-yl)-2,2-dimethylprop-1-ol and appropriately substituted boronic acid, it is prepared in three steps, including palladium-mediated coupling, alkylation, and deprotection. Methyl amino-hexahydropyridazine-3-carboxylate-boronic acid ester (2) can be prepared in three steps, including protection, iridium-catalyst-mediated borylation, and deprotection with ( S Coupling with methyl methyl hexahydropyridazine-3-carboxylic acid.

[0150] Appropriately substituted acetylpyrrolidine-3-carbonyl-N-methyl-L-valine (or alternative amino acid derivatives) (4) can be prepared by reacting a methyl-L-valine ester with a protected ( S The process involves coupling with pyrrolidine-3-carboxylic acid, followed by deprotection, coupling with a carboxylic acid containing a suitably substituted Michael acceptor, and hydrolysis.

[0151] The final macrocyclic ester can be prepared by coupling methyl amino-hexahydropyridazine-3-carboxylate-boronate (2) with aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylprop-1-ol (1) in the presence of a Pd catalyst, followed by hydrolysis and macrocyclic lactone formation to yield a suitably protected macrocyclic intermediate (5). Deprotection and coupling with a suitably substituted intermediate 4 produce the macrocyclic product. Additional deprotection and / or functionalization steps may be required to prepare the final compound.

[0152] Option 2. Substitution of macrocyclic esters in general synthesis Alternatively, the macrocyclic ester can be prepared as described in Scheme 2. A suitably protected bromo-indole group (6) is coupled to a borate ester (3) in the presence of a Pd catalyst, followed by iodination, deprotection, and ester hydrolysis. Subsequently, it is reacted with ( S Coupling with methyl hexahydropyridazine-3-carboxylate followed by hydrolysis and macrocyclic lactone formation yields an iodine intermediate (7). Coupling with a suitably substituted borate ester and alkylation in the presence of a Pd catalyst yields a fully protected macrocycle (5). Additional deprotection or functionalization steps are required to prepare the final compound.

[0153] Furthermore, those skilled in the art will understand that the compounds of this disclosure can be synthesized using the methods described in the following examples, as well as synthetic methods known in the field of synthetic organic chemistry or variations thereof. These methods include, but are not limited to, the methods described in the following examples. For example, those skilled in the art will be able to attach the desired -BLW group to a macrocyclic ester of formula (I), wherein B, L, and W are as defined herein, including by using the methods exemplified in the Examples section of this document.

[0154] 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.

[0155] Scheme 3. General Synthesis of Macrocyclic Esters Scheme 3 outlines the general alternative synthesis of macrocyclic esters. Appropriately substituted indolylboronic esters (8) can be prepared in four steps from protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylprop-1-ol and appropriately substituted boronic acid, including palladium-mediated coupling, alkylation, deprotection and palladium-mediated borylation.

[0156] Methyl amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (10) can be obtained via (S)-2-amino-3-(4-bromothiazol-2-yl)propionic acid (9) and ( S It is prepared by coupling with methyl hexahydropyridazine-3-carboxylate.

[0157] The final macrocyclic ester can be prepared by coupling methyl amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (10) with a suitably substituted indoleboronic ester (8) in the presence of a Pd catalyst, followed by hydrolysis and macrocyclic lactone esterification steps to obtain a suitably protected macrocyclic intermediate (11). Deprotection and coupling with a suitably substituted intermediate 4 yields the macrocyclic product. Additional deprotection or functionalization steps may be required to prepare the final compound 13 or 14.

[0158] Scheme 4. General Synthesis of Macrocyclic Esters Scheme 4 outlines the alternative general synthesis of macrocyclic esters. A suitably substituted morpholine or alternative heterocyclic intermediate (15) can be coupled to a suitably protected intermediate 1 via palladium-mediated coupling. This is followed by ester hydrolysis and coupling with a piperazoic ester to give intermediate 16.

[0159] Macrocyclic esters can be prepared via hydrolysis, deprotection, and macrocyclization. Deprotection is then performed, followed by coupling with intermediate 4 (or an analogue) to yield a suitably substituted final macrocyclic product. Additional deprotection or functionalization steps may be required to prepare the final compound 17.

[0160] Scheme 5. General Synthesis of Macrocyclic Esters Scheme 5 outlines the alternative general synthesis of macrocyclic esters. A suitably substituted macrocycle (20) can be prepared from a suitably protected borate ester 18 and a bromoindole intermediate (19) as starting materials, involving palladium-mediated coupling, hydrolysis, coupling with a piperazine ester, hydrolysis, deprotection, and macrocyclization steps. Subsequently, coupling with a suitably substituted protected amino acid, followed by palladium-mediated coupling, yields intermediate 21. Additional deprotection and derivatization steps, including alkylation, may be required at this point.

[0161] The final macrocyclic ester can be prepared by coupling intermediate (22) with a suitably substituted carboxylic acid intermediate (23). Additional deprotection or functionalization steps may be required to prepare the final compound (24).

[0162] Furthermore, the compounds of this disclosure can be synthesized using the methods described in the following examples, as well as synthetic methods known in the field of 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 attach the desired -BLW group to a macrocyclic ester of compound (I), wherein B, L, and W are as defined herein, including by using the methods exemplified in the Examples section of this document.

[0163] 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.

