Ras inhibitors

Abstract

The present disclosure is characterized by macrocyclic compounds capable of inhibiting Ras protein, as well as their pharmaceutical components and protein complexes, and their use in cancer treatment.

Description

Prior Technology

[0001] The vast majority of small molecule drugs work by binding to functionally important pockets on the target protein, thereby regulating the activity of the protein. For example, cholesterol-lowering drugs known as statins bind to the enzymatic active site of HMG-CoA reductase, thereby preventing the enzyme from engaging its substrate. In fact, many such drug / target interaction pairs are known, which may be misleading to believe that small molecule modulators against 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 can be targeted by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019). The remaining 90% are currently considered refractory or refractory to the aforementioned small molecule drug discovery. Such targets are often referred to as "undruggable". Such undruggable targets include the vast and often untapped reservoir of medically important human proteins. Therefore, there is great interest in discovering novel molecular modalities that can modulate the function of such undruggable targets.

[0002] It is well established in the literature that Ras proteins (K-Ras, H-Ras, and N-Ras) play critical roles in a variety of human cancers and are therefore suitable targets for anticancer therapy. In fact, about 30 percent of all human cancers in the United States are caused by mutations in the Ras protein, and many of these cancers are fatal. Ras protein dysregulation caused by activating mutations, overexpression or upstream activation is common in human tumors, and activating mutations of Ras are often found in human cancers. For example, an activating mutation at codon 12 in the Ras protein significantly biased the population of Ras muteins toward the "on" (GTP-bound) state by inhibiting the GTPase-activating protein (GAP)-dependent and intrinsic GTP hydrolysis rate (Ras (ON)), leading to oncogenic MAPK signaling to function. Notably, Ras exhibits picomolar affinity for GTP, enabling Ras activation even in the presence of low concentrations of this nucleotide. Mutations in Ras at codons 13 (eg G13D) and 61 (eg Q61K) also result in oncogenic activity in some cancers.

[0003] Despite extensive drug discovery efforts targeting Ras over the past few decades, no drugs that directly target Ras have been approved. More efforts are needed to discover additional medicines for cancers driven by various Ras mutations.

Content of invention

[0005] Provided herein are Ras inhibitors. The methods described herein require the formation of a high-affinity three-component complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g. Ras), and cytoplasmic chaperones (presentation proteins) that are ubiquitously expressed in cells (such as cyclophilin A). More specifically, in some embodiments, the Ras inhibitors described herein work by driving the formation of a high-affinity ternary complex or conjugate between a Ras protein and the ubiquitously expressed cytoplasmic chaperone protein cyclophilin A (CYPA). Induction of new binding pockets in Ras. Without being bound by theory, the inventors believe that one way in which the compounds of the present invention and complexes or conjugates thereof exert inhibitory effects on Ras is by sterically blocking Ras and downstream effector molecules, such as RAF, required for the propagation of oncogenic signaling. and the interaction site between PI3K.

[0006] Accordingly, in some embodiments, the disclosure features a compound of formula I, or a pharmaceutically acceptable salt thereof: Formula I wherein the dotted lines represent zero, one, two, three or four Non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; 3 to 6 members optionally substituted Cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkyl; optionally substituted 6 membered aryl; or optionally substituted 5 to 10 membered heteroaryl; B is -CH (R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6-membered heterocycloalkylene; optionally substituted 6-membered aryl; or 5-6 membered heteroaryl; G is optionally substituted C1-C4 alkylene; optionally substituted C1- C4 alkenylene; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH (R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3 to 8 membered heteroaryl; L is absent or is a linker; W is hybrid A linking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, Trifluoromethylketone, boronic acid, borate esters, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, Azolium or enose; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O )OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or as the case may be Substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-C6 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl, or R1 and R2 in combination with The connected atoms are combined to form an optionally substituted 3- to 14-membered heterocycloalkyl; R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl , optionally substituted C2-C6 alkynyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-7 membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted Optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered cycloalkyl Member heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano or methyl substituted by 1 to 3 halogens as appropriate; R5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, Hydroxy or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or the carbon to which R6 and R7 are attached Atoms are combined to form optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R8 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 3-8 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 the carbon atom to which R7 and R8 are attached Combined together form C=CR7'R8'; 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; R7a and R8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or a combination of carbons to which they are attached together form a carbonyl group; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted Substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-C6 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7' and R8' are combined with the carbon atoms to which they are attached to form optionally Substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 Heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl, or R9 and L combined with the atoms to which they are attached form optionally substituted 3 to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl (eg methyl).

[0007] A pharmaceutical composition is also provided, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] Further provide a conjugate or a salt thereof, comprising a structure of formula IV: M-L-P formula IV wherein L is a linker; P is a monovalent organic moiety; and M has a structure of formula V: formula V wherein the dotted line represents zero, One, two, three or four non-adjacent double bonds; A series -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bound to the carbon atom of -CH(R10)- ; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered arylylene; or optionally substituted 5 to 6 membered Membered heteroaryl; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6 membered ring Alkyl; optionally substituted 3 to 6 membered heterocycloalkyl; optionally substituted 6 membered aryl; or 5 to 6 membered heteroaryl; G is optionally substituted C1-C4 Alkyl; optionally substituted C1-C4 alkenylene; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8) -; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkyl; or 3 to 8 membered heteroaryl; X1 It is an optionally substituted C1-C2 alkylene group, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, Optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O) ) N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkane Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R1 is cyano, Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted Optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl, or R1 and R2 are combined with the atoms to which they are attached Form an optionally substituted 3 to 14 membered heterocycloalkyl; R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2 - C6 alkynyl, 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 R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 14 membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxyl or C1-C4 alkoxy R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms they are attached to form as appropriate Substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R8 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 3-8 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 R7 and R8 are combined with the carbon atom to which they are attached to form C=CR7 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; R7a and R8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or carbonyl combined with the carbon to which they are attached; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' 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 R7' and R8' combined with the carbon atom to which they are attached form an optionally substituted 3 to 6 membered Cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted Substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl, or R9 and L combined with the atoms to which they are attached form an optionally substituted 3 to 14 membered heterocycloalkyl ; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl (eg methyl).

[0009] There is also provided a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, there is provided a method of treating Ras protein-related disorders in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0011] 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.

[0012] In particular, any limitations discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention, with due consideration. Additionally, any compound or composition of the invention can be used in any method of the invention, and any method of the invention can be used to make or utilize any compound or composition of the invention.

Implementation

[0013] Cross reference to related applications

[0014] This application claims U.S. Application No. 62 / 930,406 filed on November 4, 2019; U.S. Application No. 62 / 951,562 filed on December 20, 2019; filed on March 26, 2020 Priority benefit of U.S. Application No. 63 / 000,355, filed June 24, 2020, and U.S. Application No. 63 / 043,523, filed June 24, 2020, all of which are hereby incorporated by reference in their entirety. Definitions and Chemical Terms

[0015] In this application, unless otherwise clear from the context, (i) the term "a (one)" means "one or more"; (ii) the term "or" is used to mean "and / or ”, unless expressly indicated that the term means that the alternatives are the only ones or that the alternatives are mutually exclusive, however, the definition supported by this disclosure means the only alternatives and “and / or”; (iii) the term “comprises” and "comprising" should be understood to encompass the listed components or steps, whether presented alone or in combination with one or more additional components or steps; and (iv) where a range is provided , the endpoint is included.

[0016] As used herein, the term "about" is used to indicate that a value includes the standard deviation of error of the apparatus or method used to determine the value. In certain embodiments, the term "about" refers to a value 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 unless Otherwise stated or otherwise evident from the context (for example when the number would exceed 100% of the possible value).

[0017] As used herein, the term "adjacent" in the context of describing adjacent atoms refers to divalent atoms that are directly linked by a covalent bond.

[0018] As used herein, "compounds of the present invention" and similar terms, whether expressly indicated or not, all refer to the Ras inhibitors described herein, including compounds of formula I and subformulas thereof, and Table 1 and Table 1 2, and salts (such as pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers) and tautomers thereof.

[0019] The term "wild-type" refers to an entity having a structure or activity found in nature in a "normal" (as opposed to mutant, diseased, altered, etc.) state or situation. Those skilled in the art will appreciate that wild-type genes and polypeptides often exist in multiple different forms (eg, alleles).

[0020] Those skilled in the art will appreciate that certain compounds described herein may be present in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) ) or in isotopic form (for example wherein one or more atoms are substituted by a different isotope of the atom, such as hydrogen by deuterium). Unless otherwise indicated or clear from context, depicted structures are understood to represent any such isomeric or isotopic forms, individually or in combination.

[0021] The compounds described herein may be asymmetric (eg, have one or more stereocenters). Unless otherwise indicated, all stereoisomers such as enantiomers and diastereomers are contemplated. Compounds of the disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthetic methods. Many geometric isomers of alkenes, C=N double bonds, and the like may also exist in the compounds described herein, and all such stable isomers are contemplated by this disclosure. Cis and trans geometric isomers of the compounds of the disclosure have been described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0022] In some embodiments, one or more compounds depicted herein can exist in different tautomeric forms. As will be clear from the context, reference to such compounds encompasses all such tautomeric forms unless expressly excluded. In some embodiments, tautomeric forms result from the exchange of one single bond for an adjacent double bond with concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation state having the same empirical formula and overall charge as the reference form. Examples of moieties with prototropic tautomeric forms are keto-enol pairs, amido-imidic acid pairs, lactam-lactamic acid pairs, amido-imidic acid pairs, enamine-imidic acid pairs For cyclic forms, in which protons can occupy two or more positions in the heterocyclic ring system, such as 1H-imidazole and 3H-imidazole, 1H-triazole, 2H-triazole and 4H- 1 ,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. In some embodiments, tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms are obtained by interconversion of acetals.

[0023] Unless otherwise specified, structures depicted herein are also intended to include compounds that differ only by the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I and 125I. Isotopically labeled compounds (eg, compounds labeled with 3H and 14C) can be used in compound or substrate tissue distribution analysis. Tritiated (ie, 3H) and carbon-14 (ie, 14C) isotopes are useful for their ease of preparation and detection. In addition, substitution with heavier isotopes, such as deuterium (ie, 2H), may confer certain therapeutic benefits due to enhanced metabolic stability (eg, increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2H or 3H, or one or more carbon atoms are replaced by a 13C or 14C enriched carbon. Positron emitting isotopes such as 15O, 13N, 11C and 18F 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 following procedures analogous to those disclosed for the compounds of the invention described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0024] As is known in the art, many chemical entities may exist in various solid forms, such as amorphous or crystalline forms (eg, polymorphs, hydrates, solvates). In some embodiments, the compounds of the invention can be used in any such form, including any solid form. In some embodiments, compounds described or depicted herein may be provided in hydrated or solvated form.