[0164] As used herein, the term "pharmaceutical composition" refers to a compound formulated with a pharmaceutically acceptable excipient, such as the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the compound is present in the pharmaceutical composition in a unit dose suitable for administration in a treatment regimen, the compound showing a statistically significant likelihood of achieving a predetermined therapeutic effect when administered to the relevant population. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for administration by: oral administration, such as solutions (aqueous or non-aqueous solutions or suspensions), tablets (e.g., tablets targeted for buccal, sublingual, and systemic absorption), pills, powders, granules, pastes for application to the tongue; parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, such as sterile solutions or suspensions, or sustained-release formulations; surface administration, such as creams, ointments, or controlled-release patches or sprays for application 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.

[0166] As used herein, “pharmaceuticalally acceptable excipients” refers to 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 (flow improvers), 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), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. A variety of reagents and materials are well known to those skilled in the art 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.

[0167] Unless expressly stated otherwise, the compounds described herein, whether or not explicitly stated, may be provided or utilized in salt form, such as 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, anaphylactic 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 salt can be prepared in situ during the final separation and purification of the compounds described herein, or separated by reacting the free base group with a suitable organic acid.

[0168] The compounds of the present invention may have ionizable groups, thereby enabling their preparation into pharmaceutically acceptable salt forms. These salts may be acid addition salts involving inorganic or organic acids, or, where the compounds of the present invention are in acid form, the salts may be prepared from inorganic or organic bases. In some embodiments, the compounds are prepared or used in pharmaceutically acceptable salt forms, which are prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, or tartaric acid, for forming acid addition salts; and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, etc., for forming base salts. Methods for preparing suitable salts are recognized in the art.

[0169] 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, hydrobromide, 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.

[0170] 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.

[0171] As used herein, the term "dosage form" refers to a physically discrete unit of a compound (such as the compound of the present invention) intended for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, this amount is an amount (or a whole portion thereof) of a unit dose suitable for administration according to a dosing regimen, said amount being determined to be associated with a desired or beneficial outcome when administered to a relevant population (i.e., according to a treatment 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.

[0172] As used herein, the term "dosing regimen" refers to a set of unit doses (typically more than one unit dose) administered individually 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, which may involve one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each of which is spaced at equal intervals; in some embodiments, the dosing regimen comprises multiple doses and 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 the 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 the 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.

[0173] "Treatment regimen" refers to a dosing regimen in a relevant population that is associated with the desired or beneficial treatment outcome.

[0174] The term "treatment" ("treatment / treat / treating") in its broadest sense refers to any application of a substance (e.g., the compounds of the present invention) that partially or completely relieves, improves, alleviates, 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, this 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 said disease, condition, or disorder. Alternatively or additionally, in some embodiments, the treatment may be administered to a subject who exhibits one or more defined signs of the relevant disease, condition, or disorder. In some embodiments, the treatment may be used on a subject diagnosed with the relevant disease, condition, or disorder. In some embodiments, the 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.

[0175] The term "therapeuticly effective amount" means an amount sufficient to treat a disease, condition, or ailment when administered according to a therapeutic dosing regimen to a population suffering from or susceptible to such a disease, condition, or ailment. 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 ailment 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 this treatment. It is particularly important to understand that a particular subject may actually be "therapeuticly effective" and "refractory." In some embodiments, a 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 ailment) 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 amount may be formulated as multiple doses, for example, as part of a dosing regimen, or administered in multiple doses.

[0176] For use as a treatment for subjects, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the desired type of treatment, such as prevention, control, or treatment, the compounds or pharmaceutically acceptable salts thereof are formulated in a manner consistent with these parameters. An overview of such techniques can be found in […]. 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 incorporated herein by reference.

[0177] 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 1-95% by weight of the total amount of the composition, such as the pharmaceutical composition.

[0178] The composition may be provided in dosage forms suitable for administration such as intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, skin, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, sac-like, intraurethral, ​​intrathecal, epidural, ear, or eye, 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, liquids, 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.

[0179] 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) may be performed via any suitable route. For example, in some embodiments, administration may be performed via bronchial (including bronchial infusion), buccal, intestinal, interdermal, intra-arterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intrasacral, transmucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including intratracheal infusion), transdermal, vaginal, or vitreous administration.

[0180] Formulations can be prepared 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 typically 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.

[0181] For injection, the formulation can be prepared in conventional forms, such as liquid solutions or suspensions, or in solid forms suitable for preparation as solutions or suspensions in liquids prior to injection, or in emulsion forms. Suitable excipients include, for example, water, physiological saline, dextrose, glycerol, etc. Such compositions may also contain a certain amount of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitol monolaurate, etc.

[0182] Various sustained-release drug delivery systems have also been designed. See, for example, U.S. Patent No. 5,624,677.

[0183] Systemic administration may also include relatively non-invasive methods, such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or their pharmaceutically acceptable salts. It will be understood in the art that suitable forms include syrups, capsules, and tablets.

[0184] 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.

[0185] Individually or separately formulated medications may be packaged together in a pillbox. Non-limiting examples include, but are not limited to, pillboxes containing, for example, two pills, one pill and powder, suppositories, or liquids in vials, two topical creams, etc. The pillbox may include optional components to facilitate the administration of a unit dose to a subject, such as vials for reconstitution of the powder form, syringes, custom IV delivery systems, inhalers, etc. Additionally, the unit-dose pillbox may contain instructions for the preparation and administration of the composition. The pillbox may be manufactured for 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 pillbox may contain multiple doses suitable for administration to multiple subjects (“integral package”). The pillbox assembly may be assembled in a carton, blister pack, bottle, tube, etc.