[0025] Throughout this specification, substituents of compounds of the disclosure are disclosed as groups or as ranges. In particular, the disclosure is intended to include each individual subgroup of members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl individually. Furthermore, where a compound includes multiple positions, and at those positions substituents are disclosed in groups or in ranges, unless otherwise indicated, the disclosure is intended to encompass every single position containing a member at each position. Individual compounds and groups of compounds (eg, classes and subclasses) in different subgroups.

[0026] The term "optionally substituted X" (eg, "optionally substituted alkyl") is intended to be equivalent to "X, wherein X is optionally substituted" (eg, "alkyl, wherein the alkyl is optionally superseded"). It is not intended to imply that the feature "X" (eg, alkyl) itself is optional. As described herein, certain compounds of interest may contain one or more "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced by a suitable substituent, such as any of the substituents or groups described herein replacement. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be selected from a specified group When more than one substituent is substituted, the substituents at each position may be the same or different. For example, in the term "optionally substituted C1-C6 alkyl-C2-C9 heteroaryl", the alkyl moiety, the heteroaryl moiety, or both are optionally substituted. Combinations of substituents contemplated by this disclosure are preferably those that result in stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially stable when subjected to conditions that permit its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein. do not change.

[0027] Suitable monovalent substituents on substitutable carbon atoms of "optionally substituted" groups may independently be deuterium; halogen; -(CH2)0-4R°; -(CH2)0-4OR°;- O(CH2)0-4R°; -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2) 0-4Ph, which may be substituted by R°; -(CH2)0-4O(CH2)0-1Ph, which may be substituted by R°; -CH=CHPh, which may be substituted by R°; -(CH2)0- 4O(CH2)O-1-pyridyl, which may be substituted by R°; 4 to 8 membered saturated or unsaturated heterocycloalkyl (e.g. pyridyl); 3 to 8 membered saturated or unsaturated cycloalkyl (e.g. ring Propyl, cyclobutyl or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R °; -N(R°)C(S)R°; -(CH2)0-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -( CH2)0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR °2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; -C(S)R°; -(CH2)0-4C( O)OR°; -(CH2)0-4-C(O)-N(R°)2; -(CH2)0-4-C(O)-N(R°)-S(O)2- R°; -C(NCN)NR°2; -(CH2)0-4C(O)SR°; -(CH2)0-4C(O)OSiR°3; -(CH2)0-4OC(O)R °; -OC(O)(CH2)0-4SR°; -SC(S)SR°; -(CH2)0-4SC(O)R°; -(CH2)0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; -(CH2)0-4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C (O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°;- (CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R°; -S(O)2NR°2; -(CH2)0-4S(O)R°; -N( R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NOR°)NR°2; -C(NH)NR° 2; -P(O)2R°; -P(O)R°2; -P(O)(OR°)2; -OP(O)R°2; -OP(O)(OR°)2; -OP (O) (OR °) R °; -SiR ° 3; - (C1-C4 straight chain or branched chain alkyl) O-N (R °) 2; or - (C1-C4 straight chain or branched chain alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, -C1-C6 aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (5 to 6 membered heteroaryl ring), or a 3 to 6 membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur , or notwithstanding the above definition, two independently present R° taken together with intervening atoms form a 3 to 12 membered saturated, partially unsaturated or aryl group having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur Monocyclic or bicyclic, which may be substituted as defined below.

[0028] Suitable monovalent substituents on R° (or a ring formed by two independently existing R° and their intervening atoms) may independently be halogen, -(CH2)0-2R1, -(haloR1), -(CH2)0-2OH, -(CH2)0-2OR1, -(CH2)0-2CH(OR1)2, -O(halogen R1), -CN, -N3, -(CH2)0-2C( O)Rl, -(CH2)0-2C(O)OH, -(CH2)0-2C(O)ORl, -(CH2)0-2SRl, -(CH2)0-2SH, -(CH2)0- 2NH2, -(CH2)0-2NHRl, -(CH2)0-2NRl2, -NO2, -SiRl3, -OSiRl3, -C(O)SRl, -(C1-4 straight chain or branched chain alkyl) C (O) OR1 or -SSR1, wherein each R1 is unsubstituted or substituted with only one or more halogens when preceded by "halo", and is independently selected from C1-C4 aliphatic groups, -CH2Ph , -O(CH2)0-1Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on saturated carbon atoms of R° include =O and =S.

[0029] Suitable divalent substituents on the saturated carbon atoms of the "optionally substituted" groups 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*, at each independent occurrence, is selected from hydrogen; a C1-C6 aliphatic group, which may be substituted as defined below; or an untreated group having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur Substituted 5 to 6 membered saturated, partially unsaturated or aryl rings. Suitable divalent substituents bonded to adjacent substitutable carbons of an "optionally substituted" group include: -O(CR*2)2-3O-, where R*, at each independent occurrence, is selected from hydrogen; C1-C6 aliphatic group, which may be substituted as defined below; or unsubstituted 5-6 membered saturated, partially unsaturated or having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur Aryl ring.

[0030] Suitable substituents on the aliphatic group of R* include halogen, -R1, -(halo R1), -OH, -OR1, -O(halo R1), -CN, -C(O) OH, -C(O)OR1, -NH2, -NHR1, -NR12 or -NO2, wherein each R1 is unsubstituted or substituted with one or more halogens in the case of preceding "halogen", and independently is a C1-C4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 membered saturated, partially unsaturated or having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur Aryl ring.

[0031] Suitable substituents on substitutable nitrogens of "optionally substituted" groups 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†; wherein each R† is independently hydrogen; a C1-C6 aliphatic group which may be substituted as defined below; unsubstituted- OPh; or an unsubstituted 3 to 6 membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or notwithstanding the above definition, two independently R† together with its intervening atoms form a 3 to 12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0032] Suitable substituents on the aliphatic group of R† are independently halogen, -R1, -(haloR1), -OH, -OR1, -O(haloR1), -CN, -C( O)OH, -C(O)OR1, -NH2, -NHR1, -NR12 or -NO2, wherein each R1 is unsubstituted or, where preceded by "halo", is only substituted with one or more halogens, And independently C1-C4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph or 5 to 6 membered saturated, partially unsaturated with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur or aryl ring. Suitable divalent substituents on saturated carbon atoms of R† include =O and =S.

[0033] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0034] As used herein, the term "alkoxy" refers to an -O-C1-C20 alkyl group, wherein the alkoxy group is attached to the rest of the compound through an oxygen atom.

[0035] As used herein, the term "alkyl" refers to a saturated, linear or branched monovalent hydrocarbon group containing 1 to 20 (eg, 1 to 10 or 1 to 6) carbons. In some embodiments, the alkyl group is unbranched (ie, linear); in some embodiments, the alkyl group is branched. Alkyl groups such as, but not limited to, methyl, ethyl, n- and isopropyl, n-butyl, second-, iso-, and third-butyl, and neopentyl.

[0036] As used herein, the term "alkylene" means a saturated divalent hydrocarbon group obtained from a straight-chain or branched saturated hydrocarbon by removing two hydrogen atoms, and examples thereof are methylene, ethylene , isopropyl and similar groups. The term "Cx-Cy alkylene" means an alkylene group having between x and y carbons. Exemplary x values ​​are 1, 2, 3, 4, 5, and 6, and exemplary y values ​​are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (eg C1-C6, C1-C10, C2-C20, C2-C6, C2-C10 or C2-C20 alkylene). In some embodiments, the alkylene group can be further substituted with 1, 2, 3 or 4 substituents as defined herein.

[0037] Unless otherwise specifically stated, otherwise, as used herein, the term "alkenyl" refers to a compound having 2 to 20 carbons (eg, 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds. The monovalent linear or branched chain groups and examples thereof are vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. Alkenyl includes both cis and trans isomers. As used herein, unless specifically stated otherwise, the term "alkenylene" refers to a bis having 2 to 20 carbons (eg, 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds. Valence straight chain or branched chain group.

[0038] As used herein, the term "alkynyl" means a monovalent straight chain having 2 to 20 carbons (eg, 2 to 4, 2 to 6, or 2 to 10 carbons) containing carbon-carbon double bonds or There are branched groups and examples thereof are ethynyl and 1-propynyl.

[0039] As used herein, the term "alkynyl group" means a group comprising the structure wherein R is any chemically feasible substituent described herein.

[0040] As used herein, the term "amino" means -N(R†)2, such as -NH2 and -N(CH3)2.

[0041] As used herein, the term "aminoalkyl" means an alkyl moiety having one or more carbon atoms substituted with one or more amine moieties.

[0042] As described herein, the term "amino acid" refers to a molecule having a side chain, an amine group, and an acid group (such as -CO2H or -SO3H), wherein the amino acid is Acid groups (eg, side chains) are attached to the parent molecular group. 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, eg, via the formation of one or more peptide bonds. In some embodiments, the amino acid has the general 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 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, glutamic acid, glycine, histidine, optionally substituted Hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine amino acid, serine, taurine, threonine, tryptophan, tyrosine and valine.

[0043] As used herein, the term "aryl" denotes a monovalent monocyclic, bicyclic or polycyclic ring system formed of carbon atoms, wherein the ring attached to the pendant group is an aromatic ring. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl and anthracenyl. An aromatic ring may be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure and unless specifically stated otherwise, any ring atom may be optionally substituted.

[0044] As used herein, the term "CO" means a bond. For example, a portion of the term -N(C(O)-(C0-C5alkylene-H)- includes -N(C(O)-(C0alkylene-H)-, which is also represented as- N(C(O)-H)-.

[0045] As used herein, the terms "carbocycle" and "carbocyclyl" refer to monovalent, optionally substituted 3 to 12 membered monocyclic, bicyclic or tricyclic structures which may be bridged, fused Or a spirocyclic ring, wherein all rings are formed by carbon atoms and at least one ring system is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of carbocyclyl are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fenyl, indenyl, dihydroindene group, decahydronaphthyl group and similar groups. A carbocycle may be attached to its pendant group at any ring atom that results in a stable structure and unless specifically stated otherwise, any ring atom may be optionally substituted.

[0046] As used herein, the term "carbonyl" means a C(O) group, which can also be expressed as C=O.

[0047] As used herein, the term "carboxy" means -CO2H, (C=O)(OH), COOH, or C(O)OH, or the unprotonated counterpart.

[0048] As used herein, the term "cyano" means a -CN group.

[0049] As used herein, the term "cycloalkyl" refers to a monovalent saturated cyclic hydrocarbon group, which may be a bridged ring, fused ring or spiro ring having three to eight ring carbons unless otherwise specified, and which Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloheptyl.

[0050] As used herein, the term "cycloalkenyl" means a monovalent, non-aromatic saturated cyclic hydrocarbon group which, unless otherwise specified, may have three to eight ring carbons and contain one or more carbon-carbon Double bond bridged ring, fused ring or spiro ring.

[0051] As used herein, the term "diastereomer" means stereoisomers that are not mirror images of each other and are not superimposable.

[0052] As used herein, the term "enantiomer" means having at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), less Each individual optically active form of a compound of the invention is preferably at least 90% and more preferably at least 98% in optical purity or enantiomer excess (as determined by methods standard in the art).

[0053] The term "guanidino" refers to a group having the structure: wherein each R is independently any chemically feasible substituent described herein.

[0054] As used herein, the term "guanidinoalkylalkyl" means an alkyl moiety having one or more carbon atoms substituted with one or more guanidino moieties.

[0055] As used herein, the term "haloacetyl" refers to an acetyl group in which at least one hydrogen has been replaced with a halogen.

[0056] As used herein, the term "haloalkyl" means an alkyl moiety in which one or more carbon atoms are substituted with one or more halo moieties, which may be the same or different.

[0057] As used herein, the term "halogen" means a halogen selected from bromine, chlorine, iodine or fluorine.

[0058] As used herein, the term "heteroalkyl" refers to an "alkyl" as defined herein in which at least one carbon atom is replaced by a heteroatom (eg, an O, N, or S atom). Heteroatoms can be present either centrally or terminally in the group.

[0059] As used herein, the term "heteroaryl" denotes a monovalent, monocyclic or polycyclic structure containing at least one fully aromatic ring: that is, it contains 4n+2 within the monocyclic or polycyclic system π electrons and contains at least one heteroatom selected from N, O or S in the aromatic ring. Exemplary unsubstituted heteroaryls have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9 )carbon. The term "heteroaryl" includes bicyclic, tricyclic and tetracyclic groups in which any of the aforementioned heteroaromatic rings is fused with one or more aromatic or carbocyclic rings, such as phenyl rings or cyclohexane rings. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolyl, and 4- Azaindolyl. A heteroaryl ring may be attached to its pendant group at any ring atom that results in a stable structure and unless specifically stated otherwise, any ring atom may be optionally substituted. In a certain embodiment, the heteroaryl is substituted with 1, 2, 3 or 4 substituents.

[0060] As used herein, the term "heterocycloalkyl" means at least one ring system non-aromatic ring and wherein the non-aromatic ring contains one, two, three or four independently selected from nitrogen, oxygen and Monovalent, monocyclic, bicyclic or polycyclic ring systems of heteroatoms grouped by sulfur, which may be bridged, fused or spiro rings. 5-membered rings have zero to two double bonds, and 6- and 7-membered rings have zero to three double bonds. Exemplary unsubstituted heterocycloalkyl 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 a) carbon. The term "heterocycloalkyl" also refers to heterocyclic compounds having bridged polycyclic ring structures in which one or more carbon or heteroatoms bridge nonadjacent members of a monocyclic ring, eg, quinuclidinyl. The term "heterocycloalkyl" includes any of the aforementioned heterocycles with one or more aromatic rings, carbocycles, heteroaromatic rings or heterocyclic rings, such as aryl rings, cyclohexane rings, cyclohexene rings, cyclopentene rings, Alkane ring, cyclopentene ring, pyridine ring or pyrrolidine ring fused bicyclic, tricyclic and tetracyclic groups. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridinyl and decahydronaphthyridinyl. A heterocycloalkyl ring may be attached to its pendant group at any ring atom that results in a stable structure and unless specifically stated otherwise, any ring atom may be optionally substituted.

[0061] As used herein, the term "hydroxyl," means an -OH group.

[0062] As used herein, the term "hydroxyalkyl" means an alkyl moiety in which one or more carbon atoms are substituted with one or more -OH moieties.

[0063] As used herein, the term "isomer" means any tautomer, stereoisomer, atropisomer, enantiomer or diastereoisomer of any compound of the present invention . It is recognized that the compounds of the present invention may possess one or more chiral centers or double bonds, and therefore, in stereoisomeric forms, such as double bond isomers (i.e., E / Z geometric isomers ) or diastereomers (eg, enantiomers (ie, (+) or (-)) or cis / trans isomers). According to the present invention, the chemical structures depicted herein and thus the compounds of the present invention encompass all corresponding stereoisomers, i.e., stereomerically pure (e.g. geometrically pure, enantiomerically pure or diastereomerically pure) ) forms as well as enantiomers and stereoisomer mixtures, such as racemates. Enantiomers and stereoisomer mixtures of the compounds of the present invention can typically be obtained by well-known methods, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, and the compound as a chiral salt. Crystallization of the complex form or resolution of the compound into its component enantiomers or stereoisomers by crystallization in chiral solvents. Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents and catalases by well-known asymmetric synthesis methods.

[0064] As used herein, the term "linker" refers to the linking of moiety B to moiety W in a compound of formula I such that the resulting compound can be obtained in the Ras-RAF disruption assay scheme provided in the examples below and provided herein Divalent organic moieties with IC50 values ​​of 2 uM or less: The purpose of this biochemical assay is to measure the ability of a test compound to promote the formation of a ternary complex between a nucleotide-loaded Ras isoform and cyclophilin A ; the resulting ternary complex disrupts binding to the BRAFRBD construct, inhibiting Ras signaling through RAF effectors.

[0065] Containing 25 mM HEPES pH 7.3, 0.002% Tween20, 0.1% BSA, 100 mM NaCl and 5 mM MgCl In the assay buffer solution, unlabeled cyclophilin A, His6-K-Ras-GMPPNP (or other Ras variants) and GST-BRAFRBD were combined in 384-well assay plates at final concentrations of 25 µM, 12.5 nM and 50 nM, respectively. Compounds present in each well of the assay plate were diluted through 10-point 3-fold serial dilutions starting at a final concentration of 30 µM. After 3 hours of incubation at 25°C, the mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was then added to the assay wells to final concentrations of 10 nM and 50 nM, respectively, and the reaction was incubated for an additional 1.5 hours. The TR-FRET signal was read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that promote disruption of the Ras:RAF complex were identified as those that decreased TR-FRET ratios relative to DMSO control wells.

[0066] In some embodiments, the linker comprises 20 or fewer linear atoms. In some embodiments, the linker comprises 15 or fewer linear atoms. In some embodiments, the linker comprises 10 or fewer linear atoms. In some embodiments, the molecular weight of the linker is less than 500 g / mol. In some embodiments, the molecular weight of the linker is less than 400 g / mol. In some embodiments, the molecular weight of the linker is less than 300 g / mol. In some embodiments, the molecular weight of the linker is less than 200 g / mol. In some embodiments, the molecular weight of the linker is less than 100 g / mol. In some embodiments, the molecular weight of the linker is less than 50 g / mol.

[0067] As used herein, a "monovalent organic moiety" is less than 500 kDa. In some embodiments, a "monovalent organic moiety" is less than 400 kDa. In some embodiments, a "monovalent organic moiety" is less than 300 kDa. In some embodiments, a "monovalent organic moiety" is less than 200 kDa. In some embodiments, a "monovalent organic moiety" is less than 100 kDa. In some embodiments, a "monovalent organic moiety" is less than 50 kDa. In some embodiments, a "monovalent organic moiety" is less than 25 kDa. In some embodiments, a "monovalent organic moiety" is less than 20 kDa. In some embodiments, a "monovalent organic moiety" is less than 15 kDa. In some embodiments, a "monovalent organic moiety" is less than 10 kDa. In some embodiments, a "monovalent organic moiety" is less than 1 kDa. In some embodiments, the "monovalent organic moiety" is less than 500 g / mol. In some embodiments, the "monovalent organic moiety" ranges between 500 g / mol and 500 kDa.

[0068] As used herein, the term "stereoisomer" refers to a compound (such as a compound of any of the formulas described herein) that may have all possible different isomeric and configurational forms, particularly those of the basic molecular structure. All possible stereochemical and conformational isomeric forms, all diastereoisomers, enantiomers or configurational isomers, including atropisomers. Some of the compounds of the present invention may exist in different tautomeric forms and all such tautomeric forms are included within the scope of the present invention.

[0069] As used herein, the term "sulfonyl" means a -S(O)2- group.

[0070] As used herein, the term "thiocarbonyl" refers to a -C(S)- group.

[0071] As used herein, the term "vinyl ketone" refers to a group comprising a carbonyl group directly attached to a carbon-carbon double bond.

[0072] As used herein, the term "vinylsulfone" refers to a group comprising a sulfonyl group directly attached to a carbon-carbon double bond.

[0073] As used herein, the term "alkynone" refers to a group comprising the structure wherein R is any chemically feasible substituent described herein.

[0074] Those skilled in the art will appreciate upon reading 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, Isomeric forms (eg, optical or structural isomers), isotopic forms, and the like. In some embodiments, reference to a particular compound may refer to a particular form of that compound. In some embodiments, reference to a particular compound may refer to that compound in any form. In some embodiments, for example, preparations of a single stereoisomer of a compound may be considered as different forms of the compound rather than a racemic mixture of the compound; A different form of another salt; preparations containing one conformational isomer ((Z) or (E)) with a double bond may be considered as identical to the other conformational isomer containing the double bond ((E) ) or (Z)) in different forms; preparations whose isotopes of one or more atoms differ from the isotopes present in the reference preparation may be considered to be in different forms. compound

[0075] Provided herein are Ras inhibitors. The methods described herein require the formation of a high-affinity three-component complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein of interest (e.g. Ras), and cytoplasmic chaperones (presentation proteins) that are ubiquitously expressed in cells (such as cyclophilin A). More specifically, in some embodiments, the Ras inhibitors described herein work by driving the formation of a high-affinity ternary complex between the Ras protein and the ubiquitously expressed cytoplasmic chaperone cyclophilin A (CYPA). Induces new binding pockets. Without being bound by theory, the inventors believe that one way in which the compounds of the present invention and complexes or conjugates formed by them exert their inhibitory effect on Ras is by sterically blocking Ras and downstream effector molecules such as RAF required for the propagation of oncogenic signaling. interaction sites between them.

[0076] Without being bound by theory, the inventors hypothesize that covalent and non-covalent interactions of the compounds of the invention with Ras and chaperone proteins (eg, cyclophilin A) may contribute to the inhibition of Ras activity. In some embodiments, the compounds of the invention form covalent bonds with side chains of the Ras protein (e.g., -CH2-COOH or -CH2-COO- side chains of aspartic acid at positions 12 or 13 of a mutant Ras protein). adduct. It can also form covalent adducts with other side chains of Ras. Additionally or alternatively, non-covalent interactions may play a role: for example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, and combinations thereof may contribute to the formation of compounds of the invention complex and the ability to act as a Ras inhibitor. Therefore, the compounds of the present invention can inhibit various Ras proteins (such as K-Ras, N-Ras, H-Ras and mutants thereof at 12, 13 and 61 mutations, such as G12C, G12D, G12V, G12S, G13C , G13D and Q61L, and other mutants described herein).