[0186] Oral formulations include tablets containing a mixture of an active ingredient and a non-toxic, pharmaceutically acceptable excipient. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating agents and disintegrants (e.g., cellulose derivatives, including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginate, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, optionally substituted hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow aids, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may include colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0187] Two or more compounds may be mixed together in tablets, capsules, or other media, or they may be separated. In one example, the first compound is contained on the inside of the tablet, and the second compound is on the outside, such that the majority of the second compound is released before the first compound is released.

[0188] Oral formulations 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, for example, a mixer, a fluid bed apparatus, or a spray drying device.

[0189] Controlled release through dissolution or diffusion can be achieved by appropriately coating the compound into 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 aforementioned coating substances, 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 hydrogels, 1,3-butanediol, ethylene glycol methacrylate, or polyethylene glycol. In controlled-release matrix formulations, matrix materials may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene or halogenated fluorocarbons.

[0190] Liquid forms of compounds or pharmaceutically acceptable salts and compositions thereof that can be incorporated into the present invention for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical carriers.

[0191] Generally, when administered to humans, the oral dose of any of the compounds 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. Dosages 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.

[0192] In some embodiments, the pharmaceutical composition may further comprise additional compounds having antiproliferative activity. Depending on the administration regimen, the compounds or pharmaceutically acceptable salts thereof will be formulated into suitable compositions for easy delivery. Each compound 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. Ideally, the first and second agents are formulated together for simultaneous or near-simultaneous administration of the agents.

[0193] It should be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated together with one or more other desired therapeutic agents or medical procedures, or administered concurrently with, before, or after the administration of said one or more other desired therapeutic agents or medical procedures. The specific combination of the therapies (therapeutic agents or procedures) used in a 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 they may achieve different effects (e.g., controlling any adverse effects).

[0194] As described in this article, each drug in the combination therapy can be administered independently from once to four times daily for one day to one year, and even for the subject's entire life. Chronic long-term administration may be required.

[0195] 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.

[0196] 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 a 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, appendiceal 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 appendiceal 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 a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.

[0197] 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 that can be treated by the compounds of the present invention or salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods include, but are not limited to, the following tumor types: astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral cavity, ovarian, prostate, and thyroid cancers 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, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal tract, such as: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet tumor, 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 tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian 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.

[0198] In some implementations, the Ras protein is wild-type (Ras WT Therefore, in some embodiments, the compounds of the present invention are used to treat patients suffering from Ras WT (e.g. K-Ras) WT H-Ras WT or N-Ras WT In methods for treating cancer patients, Ras protein is amplified (e.g., K-Ras) in some implementations. amp Therefore, in some embodiments, the compounds of the present invention are used to treat patients suffering from Ras amp (K-Ras amp H-Ras amp or N-Ras amp In methods for treating patients with cancer. In some embodiments, the cancer comprises a Ras mutation, such as the Ras mutation described herein. In some embodiments, the mutation is selected from: (a) The following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V, and combinations thereof; (b) The following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R, and combinations thereof; and (c) The following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T, and combinations thereof; Or a combination of any of the foregoing. In some embodiments, the cancer contains 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 contains N-Ras mutations selected from the group consisting of: G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer contains H-Ras mutations selected from the group consisting of Q61H and Q61L. In some embodiments, the cancer contains 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 more than one Ras mutant. 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. 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-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 WT 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 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).

[0199] Methods for detecting Ras mutations are known in the art. Such methods include, but are not limited to, direct sequencing and the use of highly sensitive diagnostic assays (using CE-IVD markers), such as those described in Domagala et al., Pol J Pathol 3: 145-164 (2012), which are incorporated herein by reference in their entirety, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreenPyro. See also, for example, WO 2020 / 106640.

[0200] In some embodiments, the cancer is non-small cell lung cancer and the Ras mutation includes a K-Ras mutation, such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is colorectal cancer and the Ras mutation includes a K-Ras mutation, such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is pancreatic cancer and the Ras mutation includes a K-Ras mutation, such as K-Ras G12D or K-Ras G12V. In some embodiments, the cancer is pancreatic cancer and the Ras mutation includes an N-Ras mutation, such as N-Ras G12D. In some embodiments, the cancer is melanoma and the Ras mutation includes an N-Ras mutation, such as N-Ras Q61R or N-Ras Q61K. 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 ).

[0201] 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 Mutation. In some embodiments, the cancer is non-small cell lung cancer and contains K-Ras G12C mutation and STK11 mutation. LOF Mutations. In some implementations, the cancer includes K-Ras G13C 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 G12C or 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, ovarian cancer, bile duct cancer, or mucinous appendix 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 ).

[0202] 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.

[0203] Combination therapy The methods of the present invention may include the compounds of the present invention used alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). 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 through isoradiometric analysis (e.g., Black et al.). Neurology 65:S3-S6 (2005)).

[0204] The compounds of the present invention may be administered before, after, or simultaneously with one or more of such additional therapies. When combined, the dosage of the compounds of the present invention and the dosage of the one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). The compounds of the present invention and additional therapies, such as anticancer agents, may be administered together, for example, as a single pharmaceutical composition, or separately, and when administered separately, this may occur simultaneously or sequentially. Such sequential administration may be close or distant in time.

[0205] In some embodiments, the additional therapy is the administration of a side effect limiter (e.g., an agent designed to reduce the occurrence or severity of treatment side effects). For example, in some embodiments, the compounds of the present invention may also be used in combination with a therapeutic agent for treating nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0206] 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.

[0207] In this combination therapy section, all references are incorporated by way of citation for the drugs described, whether or not they are explicitly stated.

[0208] 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 acceptor metastasis (ACT) therapy.

[0209] 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.

[0210] Radiation therapy can be used to inhibit abnormal cell growth or treat hyperproliferative conditions, such as cancer, in subjects (e.g., mammals, such as humans). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered via one or a combination of several methods, including but not limited to external beam therapy, internal radiation therapy, implantation radiation, stereotactic radiosurgery, whole-body radiation therapy, radiotherapy, and sustained or transient interstitial brachytherapy. As used herein, the term "brachytherapy" 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. The term is intended, but 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 opsonizers in this invention include solids and liquids. As a non-limiting example, the radioactive source may be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material may also be a fluid made from a solution of any radionuclide, such as a solution of I-125 or I-131, or the radioactive fluid may be prepared using a slurry of a suitable fluid containing solid radionuclide particles, such as Au-198 or Y-90. Furthermore, the radionuclide may be embedded in a gel or radioactive microspheres.

[0211] In some embodiments, the compounds of the present invention can make abnormal cells more sensitive to radiotherapy, thereby killing or inhibiting the growth of such cells. Therefore, the present invention also relates to a method for making abnormal cells in a mammal sensitive to radiotherapy, the method comprising administering to the mammal a quantity of a compound of the present invention, said quantity being effective in making the abnormal cells sensitive to radiotherapy. The amount of the compound in this method may be determined according to the manner used to determine the effective amount of such compounds 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.

[0212] In some embodiments, the non-pharmacological treatment is T-cell acceptor transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells may be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. The source of the T cells is obtained from a subject before the T cells are expanded and genetically modified. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments of 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), the T cells can typically be activated and expanded using methods described, for example, in the following U.S. patents: 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041.

[0213] Therapeutic agents Therapeutic agents can be compounds used to treat cancer or its related symptoms.

[0214] 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 cortisone. isone, cortivazol, deflazacort, desonide, deoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasolpropionate, halometasone, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate furoate, paramethasone, prednicarbate, prednisolone, prednisolone 2,5-diethylaminoacetic acid, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0215] 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 others. International 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.

[0216] The therapeutic agent may be a biological agent (e.g., a cytokine, such as interferon or interleukin, such as 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.

[0217] 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 an inhibitor or antagonist of PDL-2 (e.g., an inhibitory antibody or Fc fusion compound or a small molecule inhibitor) (e.g., a PDL-2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist 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 (e.g., an inhibitory antibody or a small molecule inhibitor).In some embodiments, 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.

[0218] Therapeutic agents may be anti-TIGIT antibodies, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A or OMP-313M32 (etigilimab).

[0219] 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, chemotherapeutic agents or targeted therapies.

[0220] 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).

[0221] Other non-limiting examples of anticancer agents include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); and Iressa®. Gefitinib; alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; azacyclopropanes, such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and tris(hydroxymethylmelamine); polyacetyl (especially bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin, and bizelesin); cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues, 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 enediyne 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, cactinomycin C, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins, actinomycin D (dactinomycin), daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, adriamycin (doxorubicin), morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinyl-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (such as mitomycin C), mycophenolic acid, nogalamycin, olivomycin, pelomycin Peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, pteropterin, and trimetrexate;Purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azouridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and fluxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenergics, such as aminoglutethimide, mitotane, and trilostane; and folic acid supplements, such as frolic acid. 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 ansamitocin; 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; tenuazonicacid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecene, 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 engineered with albumin and free of polyoxyethylene hydrogenated castor oil), 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®; novantrone;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.

[0222] Additional, unrestricted 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 sulfoxide sulfoximine), CBV(Chemotherapy), calyculin, dichloroacetic acid, discormolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, lanigida (l aniquidar), 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, triplatintetranitrate, tri(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar.

[0223] 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, bleomycin, 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 abemacic acid). lib), 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 analogues),And streptozocin), trazenes-dacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites (e.g., folic acid analogs), pyrimidine analogs (e.g., fluorouracil, azuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole) and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoyl anilidehydroamic acid, vorinostat, LBH) 589. Romidesin, 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., GRN163L), 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), PI3K / 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.

[0224] In some implementations, the anticancer agent is selected from methicillin, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analogue or derivative variant thereof.

[0225] In some embodiments, the anticancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies, such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); and small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa®), erlotinib (Tarceva®), pilitinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW2992, ARRY-334543, and JNJ-26483327.

[0226] 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.

[0227] 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), SOS1 inhibitors (e.g., BI-1701963, BI-3406), Raf inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, AKT inhibitors, or mTOR inhibitors (e.g., mTORC1 inhibitors or mTORC2 inhibitors). 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, JNJ-74699157 (ARS-3248), LY3499446). (ARS-853 or ARS-1620) or Ras vaccines or other therapeutic modalities designed to directly or indirectly reduce the carcinogenic activity of Ras.Other examples of Ras inhibitors that can be combined with the Ras inhibitors 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.

[0228] 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. 25 November 2014; 9(11) in; and GSK1120212 (or JTP-74057, described in Clin Cancer Res. 1 March 2011; 17(5):989-1000 in). MAPK inhibitors may be PLX8394, LXH254, GDC-5573 or LY3009120.

[0229] In some implementations, the anticancer agent is a disruptor or 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.

[0230] In some implementations, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0231] 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.

[0232] IGF-1R inhibitors include linsitinib or its pharmaceutically acceptable salts.

[0233] 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 may be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999, ibid.) or Mab C225 (ATCC accession number HB-8508) or antibodies or antibody fragments having binding specificity to them.