[0077] Methods for determining the formation of covalent adducts are known in the art. One way to determine the formation of covalent adducts is to perform a "cross-linking" assay, such as the one described in the Examples and below: NOTE: The following protocol describes monitoring of K-Ras G12C (GMP-PNP) with compounds of the invention The cross-linking procedure. This protocol can also be implemented using other Ras proteins or nucleotides, such as K-Ras G12D.

[0078] The purpose of this biochemical assay is to measure the ability of a test compound to covalently label a nucleotide-loaded K-Ras isoform. 5 µM K-Ras loaded with GMP-PNP ( 1-169) The stock solution of G12C was diluted 10-fold to a final concentration of 0.5 µM; and the final sample volume was 100 µL.

[0079] Samples were incubated at 25°C for a period of up to 24 hours and then quenched by adding 10 µL of 5% formic acid. Quenched samples were centrifuged at 15,000 rpm in a benchtop centrifuge for 15 minutes, after which 10 µL aliquots were injected onto reversed-phase C4 columns and eluted into the mass spectrometer using an increasing gradient of acetonitrile in the mobile phase. Analysis of raw data can be performed using Waters MassLynx MS software, where % binding is calculated from deconvoluted protein peaks of labeled and unlabeled K-Ras.

[0080] Therefore, this paper provides a compound with formula I structure or a pharmaceutically acceptable salt thereof: formula I wherein the dotted line represents zero, one, two, three or four non-adjacent double bonds; - N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted Substituted 3 to 6 membered heterocycloalkyl; optionally substituted 6 membered aryl; or optionally substituted 5 to 10 membered heteroaryl; B is -CH(R9)- or >C= CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; Optionally substituted 6-membered aryl; or 5 to 6-membered heteroaryl; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenyl; Substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, where C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, where C is bonded to To -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3 to 8 membered heteroaryl; L does not exist or is a linker; W is a crosslinking group, which contains carbon dioxide Imine, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, Borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazolium or enose; X1 series Optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; Optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O) N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl ; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R1 is cyano, depending 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 A substituted 3 to 6 membered heterocycloalkyl group, an optionally substituted 6 to 10 membered aryl group or an optionally substituted 5 to 10 membered heteroaryl group, or R1 and R2 are combined with the atoms to which they are attached to form Optionally substituted 3 to 14 membered heterocycloalkyl; R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2- C6 alkynyl, 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; R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 14 membered heterocycloalkyl; R4 is Absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxyl or C1-C4 alkoxy , cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms to which they are attached to form an optional Substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted Substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-C6 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R7 and R8 are combined with the carbon atoms to which they are attached to form C=CR7' C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3 to 6 membered cycloalkyl; A 3- to 7-membered heterocycloalkyl group substituted in some cases; R7a and R8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or a carbonyl group formed when combined with the carbon to which it is attached; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' 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 Optionally substituted 5 to 10 membered heteroaryl or optionally substituted 6 to 10 membered aryl, or R7' and R8' combined with the carbon atoms to which they are attached form an optionally substituted 3 to 6 membered ring Alkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted A 3 to 6 membered cycloalkyl group or an optionally substituted 3 to 7 membered heterocycloalkyl group, or R9 and L are combined with the atoms to which they are attached to form an optionally substituted 3 to 14 membered heterocycloalkyl group; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R10a is hydrogen or halo; and R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl (eg methyl).

[0081] In some embodiments, R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted Substituted 3 to 7 membered heterocycloalkyl.

[0082] In some embodiments, R34 is hydrogen.

[0083] In some embodiments of the compounds of the present invention, G is an optionally substituted C1-C4 heteroalkylene.

[0084] In some embodiments, the compound of the present invention has the structure of Formula Ia, or a pharmaceutically acceptable salt thereof: Formula Ia wherein the dotted lines represent zero, one, two, three or four non-adjacent double bonds ; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; Optionally substituted 3-6 membered heterocycloalkyl; optionally substituted 6-membered aryl; or optionally substituted 5-6 membered heteroaryl; B is -CH(R9)-, where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted Substituted 6-membered aryl; or 5 to 6-membered heteroaryl; L does not exist or is a linker; W is a cross-linking group, which includes carbodiimide, oxazoline, thiazoline, and ethyl chloride Urea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester, N-ethoxycarbonyl-2- Ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enose; X2 is O or NH; X3 is N or CH; n is 0 , 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R ', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' independently is H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 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 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 aromatic radical, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3 to 14-membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 and their The linked carbon atoms are combined to form an optionally substituted 3 to 6 membered cycloalkyl or an optionally substituted 3 to 7 membered heterocycloalkyl; R8 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 members Cycloalkyl, optionally substituted 3 to 14 membered heterocycloalkyl, optionally substituted 5 to 10 membered heteroaryl, or optionally substituted 6 to 10 membered aryl, or to which R7 and R8 are attached The carbon atoms are combined to form C=CR7'R8'; 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; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' 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 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 R7' and R8' are combined with the carbon atoms to which they are attached to form optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, or optionally substituted 3 to 7 membered heterocycloalkyl; R10 is hydrogen, Hydroxy, C1-C3 alkoxy or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0085] In some embodiments of the compounds of the invention, X2 is NH. In some embodiments, X3 is CH.

[0086] In some embodiments of the compounds of the invention, R11 is hydrogen. In some embodiments, R11 is C1-C3 alkyl, such as methyl.

[0087] In some embodiments, the compound of the present invention has a structure of formula Ib, or a pharmaceutically acceptable salt thereof: Formula Ib wherein the dotted lines represent zero, one, two, three or four non-adjacent double bonds ; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; Optionally substituted 3-6 membered heterocycloalkyl; optionally substituted 6-membered aryl; or optionally substituted 5-6 membered heteroaryl; B is -CH(R9)-, where the carbon is bound to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered Extended aryl; or 5 to 6 membered heteroaryl; L does not exist or is a linker; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl Thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester, N-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazolium or enose; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R ')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally Substituted 6-10 membered aryl or optionally substituted 5-10 membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 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; R3 Absent, or R2 and R3 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 14 membered heterocycloalkyl; R4 is absent, hydrogen, Halogen, cyano or optionally methyl substituted by 1 to 3 halogens; R5 is hydrogen, optionally halogen substituted C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or Cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms to which they are attached to form optionally substituted 3 to 6 Cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl; R8 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 heterocycloalkane radical, optionally substituted 5 to 10 membered heteroaryl or optionally substituted 6 to 10 membered aryl, or R7 and R8 are combined with the carbon atom to which they are attached to form C=CR7'R8'; C= 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; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' 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 3-8 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 R7' and R8' combined with the carbon atoms to which they are attached Form an optionally substituted 3 to 6 membered cycloalkyl or an optionally substituted 3 to 7 membered heterocycloalkyl; R9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heterocycloalkyl; Alkyl, optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; and R10 is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl.

[0088] In some embodiments of the compounds of the present invention, X1 is an optionally substituted C1-C2 alkylene. In some embodiments, X1 is methylene.

[0089] In some embodiments of the compounds of the invention, R4 is hydrogen.

[0090] In some embodiments of the compounds of the invention, R5 is hydrogen. In some embodiments, R5 is C1-C4 alkyl optionally substituted with halogen. In some embodiments, R5 is methyl.

[0091] In some embodiments of the compounds of the invention, Y4 is C. In some embodiments, R4 is hydrogen. In some embodiments, Y5 is CH. In some embodiments, Y6 is CH. In some embodiments, Y1 is C. In some embodiments, Y2 is C. In some embodiments, Y3 is N. In some embodiments, R3 is absent. In some embodiments, Y7 is C.

[0092] In some embodiments, the compound of the present invention has a structure of formula Ic, or a pharmaceutically acceptable salt thereof: formula Ic wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6-membered aryl; or optionally substituted 5 to 6-membered heteroaryl; B is -CH(R9)-, 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 heterocycloalkylene; optionally substituted 6 membered aryl; or 5 to 6 membered heteroaryl; L is absent or linked body; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, Aziridine, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, Epoxide, oxazolium or enose; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkane radical, 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 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-C6 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form optionally substituted Substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 14 membered heterocycloalkyl; R5 is hydrogen, optionally halogen substituted C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms they are attached to form as appropriate Substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R8 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 3-8 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 R7 and R8 are combined with the carbon atom to which they are attached to form C=CR7 'R8'; 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; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' 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 3-8 membered cycloalkane radical, optionally substituted 3 to 14 membered heterocycloalkyl, optionally substituted 5 to 10 membered heteroaryl, or optionally substituted 6 to 10 membered aryl, or R7' and R8' are attached to The carbon atoms of R are combined to form an optionally substituted 3-6 membered cycloalkyl or an optionally substituted 3-7 membered heterocycloalkyl; R9 is an optionally substituted C1-C6 alkyl, optionally substituted Substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl; and R10 is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl.

[0093] In some embodiments of the compounds of the invention, R6 is hydrogen.

[0094] In some embodiments of the compounds of the present invention, R2 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, R2 is optionally substituted C1-C6 alkyl, such as ethyl.

[0095] In some embodiments of the compounds of the present invention, R7 is optionally substituted C1-C3 alkyl. In some embodiments, R7 is C1-C3 alkyl.

[0096] In some embodiments of the compounds of the present invention, R8 is optionally substituted C1-C3 alkyl. In some embodiments, R8 is C1-C3 alkyl.

[0097] In some embodiments, the compound of the present invention has a structure of formula Id, or a pharmaceutically acceptable salt thereof: formula Id wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6-membered aryl; or optionally substituted 5 to 6-membered heteroaryl; B is -CH(R9)-, 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 heterocycloalkylene; optionally substituted 6 membered aryl; or 5 to 6 membered heteroaryl; L is absent or linked body; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, Aziridine, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, Epoxide, oxazolium or enose; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkane radical, 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 is C1-C6 alkyl or 3 to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, Optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl.

[0098] In some embodiments of the compounds of the invention, R1 is 5 to 10 membered heteroaryl. In some embodiments, R1 is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl.

[0099] In some embodiments, the compound of the present invention has a structure of formula Ie, or a pharmaceutically acceptable salt thereof: Formula Ie wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6-membered aryl; or optionally substituted 5 to 6-membered heteroaryl; B is -CH(R9)-, 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 heterocycloalkylene; optionally substituted 6 membered aryl; or 5 to 6 membered heteroaryl; L is absent or linked body; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, Aziridine, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, Epoxide, oxazolium or enose; R2 is C1-C6 alkyl or 3 to 6 membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, or optionally substituted 3 to 7 membered heterocycloalkyl; Xe is N or CH; and R12 is optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl.