[0234] 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 disclosures, and all pharmaceutically acceptable salts of such EGFR inhibitors: EP0520722; EP 0566226; WO96 / 33980; U.S. Patent No. 5,747,498; WO96 / 30347; EP 0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; WO97 / 49688; EP 837063; WO98 / 02434; WO97 / 38983; WO95 / 19774; WO95 / 19970; WO97 / 13771; WO98 / 024 37; WO98 / 02438; WO97 / 32881; DE19629652; 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).

[0235] 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.

[0236] 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)-1-(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 (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinopyridino[3',2':4,5]furano[3,2-d]pyrimidin-2-yl]phenol hydrochloride (available from Axon Medchem); PIK 75 (2-Methyl-5-nitro-2-[(6-bromoimidazolo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazine-benzenesulfonic acid monohydrochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)nicotinamide) (available from Axon Medchem); AS-252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidin-2,4-dione) (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one) (available from Axon Medchem) Medchem); 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.

[0237] 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., U.S. Patent No. 6,656,963; Sarkar and Li J Nutr. 2004, 134(12 Supplement):3493S-3498S); perifoxine (e.g., interfering with Akt membrane localization; Dasmahapatra et al., Clin. Cancer Res. 2004,10(15):5242-52); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res. 2004,64:4394-9).

[0238] 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); Defolimus (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-defolimus Oxyrapamycin; 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 / 05179, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, Derivatives disclosed in 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.

[0239] 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.

[0240] 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.

[0241] 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 contributes to 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.

[0242] SHP2 is involved in signaling 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 self-inhibitory conformation of SHP2 and promote its self-activation or enhanced growth factor-driven activation. Therefore, SHP2 represents a particularly promising target for developing novel therapies for 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 could be a general strategy for preventing tumor resistance in a variety of malignancies.

[0243] 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; WO2017211 303; WO2012041524; WO2017211303; WO2019051084; WO2017211303; US20160030594; US20110281942; WO2010011666; WO2014113584; WO2014176488; WO2017100279; WO20 19051469; US8637684; WO2007117699; WO2015003094; WO2005094314; WO200812481 5; WO2009049098; WO2009135000; WO2016191328; WO2016196591; WO2017078499; WO2 017210134; WO2018013597; WO2018129402; WO2018130928; WO20181309928; WO2018136264; WO2018136265; WO2018160731; WO2018172984; and WO2010121212 are each incorporated into this paper by reference.

[0244] 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.

[0245] 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. 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 MEK inhibitors and SOS1 inhibitors. In some embodiments, the Ras inhibitor of the present invention is used in combination with PDL-1 inhibitors and SOS1 inhibitors. In some embodiments, the Ras inhibitor of the present invention is used in combination with PDL-1 inhibitors and SHP2 inhibitors. In some embodiments, the Ras inhibitor of the present invention is used in combination with MEK inhibitors and SHP2 inhibitors. In some embodiments, the cancer is colorectal cancer and treatment includes administration of a combination of the Ras inhibitor of the present invention and a second or third therapeutic agent.

[0246] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0247] 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.

[0248] 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).

[0249] 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 / 121168 A1), and are also described elsewhere in this article.

[0250] 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.

[0251] 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 may be agonists, antagonists, allosteric modulators, toxins, or more generally, may 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.

[0252] 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, tesiromolimus (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 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.

[0253] Other exemplary anti-angiogenic agents include 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™, and 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); AZD 2171 (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); Motolamine C (motuporamine C) (BritishColumbia University, Canada); CDP 791 (Celltech Group, UK); atiprimod (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (HarvardUniversity, USA); AE 941 (Aeterna, Canada); Angiogenesis vaccine (EntreMed, USA); Urokinase plasminogen activator inhibitor (Dendreon, USA); Oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, UK); CEP 5214 (Cephalon, USA); BAYRES 2622 (Bayer, Germany); InKine (USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP564959 (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 FLT1 (vascular endothelial growth factor receptor 1) (Merck&Co, USA); Tie-2 ligand (Regeneron, USA); and thromboprotein 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0254] 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.

[0255] 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), leucine, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vincristine. Additionally, antisense or siRNAs that inhibit the expression of proteins including, but not limited to, ATG5 (involved in autophagy) may also be used. In some embodiments, one or more of the additional therapies include an autophagy inhibitor.

[0256] 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, cytarabineocfosfate, and DA 3030. (Dong-A), daclizumab, 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, beta-epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphatePhosphate), formestane, formustin, gallium nitrate, gemcitabine, gemtuzumab / ozogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid (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-1β, Iobenguane, Irinotecan, Isograstim, Lanreotide, LC 9018 (Yakult), Leflunomide, Lenograstim, Lentinansulfate, 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, erythropoiesis-stimulating protein, NSC 631570 Octreotide, Oprelvekin, Osaterone, Oxaliplatin, Pacific Paclitaxel, Pamidronicacid, Pegaspargase, Pegylated Interferon Alpha-2b, Pentosan Polysulfatesodium), pentostatin, picibanil, pirubicin, rabbit anti-thymocyte polyclonal antibody, pegylated interferon α-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium hydroxyethylphosphonate Re 186, retinamide (RII), rituximab, romurtide, samarium lecithin (153) Sm)(samarium lexidronam), sargramostim, sizofiran, sobuzoxane, sonermin, strontium chloride-89, suramin, tasonermin, tazarotene, tegafur, 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, zinostatinstimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01Amgen, fulvestrant, galocitabine, gastrin-17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab 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, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl proerythrin ethyletiopurpurin), tirapazamine, Biomira cancer vaccine, melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysis product vaccine (New York Medical Center)College, viral melanoma cell lysis product vaccine (Royal Newcastle Hospital), or valspodar.