[0100] In some embodiments of the compounds of the invention, Xe is N. In some embodiments, Xe is CH.

[0101] In some embodiments of the compounds of the invention, R12 is optionally substituted C1-C6 heteroalkyl. In some embodiments, R12 is , or . In some embodiments, R12 is.

[0102] In some embodiments, the compound of the present invention has a structure of formula If, or a pharmaceutically acceptable salt thereof: formula If wherein the dotted line represents zero, one, two, three or four non-adjacent double bonds ; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; Optionally substituted 3-6 membered heterocycloalkyl; optionally substituted 6-membered aryl; or optionally substituted 5-6 membered heteroaryl; B is -CH(R9)-, where the carbon is bound to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted Substituted 6-membered aryl; or 5 to 6-membered heteroaryl; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenyl; optionally substituted C1 -C4 Heteroalkylene; -C(O)O-CH(R6)-, wherein C is bound to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C is bound to -C (R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3 to 8-membered heteroaryl; L does not exist or is a linker; W is a crosslinking group comprising carbodiimide, Oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester , N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enose; Substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R ')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally Substituted 6-10 membered aryl or optionally substituted 5-10 membered heteroaryl; R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 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; R3 Absent, or R2 and R3 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 14 membered heterocycloalkyl; R4 is absent, hydrogen, Halogen, cyano or optionally methyl substituted by 1 to 3 halogens; R5 is hydrogen, optionally halogen substituted C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or Cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms to which they are attached to form optionally substituted 3 to 6 Cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl; R8 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 heterocycloalkane radical, optionally substituted 5 to 10 membered heteroaryl or optionally substituted 6 to 10 membered aryl, or R7 and R8 are combined with the carbon atom to which they are attached to form C=CR7'R8'; C= 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; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' 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 3-8 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 R7' and R8' combined with the carbon atoms to which they are attached Form an optionally substituted 3 to 6 membered cycloalkyl or an optionally substituted 3 to 7 membered heterocycloalkyl; R9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heterocycloalkyl; Alkyl, optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R10 is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0103] In some embodiments, the compound of the present invention has the structure of formula VI, or a pharmaceutically acceptable salt thereof: formula VI wherein the dotted lines represent zero, one, two, three or four non-adjacent double bonds ; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; Optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered arylylene (such as phenyl or phenol); or optionally substituted 5 to 10 membered heteroarylylene; -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered aryl; or 5 to 6 membered heteroaryl; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenylene; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH -CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3 to 8 membered heteroaryl; L does not exist or is a linker; W It is a crosslinking group, which contains carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, nitrogen heterocycle Propane, trifluoromethyl ketone, boronic acid, borate esters, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides , oxazolium or enose; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C (O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or Optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, 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; R3 is absent, or R2 and R3 and the atoms to which it is attached are combined to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 14 membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano or Methyl optionally substituted by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl optionally substituted by halogen; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atom to which they are attached to form an optionally substituted 3 to 6 membered cycloalkyl or Optionally substituted 3- to 7-membered heterocycloalkyl; R8 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 Substituted 5 to 10 membered heteroaryl or optionally substituted 6 to 10 membered aryl, or R7 and R8 are combined with the carbon atom to which they are attached to form C=CR7'R8'; 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 heterocycle Alkyl; R7a and R8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or a combination of the carbon to which it is attached to form a carbonyl; R7' is hydrogen, halogen or optionally substituted C1 -C3 alkyl; R8' 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 an optionally substituted 6 to 10 membered aryl group, or R7' and R8' combined with the carbon atom to which they are attached form an optionally substituted 3 to 6 membered cycloalkyl group or an optionally substituted 3 to 10 membered cycloalkyl group 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl or optionally substituted A substituted 3 to 7-membered heterocycloalkyl, or R9 and L are combined with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R10a is hydrogen or halogen; R11 is hydrogen or C1-C3 alkyl; R34 is hydrogen or C1 -C3 alkyl; and Xe and Xf are independently N or CH.

[0104] In some embodiments, the compound of the present invention has the structure of Formula VIa, or a pharmaceutically acceptable salt thereof: Formula VIa wherein A is an optionally substituted 3 to 6 membered cycloalkylene, optionally substituted Substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 membered aryl (such as phenyl or phenol) or optionally substituted 5 to 6 membered heteroaryl; B is -CH(R9 )-, 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 heterocycloalkylene; optionally substituted 6-membered aryl; or 5 to 6-membered heteroaryl; L does not exist or is a linker; W is a cross-linking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea , chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester, N-ethoxycarbonyl-2-ethane Oxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enose; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl , optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; R2 is C1-C6 alkyl or 3 to 6 membered cycloalkyl; R7 is C1 -C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkane Xe and Xf are independently N or CH; R11 is hydrogen or C1-C3 alkyl; and R21 is hydrogen or C1-C3 alkyl.

[0105] In some embodiments of the compounds of the invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0106] In some embodiments, the compound of the present invention has the structure of formula VIb, or a pharmaceutically acceptable salt thereof: formula VIb wherein A is an optionally substituted 3 to 6 membered cycloalkylene, optionally substituted Substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 membered aryl (such as phenyl or phenol) or optionally substituted 5 to 6 membered heteroaryl; B is -CH(R9 )-, 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 heterocycloalkylene; optionally substituted 6-membered aryl; or 5 to 6-membered heteroaryl; L does not exist or is a linker; W is a cross-linking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea , chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester, N-ethoxycarbonyl-2-ethane Oxygen-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enose; R9 is optionally substituted C1-C6 alkyl, optionally substituted substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, or optionally substituted 3 to 7 membered heterocycloalkyl; and Xe and Xf are independently N or CH.

[0107] In some embodiments of the compounds of the invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0108] In some embodiments, the compound of the present invention has the structure of formula VII, or a pharmaceutically acceptable salt thereof: formula VII wherein the dotted lines represent zero, one, two, three or four non-adjacent double bonds ; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; Optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered aryl; or optionally substituted 5 to 10 membered heteroaryl; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocyclic ring Alkyl; optionally substituted 6-membered arylylene; or 5 to 6-membered heteroaryl; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenylene; Optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, Wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3 to 8 membered heteroaryl; L does not exist or is a linker; W is a crosslinking group, which Contains carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone , boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enose ; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyanide radical, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C (O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1- C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R1 is or ; R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3 to 6 members Cycloalkyl, optionally substituted 3 to 7 membered heterocycloalkyl, optionally substituted 6 membered aryl, optionally substituted 5 or 6 membered heteroaryl; R3 is absent, or R2 and R3 are combined with The attached atoms are combined to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 14 membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano or optionally substituted 1 to 3 halogen-substituted methyl groups; R5 is hydrogen, optionally halogen-substituted C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or Methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms to which they are attached to form optionally substituted 3 to 6 membered cycloalkyl or optionally substituted Substituted 3-7 membered heterocycloalkyl; R8 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 R7 and R8 are combined with the carbon atom to which they are attached to form C=CR7'R8'; 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; R7a and R8a are independently hydrogen, halogen, optionally substituted C1-C3 alkyl, or a combination of the carbon to which they are attached to form a carbonyl; R7' is hydrogen, halogen or optionally substituted C1-C3 alkane R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 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 Optionally substituted 6 to 10 membered aryl, or R7' and R8' are combined with the carbon atom to which they are attached to form optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered hetero Cycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl, or R9 and L are combined with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 Alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 Alkyl (eg methyl).

[0109] In some embodiments of the compounds of the invention, A is an optionally substituted 6-membered aryl. In some embodiments, A has the following structure: wherein R13 is hydrogen, hydroxyl, amino, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. In some embodiments, R13 is hydrogen. In some embodiments, R13 is hydroxyl.

[0110] In some embodiments of compounds of the invention, B is -CHR9-. In some embodiments, R9 is optionally substituted C1-C6 alkyl or optionally substituted 3-6 membered cycloalkyl. In some embodiments, R9 is: , or . In some embodiments, R9 is: . In some embodiments, R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3 to 7 membered heterocycloalkyl.

[0111] In some embodiments, B is an optionally substituted 6-membered aryl. In some embodiments, B is a 6-membered aryl group. In some embodiments, B is: .

[0112] In some embodiments of the compounds of the invention, R7 is methyl.

[0113] In some embodiments of the compounds of the invention, R8 is methyl.

[0114] In some embodiments, R34 is hydrogen.

[0115] In some embodiments of the compound of the present invention, the structure of the linker formula II: A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-(C2)j -(B4)k-A2 formula II wherein A1 is the bond between the linker and B; A2 is the bond between W and the linker; B1, B2, B3 and B4 are each independently selected from as appropriate Substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S and NRN; RN is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2 -C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3 to 14 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted C1-C7 Heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h, i, j and k are each independently 0 or 1; and D1 is optionally modified Substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted 3 to 14 membered heterocycloalkylene, optionally Substituted 5 to 10 membered heteroaryl, optionally substituted 3 to 8 membered cycloalkyl, optionally substituted 6 to 10 membered aryl, optionally substituted C2-C10 polyethylene Diol or optionally substituted C1-C10 heteroalkylene, or connecting A1-(B1)f-(C1)g-(B2)h-to-(B3)i-(C2)j-(B4 )k–A2 chemical bond. In some embodiments, the linker system is an acyclic linker. In some embodiments, the linker has the structure of Formula IIa: Formula IIa wherein Xa is absent or N; R14 is absent, hydrogen, or optionally substituted C1-C6 alkyl; and L2 is absent, -SO2 -, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene, wherein at least one of Xa, R14 or L2 is present. In some embodiments, the linker has the following structure: ,,,,,,,,,,,,,, or. In some embodiments, the linking system or comprises a cyclic group. In some embodiments, the linker has the structure of Formula IIb: Formula IIb wherein o is 0 or 1; R15 is hydrogen or optionally substituted C1-C6 alkyl; Cy is optionally substituted 3 to 8 members Cycloalkyl, optionally substituted 3 to 8 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl; and L3 is not Exist, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene. In some embodiments, the linker has the following structure: ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,or. In some embodiments, the linkage system of Formula II is selected from the group consisting of: , , and .

[0116] In some embodiments of the compounds of the invention, W comprises carbodiimide. In some embodiments, W has the structure of Formula IIIa: Formula IIIa wherein R14 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 8 member Cycloalkyl, optionally substituted 6 to 10 membered aryl, optionally substituted 3 to 14 membered heterocycloalkyl, or optionally substituted 5 to 10 membered heteroaryl. In some embodiments, W has the following structure: ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, or.