[0257] 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 bemtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); Baliximab (Simulect®); Belimumab (Benlysta®); Brentuximab vedotin (Adcetris®); Canakinumab (Ilaris®); Pediatric glycol conjugate certolizumab (Cimzia®); Zenapax®; Daratumumab (Darzalex®); Denosumab (Prolia®); Eculizumab (Soliris®); Efalizumab (Raptiva®); Gemtuzumab / Ozogamicin (Mylotarg®); Golimumab (Simponi®); ibritumomab 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.

[0258] 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 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. Such 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 and any pharmaceutical agents described herein may be formulated together into the same dosage form and administered simultaneously. Alternatively, the compounds of the present invention and any therapies described herein may be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, the compounds of this disclosure may be administered first and then followed by any therapies described herein, or vice versa. In some embodiments of separate administration, the compounds of the present invention and any therapies described herein are administered at intervals of minutes, hours, or days.

[0259] In some embodiments of any of the methods described herein, a first therapy (e.g., a 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.

[0260] The present invention also provides a medicine box comprising (a) a pharmaceutical composition including 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 medicine box comprises (a) a pharmaceutical composition including 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.

[0261] 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 combining individual pharmaceutical compositions in a kit form. The kit may contain two individual pharmaceutical compositions: the compound of the invention and one or more additional therapies. The kit may include a container for containing the individual compositions, such as a dispensing vial or a dispensing foil package. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit may include instructions for the use of the individual components. The kit form is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral), when administered at different dosing intervals, or when the prescribing healthcare professional wishes to adjust the individual components in the combination.

[0262] Implementation plan with numbering [1] A compound or a pharmaceutically acceptable salt thereof having the structure of 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heteroarylene; B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9' or >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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; 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 is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; X 1 It is optionally substituted with a 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 ynyl, 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' is 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 It can be either C or N independently; Y5 It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 1 It is a cyano group, optionally substituted C1-C6 alkyl group, optionally substituted C1-C6 heteroalkyl group, optionally substituted 3- to 6-membered cycloalkyl group, optionally substituted 3- to 6-membered cycloalkenyl group, optionally substituted 3- to 6-membered heterocycloalkyl group, optionally substituted 6- to 10-membered aryl group, or optionally substituted 5- to 10-membered heteroaryl group, or R 1 and R 2 Together with the atoms to which they are attached, they form optionally substituted 3- to 14-membered heterocyclic alkyl groups; R 2 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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 R8 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, a halogen, an optionally substituted C1-C3 alkyl group, 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 H, 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 optionally substituted C1-C6 alkyl; or R 9 and R 9' It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R 10a It is hydrogen or a halogen group; R 11 It is hydrogen or C1-C3 alkyl; and R 21 It is an H or C1-C3 alkyl group.

[0263] [2] The compound as described in paragraph [1] or a pharmaceutically acceptable salt thereof, wherein G is a C1-C4 heteroalkylene group that is optionally substituted.

[0264] [3] The compound or a pharmaceutically acceptable salt thereof as described in paragraph [1] or [2], wherein the compound has the structure of formula Ic: 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-membered heteroarylene; 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; L is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; 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 ynyl, 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' is 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 It can be either C or N independently; Y 5 and Y 6 It can be CH or N independently; R 1It is a 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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; R8' 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 a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted. R 10 It is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; and R 11 It is hydrogen or C1-C3 alkyl.

[0265] [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.

[0266] [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.

[0267] [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.

[0268] [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.

[0269] [8] The compound or a pharmaceutically acceptable salt thereof as described in paragraph [7], wherein R 11 It is a methyl group.

[0270] [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 Id: 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 ynyl, 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' is 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 It can be either C or N independently; Y 5 and Y 6 It can be CH or N independently; R 1 It is a 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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 R10 It is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl.

[0271]

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

[0272]

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

[10] , wherein X 1 It is methylene.

[0273]

[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.

[0274]

[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 is optionally substituted with a halogen.

[0275]

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

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

[0276]

[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.

[0277]

[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.

[0278]

[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.

[0279]

[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.

[0280]

[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.

[0281]

[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.

[0282]

[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.

[0283]

[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.

[0284]

[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.

[0285]

[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 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; R 1 It is a 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 3Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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 R10 It is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl.

[0286]

[25] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [3] to

[24] , wherein R 6 It is hydrogen.

[0287]

[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.

[0288]

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

[26] , wherein R 2 It is a C1-C6 alkyl group that is optionally substituted.

[0289]

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

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

[0290]

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

[28] , wherein R 7 It is a C1-C3 alkyl group that is optionally substituted.

[0291]

[30] The compound as described in paragraph 29 or a pharmaceutically acceptable salt thereof, wherein R 7 It is a C1-C3 alkyl group.

[0292]

[31] The compound or a pharmaceutically acceptable salt thereof as described in any one of paragraphs [1] to 30, wherein R 8 It is a C1-C3 alkyl group that is optionally substituted.

[0293]

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

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

[0294]

[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 If: 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; R 1 It is a 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 a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted.

[0295]

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

[33] , wherein R 1 It is a 6- to 10-membered aryl group that is optionally substituted, a 3- to 6-membered cycloalkenyl group that is optionally substituted, or a 5- to 10-membered heteroaryl group that is optionally substituted.

[0296]

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

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

[0297]

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

[35] , wherein R 1 yes .

[0298]

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

[36] , wherein R 1 yes .

[0299]

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

[37] , wherein the compound has the structure of formula Ig: 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; R 2 It is a C1-C6 alkyl, C1-C6 fluoroalkyl, 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 a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted. X e and X f It is either N or CH independently; and R 12 It is a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, or a 3- to 7-membered heterocyclic alkyl group that is optionally substituted.