[0117] In some embodiments, W comprises oxazoline or thiazoline. In some embodiments, W has the structure of Formula IIIb: Formula IIb wherein X1 is O or S; X2 is absent or NR19; R15, R16, R17 and R18 are independently hydrogen or optionally substituted C1-C6 alkane and R19 is hydrogen, C(O) (optionally substituted C1-C6 alkyl), optionally substituted C1-C6 alkyl, optionally substituted 6 to 10 membered aryl, optionally substituted Substituted 3 to 14 membered heterocycloalkyl or optionally substituted 5 to 10 membered heteroaryl. In some embodiments, W is.

[0118] In some embodiments, W comprises chloroethylurea, chloroethylthiourea, chloroethyl carbamate, or chloroethyl thiocarbamate. In some embodiments, W has the structure of Formula IIIc: Formula IIIc wherein X3 is O or S; X4 is O, S, NR26; R21, R22, R23, R24, and R26 are independently hydrogen or optionally substituted Cl -C6 alkyl; and R25 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6 to 10 membered aryl, optionally substituted 3 to 14 membered heterocycloalkyl or optionally substituted Substituted 5 to 10 membered heteroaryl. In some embodiments, W is.

[0119] In some embodiments, W comprises aziridine. In some embodiments, W has the structure of Formula IIId1, Formula IIId2, Formula IIId3, or Formula IIId4: Formula IIId1 Formula IIId2 Formula IIId3 Formula IIId4 wherein X5 is absent or NR30; Y is absent or C(O), C( S), S(O), SO2 or optionally substituted C1-C3 alkylene; R27 is hydrogen, -C(O)R32, -C(O)OR32, -SOR33, -SO2R33, optionally substituted C1-C6 alkyl, optionally substituted 6 to 10 membered aryl, optionally substituted 3 to 14 membered heterocycloalkyl, or optionally substituted 5 to 10 membered heteroaryl; R28 and R29 are independent is hydrogen, CN, C(O)R31, CO2R31, C(O)R31R31, optionally substituted C1-C6 alkyl, optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl, optionally substituted 3 to 14 membered heterocycloalkyl or optionally substituted 5 to 10 membered heteroaryl; each R31 is independently hydrogen, optionally substituted C1-C6 alkyl , optionally substituted 6 to 10 membered aryl, optionally substituted 3 to 14 membered heterocycloalkyl, or optionally substituted 5 to 10 membered heteroaryl; R30 is hydrogen or optionally substituted C1 -C6 alkyl; and R32 and R33 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6 to 10 membered aryl, optionally substituted 3 to 14 membered heterocycloalkyl Or an optionally substituted 5 to 10 membered heteroaryl. In some embodiments, W is:,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,or.

[0120] In some embodiments, W comprises an epoxy. In some embodiments, W is , , or .

[0121] In some embodiments, W is a crosslinking group bound to an organic moiety that is a Ras binding moiety, i.e., RBM-W, wherein upon contacting the RBM-W compound with a Ras protein, the RBM -W binds to the Ras protein to form a conjugate. For example, the W portion of the RBM-W compound can bind, eg, cross-link, the amino acid of the Ras protein to form the conjugate. In some embodiments, the Ras binding moiety is a K-Ras binding moiety. In some embodiments, the K-Ras binding moiety binds to residues of the K-Ras Switch-II binding pocket of the K-Ras protein. In some embodiments, the Ras-binding moiety is an H-Ras-binding moiety that binds to residues of the H-Ras Switch-II binding pocket of the H-Ras protein. In some embodiments, the Ras-binding moiety is an N-Ras-binding moiety that binds residues of the N-Ras Switch-II binding pocket of an N-Ras protein. The W of the RBM-W compound may comprise any W described herein. The molecular weight of the Ras binding moiety is typically below 1200 Da. For a description of each domain of the Ras protein, see, eg, Johnson et al., 292:12981-12993 (2017), which is incorporated herein by reference.

[0122] In some embodiments, the compound of the present invention is selected from Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the compound of the present invention is selected from Table 1, or a pharmaceutically acceptable salt or atropisomer thereof. Table 1: Certain compounds of the invention instance number structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 A and B 16 A and B 17 A and B 18 A and B 19 A and B 20 A and B twenty one A and B twenty two A and B twenty three A and B twenty four A and B 25 26 27 28 29 30 31 32 A and B 33 34 35 36 37 38 39 40 41 42A 42B 43A 43B 44 45 46 47 A and B 48 49 50 51 52 53 54 55 56* 57* 58 59 60 61 A and B 62 A and B 63 64 A and B 65 A and B 66 67 68 A and B 69 A and B 70 A and B 71 A and B 72 A and B 73 74 75 76 77 78 79 A and B 80 81 82 A and B 83 84 85 86 87 88 89 90 91* 92* 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108* 109 110 111 112 113 114 115 116 117* 118* 119* 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258* 259* 260* 261* 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281* 282* 283* 284* 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308* 309 310 311 312 313 314* 315* 316* 317 318 319 320 321 322* 323* 324 325 326 327 328 329 330 331 332 *Assumed stereochemistry at the aziridine carbon. It should be noted that bonds in some compounds are shown as flat or wedged lines. In some cases, the relative stereochemistry of stereoisomers has been determined; in some cases, the absolute stereochemistry has been determined. In some instances, individual instance numbers correspond to mixtures of stereoisomers. All stereoisomers of the compounds of the above table are included in the present invention. In certain embodiments, atropisomers of the compounds of the above table are contemplated.

[0123] In some embodiments, a compound of Table 2, or a pharmaceutically acceptable salt thereof, is provided. In some embodiments, the compound of the present invention is selected from Table 2, or a pharmaceutically acceptable salt or stereoisomer thereof. Table 2: Certain compounds of the invention instance number structure B5 B6 B8 B9 B16 B19 B29 B30 B31 B32 B35 B36 B37 B38 B40 B41 B42 B43 B44 B46 B48 B51 B53 B54 B55 B56 B57 B58 B59 B60 B61 B62 B63 B73 B74 B76 B78 B79 B80 B83 B84 B87 B88 B91 B92 B97 B98 B101 B108 B109 B113 B116 B117 B118 B119 B120 B122 B123 It should be noted that bonds in some compounds are shown as flat or wedged lines. In some cases, the relative stereochemistry of stereoisomers has been determined; in some cases, the absolute stereochemistry has been determined. All stereoisomers of the compounds of the above table are included in the present invention. In certain embodiments, atropisomers of the compounds of the above table are contemplated.

[0124] In some embodiments, compounds of the invention are or are used as prodrugs, such as for administration to a cell or an individual in need thereof.

[0125] A pharmaceutical composition is also provided, which comprises the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0126] Further provide a conjugate or a salt thereof, comprising a structure of formula IV: M-L-P formula IV wherein L is a linker; P is a monovalent organic moiety; and M has a structure of formula Va: formula Va wherein the dotted line represents zero, One, two, three or four non-adjacent double bonds; A series -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bound to the carbon atom of -CH(R10)- ; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered arylylene; or optionally substituted 5 to 6 membered Membered heteroaryl; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6 membered ring Alkyl; optionally substituted 3 to 6 membered heterocycloalkyl; optionally substituted 6 membered aryl; or 5 to 6 membered heteroaryl; G is optionally substituted C1-C4 Alkyl; optionally substituted C1-C4 alkenylene; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8) -; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkyl; or 3 to 8 membered heteroaryl; X1 It is an optionally substituted C1-C2 alkylene group, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, Optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O) ) N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkane Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R1 is cyano, Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted Optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl, or R1 and R2 are combined with the atoms to which they are attached Form an optionally substituted 3 to 14 membered heterocycloalkyl; R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2 - C6 alkynyl, 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 R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 14 membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxyl or C1-C4 alkoxy R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms they are attached to form as appropriate Substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R8 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 3-8 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 R7 and R8 are combined with the carbon atom to which they are attached to form C=CR7 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; R7a and R8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or carbonyl combined with the carbon to which they are attached; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' 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 R7' and R8' combined with the carbon atom to which they are attached form an optionally substituted 3 to 6 membered Cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 7 6-membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; or R9 and L are combined with the atoms to which they are attached to form optionally substituted 3 to 14 membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R10a is hydrogen or halo; and R11 is hydrogen or C1-C3 alkyl.

[0127] In some embodiments, the conjugate has the structure of Formula IV: M-L-P Formula IV wherein L is a linker; P is a monovalent organic moiety; and M has the structure of Formula Vb: Formula Vb wherein dashed lines represent zero, one, Two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bound to the carbon atom of -CH(R10)-; Optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered aryl; or optionally substituted 5 to 6 membered Heteroaryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered aryl; or 5 to 6 membered heteroaryl; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenylene; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH -CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkyl; or 3 to 8 membered heteroaryl; X1 is optionally substituted C1- C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 Alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 Heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl; R2 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; R3 is absent, or R2 and R3 are combined with the atoms they are connected to form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 14 membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano Or optionally methyl substituted by 1 to 3 halogens; R5 is hydrogen, optionally halogen substituted C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3-6 membered cycloalkyl Or optionally substituted 3 to 7 membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally 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 R7 and R8 are combined with the carbon atom to which they are attached to form C=CR7'R8'; 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 hetero Cycloalkyl; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' 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 R7' and R8' are combined with the carbon atoms to which they are attached to form optionally substituted Substituted 3-6 membered cycloalkyl or optionally substituted 3-7 membered heterocycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted Optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R10 is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0128] In some embodiments, the conjugate has the structure of Formula IV: M-L-P Formula IV wherein L is a linker; P is a monovalent organic moiety; and M has the structure of Formula Vc: Formula Vc wherein A is optionally substituted 3 to 6 membered cycloalkylene, optionally substituted 3 to 6 membered heterocycloalkylene, optionally substituted 6 membered arylylene (such as phenyl or phenol) or optionally substituted 5 to 6 membered arylylene 6-membered heteroaryl; B is -CH(R9)-, 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 heterocycloalkyl; optionally substituted 6-membered aryl; or 5 to 6-membered heteroaryl; X1 is optionally substituted C1-C2 alkylene, NR, O or S( O)n; X2 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 Substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O) )2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; Xe and Xf are independently N or CH; R2 is C1-C6 alkyl or 3 to 6 membered ring Alkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl.

[0129] In some embodiments of the compounds of the invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0130] In some embodiments, the conjugate has the structure of Formula IV: M-L-P Formula IV wherein L is a linker; P is a monovalent organic moiety; and M has the structure of Formula Vd: Formula Vd wherein A is optionally substituted 3 to 6 membered cycloalkylene, optionally substituted 3 to 6 membered heterocycloalkylene, optionally substituted 6 membered arylylene (such as phenyl or phenol) or optionally substituted 5 to 6 membered arylylene 6-membered heteroaryl; B is -CH(R9)-, 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 heterocycloalkyl; optionally substituted 6-membered aryl; or 5 to 6-membered heteroaryl; L does not exist or is a linker; W is a crosslinking group comprising a carbodiethylene Amine, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boron Ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enose; R9 is depending on optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, or optionally substituted 3 to 7 membered heterocycloalkyl; and Xe and Xf are independently N or CH.

[0131] In some embodiments of the compounds of the invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0132] In some embodiments of the conjugates of the present invention, the linker has the structure of formula II: A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-( C2) j-(B4) k-A2 formula II wherein A1 is the bond between the linker and B; A2 is the bond between P and the linker; B1, B2, B3 and B4 are independently selected From optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NRN; RN is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3 to 14 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted C1 -C Heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h, i, j and k are each independently 0 or 1; and D1 is depending on Optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted 3 to 14 membered heterocycloalkylene, Optionally substituted 5 to 10 membered heteroaryl, optionally substituted 3 to 8 membered cycloalkyl, optionally substituted 6 to 10 membered aryl, optionally substituted C2-C10 Polyethylene glycol or optionally substituted C1-C10 heteroalkylene, or connecting A1-(B1)f-(C1)g-(B2)h- to -(B3)i-(C2)j- (B4) The chemical bond of k-A2. In some embodiments of the conjugates of the invention, the linker is bound to the monovalent organic moiety via a bond to the carboxyl group of an amino acid residue of the monovalent organic moiety.

[0133] In some embodiments of the conjugates of the invention, the monovalent organic moiety is a protein. In some embodiments, the protein is a Ras protein. In some embodiments, the Ras protein is K-Ras G12D or K-Ras G13D.

[0134] There is further provided a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. The cancer may for example be pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myelogenous leukemia, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome or squamous cell lung cancer. In some embodiments, the cancer comprises a Ras mutation, such as K-Ras G12D or K-Ras G13D. Other Ras mutations are also described herein.

[0135] It further provides a method for treating Ras protein-related disorders in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0136] There is further provided a method of inhibiting Ras protein in a cell, the method comprising contacting the cell with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12D or K-Ras G13D. Other Ras proteins are also described herein. The cells may be cancer cells, such as pancreatic cancer cells, colorectal cancer cells, non-small cell lung cancer cells, acute myeloid leukemia cells, multiple myeloma cells, thyroid adenocarcinoma cells, myelodysplastic syndrome cells, or squamous cells lung cancer cells. Other cancer types are also described herein. The cells may be in vivo or in vitro.

[0137] For the compounds of the present invention, one stereoisomer may exhibit a superior inhibitory effect than the other stereoisomer. For example, one atropisomer may exhibit inhibition while another atropisomer may exhibit little or no inhibition.

[0138] In some embodiments, the methods or uses described herein further comprise administering an additional anti-cancer therapy. In some embodiments, the additional anticancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, AKT inhibitors, mTORC1 inhibitors, BRAF inhibitors, PD-L1 inhibitors, PD-1 inhibitors, CDK4 / 6 inhibitors, HER2 inhibitors, or combinations thereof. In some embodiments, the additional anticancer therapy is a SHP2 inhibitor. Other additional anticancer therapies are also described herein. resolve resolution

[0139] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic or enzymatic procedures.

[0140] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. For example, compounds of the present invention can be synthesized using the methods described in the following schemes, as well as synthetic methods known in the art of synthetic organic chemistry or modifications of such methods understood by those skilled in the art. Such methods include, but are not limited to, those described in the following schemes.

[0141] The compounds of Table 1 herein were prepared using the methods disclosed herein, or using the methods disclosed herein combined with the knowledge of those skilled in the art. The compounds of Table 2 can be prepared using the methods disclosed herein, or can be prepared using the methods disclosed herein combined with the knowledge of those skilled in the art. Scheme 1. General Synthetic Method of Macrocyclic Ester

[0142] The general synthesis of macrocyclic esters is outlined in Scheme 1. Properly substituted aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (1) can be protected 3- Starting from (5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol and appropriately substituted boronic acids, it was prepared in three steps involving palladium Mediated coupling, alkylation and deprotection reactions.

[0143] Amino-hexahydropyridazine-3-formic acid methyl ester-boronate (2) can be prepared in three steps, including protection, iridium catalase-mediated borylation and (S)-hexahydro Pyrazine-3-carboxylic acid methyl ester coupling.

[0144] The final macrocyclic ester can be prepared by combining amino-hexahydropyridazine-3-carboxylic acid methyl ester-boronate (2) with aryl-3-(5-bromo-1-ethane (1)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (1) was coupled in the presence of Pd catalase, followed by hydrolysis and macrolide steps for proper protection The macrocyclic intermediate (4). Additional deprotection or functionalization steps are required to prepare the final compound. For example, one skilled in the art will be able to load the -B-L-W group required for a compound of formula (I) into a macrocyclic ester, wherein B, L and W are as defined herein, including by using some of the following schemes and the methods exemplified in the Examples section herein. Scheme 2. Alternative general synthesis of macrocyclic esters

[0145] Alternatively, macrocyclic esters can be prepared as described in Scheme 2. Appropriately protected bromo-indolyl (5) can be coupled with boronate (3) in the presence of Pd catalase, followed by iodination, deprotection and ester hydrolysis. Subsequent coupling with (S)-methylhexahydropyridazine-3-carboxylate, followed by hydrolysis and macrolide, can yield the iodo intermediate (6). Coupling with an appropriately substituted boronic ester in the presence of Pd catalase affords a fully protected macrocycle (4). Additional deprotection or functionalization steps are required to prepare the final compound. For example, one skilled in the art will be able to load the -B-L-W group required for a compound of formula (I) into a macrocyclic ester, wherein B, L and W are as defined herein, including by using some of the following schemes and the methods exemplified in the Examples section herein. Scheme 3. General Synthesis of Aziridine-Containing Macrocycles

[0146] As shown in Scheme 3, such compounds can be prepared by reacting the appropriate amine (1) with an aziridine-containing carboxylic acid (2) in the presence of standard amide coupling reagents, if R1 is a protecting group, then the aziridine and, if necessary, the phenol are subsequently deprotected to give the final compound (4). Scheme 4. General Synthesis of Carbodiimide-Containing Macrocycles

[0147] As shown in Scheme 4, such compounds can be obtained by reacting the appropriate amine (1) with a thiourea-containing carboxylic acid (2) in the presence of standard amide coupling reagents, followed by 2-chloro-iodide Prepared by converting thiourea (3) to carbodiimide (4) in the presence of 1-picoline-1-ium salt. Scheme 5. General Synthesis of Macrocycles Containing Chloroethylurea

[0148] As shown in Scheme 5, such compounds can be prepared by reacting the appropriate amine (1) with an isocyanate (2) under basic conditions, followed by deprotection of the phenol, if necessary, to give the final Compound (4). Scheme 6. General synthetic method of macrocycle containing amino oxazoline

[0149] As shown in Scheme 6, such compounds can be prepared by cyclization of the appropriate chloroethylurea (1) at elevated temperature to yield the final compound (2). Scheme 7. General synthesis of epoxy-containing macrocycles

[0150] As shown in Scheme 7, such compounds can be prepared by reacting the appropriate amine (1) with an epoxy-containing carboxylic acid (2) in the presence of standard amide coupling reagents to yield the final Compound (3).

[0151] Additionally, compounds of the disclosure can be synthesized using the methods described in the Examples below, as well as synthetic methods known in the art of synthetic organic chemistry, or modifications of such methods as would be understood by those skilled in the art. Such methods include, but are not limited to, those described in the Examples below. For example, one skilled in the art will be able to load the -B-L-W groups required for compounds of formula (I) into macrocyclic esters, wherein B, L and W are as defined herein, including by using some of the schemes above and the methods exemplified in the Examples section herein. Pharmaceutical composition and method of use Pharmaceutical composition and method of administration

[0152] The compounds involved in the present invention are Ras inhibitors and can be used to treat cancer. Accordingly, one embodiment of the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and methods of using the compound of the present invention to prepare such compositions.

[0153] As used herein, the term "pharmaceutical composition" refers to a compound, such as a compound of the present invention, or a pharmaceutically acceptable salt thereof, formulated together with a pharmaceutically acceptable excipient.

[0154] In some embodiments, a compound that exhibits a statistically significant likelihood of achieving a predetermined therapeutic effect when administered to a relevant population is present in the pharmaceutical composition in an amount suitable for its unit dosage to be administered in a therapeutic regimen . In some embodiments, the pharmaceutical composition may be specifically formulated for administration in solid or liquid form, including those suitable for oral administration, such as liquid solutions (aqueous or non-aqueous solutions or suspensions), lozenges (such as intended for buccal, sublingual and systemic absorption), boluses, powders, granules, pastes for administration to the tongue; parenteral administration, for example by subcutaneous, intramuscular, intravenous or epidural injection, Such as, for example, sterile solutions or suspensions, or sustained release formulations; topical 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 Pessary, cream, or foam; sublingual administration; ocular administration; transdermal administration; or nasal, pulmonary, and other mucosal surfaces.

[0155] As used herein, a "pharmaceutically acceptable excipient" refers to any inactive ingredient (eg, a vehicle capable of suspending or dissolving an active compound) that is non-toxic and non-inflammatory in the subject. Typical excipients include, for example: antiadherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film formers Or coating agent, flavoring agent, aromatic agent, glidant (flow enhancer), lubricant, preservative, printing ink, absorbent, suspending or dispersing agent, sweetener or water of hydration. Excipients include, but are not limited to: optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, cross-linked methylcellulose, cross-linked polyvinylpyrrolidone , citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropylcellulose, optionally substituted hydroxypropylmethylcellulose, lactose, stearin Magnesium Acid, Maltitol, Mannitol, Methionine, Methylcellulose, Methylparaben, Microcrystalline Cellulose, Polyethylene Glycol, Polyvinylpyrrolidone, Povidone, Pregel Starch, Propylparaben, Retinyl Palmitate, Shellac, Silicon Dioxide, Sodium Carboxymethylcellulose, Sodium Citrate, Sodium Starch Glycolate, Sorbitol, Starch (Corn Starch), Hardened Fatty acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C and xylitol. Those skilled in the art are familiar with a wide variety of reagents and materials that can be used as excipients. See, for example, Ansel et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; we , Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments, the composition includes at least two different pharmaceutically acceptable excipients.