[0300]

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

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

[0301]

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

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

[0302]

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

[38] to

[40] , wherein R12 It is a C1-C6 heteroalkyl group that is optionally substituted.

[0303]

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

[38] to

[41] , wherein R 12 yes .

[0304]

[43] The compound or a pharmaceutically acceptable salt thereof as described in paragraph [1] or [2], wherein the compound has the structure of formula 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5 to 10-membered heteroarylene; B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9' or >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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; 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 is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, acetal, haloacetal or acetal sulfone; X 1 It is optionally substituted with a 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 ynyl, 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 It can be either C or N independently; Y 5 It is CH, CH2, or N; Y 6 It is C(O), CH, CH2, or N; R 2 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 Combined with the atoms to which they are attached, they form optionally substituted 3- to 8-membered cycloalkyl groups or optionally substituted 3- to 14-membered heterocycloalkyl groups; R 4 It is absent, and is hydrogen, halogen, cyano, or optionally substituted with 1 to 3 halogens; R 5 It is hydrogen, a C1-C4 alkyl group optionally substituted with a halogen, a cyano group, a hydroxyl group or a C1-C4 alkoxy group, a cyclopropyl group or a cyclobutyl group; 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, a halogen, an optionally substituted C1-C3 alkyl group, 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 H, 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 optionally substituted C1-C6 alkyl; or R 9 and R 9' It combines with the atoms it is attached to to form 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl; R 10 It is hydrogen, halogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R 10a It is hydrogen or a halogen group; R 11 It is hydrogen or C1-C3 alkyl; R 21 It is hydrogen or a C1-C3 alkyl group (e.g., methyl); and X e and X f It can be either N or CH on its own.

[0305]

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

[43] , wherein the compound has the structure of formula VIa: Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, or a 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; L is absent or is a connector; W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynone, or alkynyl sulfone; X 1 It is optionally substituted with a 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 ynyl, 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, C1-C6 fluoroalkyl, 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 9It is a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted. X e and X f It can be either N or CH independently; R 11 It is hydrogen or C1-C3 alkyl; and R 21 It is hydrogen or C1-C3 alkyl.

[0306]

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

[43] or

[44] , wherein the compound has the structure of formula VIb: Wherein A is a substituted 3- to 6-membered cycloalkylene, a substituted 3- to 6-membered heterocycloalkylene, a substituted 6-membered arylene, or a 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 cycloalkylene; optionally substituted 3 to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5 to 6-membered heteroarylene; R 9 It is a C1-C6 alkyl group that is optionally substituted, a C1-C6 heteroalkyl group that is optionally substituted, a 3- to 6-membered cycloalkyl group that is optionally substituted, or a 3- to 7-membered heteroalkyl group that is optionally substituted. L either does not exist or is a connector; and W is a crosslinking group, which includes vinyl ketone, vinyl sulfone, alkynyl ketone, or alkynyl sulfone.

[0307]

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

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

[0308]

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

[46] , wherein A has the following structure: Where R 13 It is hydrogen, a halogen group, a hydroxyl group, an amino group, an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C6 heteroalkyl group; and R 13a It is hydrogen or a halogen group.

[0309]

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

[47] , wherein R 13 and R 13aEach is hydrogen.

[0310]

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

[47] , wherein R 13 It is hydroxyl, methyl, fluorine or difluoromethyl.

[0311]

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

[45] , wherein A is a 5- to 6-membered heteroaryl group that is optionally substituted.

[0312]

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

[50] , wherein A is: .

[0313]

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

[45] , wherein A is an optionally substituted C1-C4 heteroalkylene group.

[0314]

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

[52] , wherein A is: .

[0315]

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

[45] , wherein A is an optionally substituted 3- to 6-membered heterocyclic alkyl group.

[0316]

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

[54] , wherein A is: .

[0317]

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

[55] , wherein A is .

[0318]

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

[56] , wherein B is -CHR 9 -

[0319]

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

[57] , wherein R 9 It is 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.

[0320]

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

[58] , wherein R 9 yes: .

[0321]

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

[59] , wherein R 9 yes: .

[0322]

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

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

[0323]

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

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

[0324]

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

[61] , wherein B is: .

[0325]

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

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

[0326]

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

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

[0327]

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

[65] , wherein the connector is a structure of formula II: Where A 1 It is the key between the connector and B; A 2 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 groups, optionally substituted C1-C3 heteroalkylene groups, 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 2Each 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 C1-C is arbitrarily replaced 10 Alkylene, optionally substituted C2-C 10 alkenyl, 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.

[0328]

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

[66] , wherein the junction is acyclic.

[0329]

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

[67] , wherein the connector has the structure of formula IIa: Where X a It either does not exist or is N; R 14 It does not contain, is hydrogen or optionally substituted C1-C6 alkyl groups; and L 2 The C1-C4 alkylene group is absent, is -SO2-, optionally substituted, or optionally substituted. Where X a R 14 or L 2 At least one of them does not exist.

[0330]

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

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

[0331]

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

[66] , wherein the connector is or comprises a cyclic portion.

[0332]

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

[70] , wherein the linker has the structure of formula IIb: Where o is 0 or 1; R 15 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; X 4 It is absent, or is optionally substituted C1-C4 alkylene, O, NCH3, or optionally substituted C1-C4 heteroalkylene; Cy is a optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heteroalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to 10-membered heteroalkylene; and L 3 It is absent, is -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene.

[0333]

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

[71] , wherein the linker has the following structure: Where R 15 It is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heteroalkylene; and R 15a R 15b R 15c R 15d R 15e R 15f and R 15g Independently, it is hydrogen, halogen, hydroxyl, cyano, amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, or R 15b and R 15d It combines with the carbon to which it is attached to form optionally substituted 3 to 8-membered cycloalkylene or optionally substituted 3 to 8-membered heteroalkylene.

[0334]

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

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

[0335]

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

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

[0336]

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

[74] , wherein W is a crosslinking group comprising vinyl ketone.

[0337]

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

[75] , wherein W has the structure of formula IIIa: Where R 16a R 16b and R 16c Independently hydrogen; -CN; halogen; or -C1-C3 alkyl group optionally substituted with one or more substituents, wherein the one or more substituents are independently selected from -OH, -O-C1-C3 alkyl, -NH 2、 -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or 4 to 7-membered saturated heterocyclic alkyl groups.

[0338]

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

[76] , wherein W is: .

[0339]

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

[74] , wherein W is a crosslinking group comprising an acetylacetonate.

[0340]

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

[78] , wherein W has the structure of formula IIIb: Where R 17 It is hydrogen; a -C1-C3 alkyl group optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or a 4- to 7-membered saturated cycloalkyl; or a 4- to 7-membered saturated heterocycloalkyl.

[0341]

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

[79] , wherein W is: .

[0342]

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

[74] , wherein W is a crosslinking group comprising vinyl sulfone.

[0343]

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

[81] , wherein W has the structure of formula IIIc: Where R 18a R 18b and R 18c Independently hydrogen; -CN; or -C1-C3 alkyl optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or 4 to 7 membered saturated heterocyclic alkyl.

[0344]

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

[82] , wherein W is: .

[0345]

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

[74] , wherein W is a crosslinking group comprising an alkynyl sulfone.

[0346]

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

[84] , wherein W has the structure of formula IIId: Where R 19 It is hydrogen; a -C1-C3 alkyl group optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or a 4- to 7-membered saturated heterocyclic alkyl group; or a 4- to 7-membered saturated heterocyclic alkyl group.

[0347]

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

[85] , wherein W is: .

[0348]

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

[74] , wherein W has the structure of formula IIIe: Where X e It is halogen; and R 20 It is hydrogen; a -C1-C3 alkyl group optionally substituted with one or more substituents, said one or more substituents being independently selected from -OH, -O-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2; or a 4- to 7-membered saturated heterocyclic alkyl group.

[0349]

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

[0350]

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

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

[0351]

[90] A conjugate or a salt thereof, said conjugate or salt thereof comprising the structure of formula IV: Where L is the connector; P is the monovalent organic fraction; and M has the structure of 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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or optionally substituted 5- to 6-membered heteroarylene; B does not exist; it is -CH(R) 9 )-、>C=CR 9 R 9' or >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 cycloalkylene; optionally substituted 3- to 6-membered heteroalkylene; optionally substituted 6-membered arylene; or 5- to 6-membered heteroalkylene; G is an opt...

Claims

1. Compounds having the structure of formula Int-1: Or its salt, wherein: Q represents hydrogen, -B(OH)2. Or halogen; Z is hydrogen or an optionally substituted C1-C6 alkyl group; Y is a halogen, -B(OH)2. -CO2H, -CO2-(C1-C6 alkyl) or -CN; E is , , or ; and PNG is a protecting group.

2. The compound of claim 1, wherein E is .

3. The compound of claim 1, wherein E is .

4. The compound of claim 3, wherein E is .

5. The compound of claim 1, wherein E is .

6. The compound of claim 1, wherein E is .

7. The compound of claim 1, wherein the compound has the structure of formula Int-1a: 。 8. The compound of claim 1, wherein the compound has the structure of formula Int-1b: 。 9. The compound of claim 1, wherein the compound has the structure of formula Int-1c: 。 10. The compound of claim 1, wherein the compound has the structure of formula Int-1d: 。 11. The compound of claim 1, wherein the compound has the structure of formula Int-1e: 。 12. The compound of claim 1, wherein the compound has the structure of formula Int-1f: 。 13. The compound of any one of claims 1 to 12, wherein Q is H.

14. The compound of any one of claims 1 to 12, wherein Q is a halogen.

15. The compound of any one of claims 1 to 12, wherein Z is H or optionally a C1-C6 alkyl group substituted with a halogen.

16. The compound of any one of claims 1 to 12, wherein Z is H or an optionally substituted ethyl group.

17. The compound of claim 16, wherein Z is .

18. The compound of claim 16, wherein Z is .

19. The compound of claim 13, wherein Z is H.

20. The compound of claim 13, wherein Z is an optionally substituted C1-C6 alkyl group.

21. The compound according to any one of claims 1 to 6, wherein: Z is H or an ethyl group with optional substitution; Q is H or a halogen; and Y is Br, -B(OH)2, or .

22. The compound of claim 1, wherein: Z is H, or ; Q is H; and Y is Br.

23. The compound according to any one of claims 1 to 6, wherein Y is Br, -B(OH)2, or .

24. The compound of claim 6, 11 or 12, wherein PNG is Ac, TBS or TBDPS.

25. A compound selected from those consisting of: , , , and .

26. The compound of claim 25, wherein the compound is: 。 27. The compound of claim 25, wherein the compound is: 。 28. The compound of claim 25, wherein the compound is: 。 29. The compound of claim 25, wherein the compound is: 。 30. The compound of claim 25, wherein the compound is: 。 31. A compound selected from those consisting of: , , , , , and .

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