[0156] Unless expressly stated to the contrary, the compounds described herein, whether expressly stated or not, may be provided or used in salt form, eg, as a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" means, within the scope of sound medical judgment, suitable for use in contact with human tissues without undue toxicity, irritation, allergic reaction and the like, and with reasonable efficacy. Salts of compounds described herein commensurate with the risk / 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, (eds. P.H. Stahl and C.G. Wermuth), Wiley- VCH, 2008. Such salts can be prepared in situ during the final isolation and purification of the compounds described herein, or isolated by reacting the free basic group with a suitable organic acid.

[0157] The compounds of the present invention may have ionizable groups and thus can be prepared in the form of pharmaceutically acceptable salts. The salts may be acid addition salts involving inorganic or organic acids, or, where the compounds of the invention are in the acid form, the salts may be prepared from inorganic or organic bases. In some embodiments, the compounds are prepared or used in the form of pharmaceutically acceptable salts, and the pharmaceutically acceptable salt forms are used as pharmaceutically acceptable Preparation of addition products of acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as hydrochloric, sulfuric, hydrobromic, acetic, lactic, citric or tartaric acids for the formation of acid addition salts; and potassium hydroxide, hydrogen Sodium oxide, ammonium hydroxide, caffeine, various amines and the like are used to form base salts. Methods for preparing appropriate salts are recognized in the art.

[0158] Representative acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, Butyrate, Camphorate, Camphorsulfonate, Citrate, Cyclopentanepropionate, Digluconate, Lauryl Sulfate, Ethanesulfonate, Fumarate, Glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-optionally substituted hydroxy-ethanesulfonate , lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotine , nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate , propionate, stearate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, valerate and similar salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, Tetraethylammonium, Methylamine, Dimethylamine, Trimethylamine, Triethylamine, Ethylamine and the like.

[0159] As used herein, the term "individual" refers to any member of the animal kingdom. In some embodiments, an "individual" refers to a human being at any stage of development. In some embodiments, "individual" refers to a human patient. In some embodiments, "individual" refers to a non-human animal. In some embodiments, the non-human animal is a mammal (eg, a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, or pig). In some embodiments, individuals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, or insects. In some embodiments, an individual may be a transgenic animal, a genetically engineered animal, or a purebred.

[0160] As used herein, the term "dosage form" refers to a physically discrete unit of a compound (eg, a compound of the invention) for administration to a subject. Each unit contains a predetermined amount of compound. In some embodiments, the amount is that amount (or an integral fraction thereof) of a unit dose suitable for administration according to a dosage regimen determined to be desirable or beneficial when administered to a relevant population (i.e., according to a therapeutic dosage regimen). The results are relevant. Those skilled in the art will appreciate that the total amount of therapeutic composition or compound administered to a particular individual is at the discretion of one or more attending physicians and may involve the administration of multiple dosage forms.

[0161] As used herein, the term "dosage regimen" refers to the individual administration of a group of unit doses (typically more than one unit dose) to an individual, typically at intervals of time. In some embodiments, a given therapeutic compound (eg, a compound of the invention) has a recommended dosage regimen, which may involve one or more doses. In some embodiments, the dosage regimen comprises multiple doses that are each separated from each other by a time period of the same length; in some embodiments, the dosage regimen comprises multiple doses with at least two different time periods separating individual doses. In some embodiments, all doses within a dosage regimen are in the same unit dose amount. In some embodiments, different doses within a dosage regimen are different amounts. In some embodiments, a dosage regimen comprises a first dose in an amount of a first dose followed by one or more additional doses in an amount of a second dose different from the first dose. In some embodiments, the dosage 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 that is the same amount as the first dose. In some embodiments, the dosage regimen is associated with a desired or beneficial outcome when administered to a relevant population (ie, is a therapeutic dosage regimen).

[0162] "Treatment regimen" means a dosage regimen associated with a desired or beneficial therapeutic outcome when administered in a relevant population.

[0163] The term "treatment" ("treatment / treat / treating") in its broadest sense means the partial or complete alleviation, amelioration, alleviation, suppression of one or more of the symptoms, characteristics or causes of a particular disease, disorder or condition ; delaying its onset; reducing its severity; or any administration of a substance (such as a compound of the invention) that reduces its occurrence. In some embodiments, such treatment may be administered to individuals who exhibit no signs of the relevant disease, disorder or disorder or who exhibit only early signs of the disease, disorder or disorder. Alternatively or additionally, in some embodiments, treatment may be administered to an individual exhibiting one or more established signs of an associated disease, disorder, or disorder. In some embodiments, treatment is for individuals diagnosed with a relevant disease, disorder or condition. In some embodiments, treatment may be used in individuals known to have one or more predisposing factors that are statistically associated with an increased risk of developing an associated disease, disorder or condition.

[0164] The term "therapeutically effective amount" means an amount sufficient to treat a disease, disorder or disorder when administered according to a therapeutic dosage regimen to a population suffering from or susceptible to the disease, disorder or disorder. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence or severity or delays the onset of one or more symptoms of the disease, disorder or disorder. Those skilled in the art will understand that the term "therapeutically effective amount" need not actually achieve the desired successful treatment in a particular individual. In fact, a therapeutically effective amount is that amount which, when administered to a patient in need of such treatment, provides a particular desired pharmacological response in a substantial number of individuals. It is particularly important to understand that a given individual may actually be "therapeutically effective" and "refractory". In some embodiments, reference to a therapeutically effective amount may refer to, for example, one or more specific tissues (e.g., tissues affected by a disease, disorder, or disorder) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). ) is the quantity measured in . Those skilled in the art will appreciate that, in some embodiments, a therapeutically effective amount may be formulated or administered in a single dose. In some embodiments, a therapeutically effective amount may be formulated in multiple doses, eg, formulated as part of a dosage regimen, or administered in multiple doses.

[0165] For use in the treatment of individuals, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be formulated in the form of pharmaceutical or veterinary compositions. Depending on the individual to be treated, the mode of administration and the type of treatment desired, eg prophylaxis, prophylaxis or therapy, the compounds or pharmaceutically acceptable salts thereof are formulated in a manner consistent with these parameters. An overview of such technologies can be found in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, each incorporated herein by reference.

[0166] Compositions can be prepared according to conventional mixing, granulation or coating methods, and the pharmaceutical composition of the present invention can contain about 0.1% to about 99%, about 5% to about 90% or about 1% to about 20% of a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is present in an amount ranging from 1-95% by weight of the total composition, such as a pharmaceutical composition.

[0167] The composition may be provided in a dosage form suitable for administration: intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, dermal, subcutaneous, topical, transdermal, sublingual, nasal , vaginal, intracapsular, intraurethral, ​​intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with nasal, urogenital, genital, or oral mucosa. Thus, 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, drops, osmotic Delivery device, suppository, enema, injection, implant, spray, formulation suitable for iontophoretic delivery, or aerosol. The compositions can be formulated according to customary medical practice.

[0168] As used herein, the term "administering" refers to administering a composition (eg, a compound or a formulation comprising a compound as described herein) to an individual or system. Administration to an animal subject (eg, to a human) can be by any suitable route. For example, in some embodiments, administration can be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, Intraperitoneal, intrathecal, intravenous, intrathecal, transmucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreous administration.

[0169] The formulations may be prepared in a manner suitable for systemic administration or for topical or localized administration. Systemic formulations include those designed for injection (eg, intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal or oral administration. Formulations will generally include diluents, and in some cases, adjuvants, buffers, preservatives and the like. The compounds, or pharmaceutically acceptable salts thereof, can also be administered in liposomal formulations or in the form of microemulsions.

[0170] For injection, the formulations can be prepared in conventional forms, either as liquid solutions or suspensions, or solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol and the like. The compositions may also contain amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like, such as sodium acetate, sorbitan monolaurate, and the like.

[0171] Various sustained release drug systems have also been devised. See, eg, US Patent No. 5,624,677.

[0172] Systemic administration can also include relatively noninvasive methods, such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for a compound of the invention, or a pharmaceutically acceptable salt thereof. As will be appreciated in the art, suitable forms include syrups, capsules and lozenges.

[0173] Each compound described herein, or a pharmaceutically acceptable salt thereof, can be formulated in a variety of ways known in the art. For example, the first agent and the second agent in a combination therapy can be formulated together or separately. Other modes of combination therapy are also described herein.

[0174] Individually or separately formulated medicaments may be packaged together in kit form. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and powder, suppositories or liquids in vials, two topical creams, and the like. The kit may include optional components to facilitate administration of the unit dose to the individual, such as vials for reconstitution of the powder form, syringes for injection, custom IV delivery systems, inhalers, and the like. Additionally, unit dosage kits can contain instructions for the preparation and administration of the compositions. The kit can be manufactured as a single unit dose for one individual, for multiple uses in a given individual (at a constant dose, or where the potency of individual compounds or pharmaceutically acceptable salts thereof may progress with treatment). may vary); or the kit may contain multiple doses suitable for administration to multiple individuals ("monolithic package"). The kit components can be assembled in cartons, blister packs, bottles, tubes and the like.

[0175] Formulations for oral use include lozenges containing the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients. Such excipients may be, for example, inert diluents or fillers such as sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate , calcium sulfate or sodium phosphate); granulating agents and disintegrants (such as cellulose derivatives, including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginate or alginic acid) Binders (such as sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, formazan cellulose, optionally substituted hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricants, glidants and antiadhesives (such as stearic acid magnesium, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oil or talc). Other pharmaceutically acceptable excipients may be coloring agents, flavoring agents, plasticizers, humectants, buffers and the like.

[0176] Two or more compounds may be mixed together in a tablet, capsule or other vehicle, or may be separated. In one example, the first compound is contained on the inside of the lozenge and the second compound is on the outside such that a substantial portion of the second compound is released before the release of the first compound.

[0177] Formulations for oral use may also be presented as chewable tablets, or as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin); or provided in soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules and pellets can be prepared in a customary manner using the ingredients mentioned above for tablets and capsules, for example using mixers, fluid bed apparatus or spray-drying equipment.

[0178] Dissolution or diffusion-controlled release can be achieved by suitably coating the compound in tablet, capsule, pellet or granular formulations, or by incorporating the compound or a pharmaceutically acceptable salt thereof into an appropriate implemented in the matrix. The controlled release coating may comprise one or more of the coating substances mentioned above, for example shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, Glyceryl stearate, glyceryl palmitostearate, ethyl cellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene , polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethacrylate, methacrylate hydrogel, 1,3 butanediol, ethylene glycol methacrylate or poly ethylene 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.

[0179] Liquid forms for oral administration that may incorporate the compounds of this invention, or pharmaceutically acceptable salts and compositions thereof, include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and preparations such as cottonseed oil. , sesame, coconut or peanut oil flavored emulsions, as well as elixirs and similar pharmaceutical vehicles.

[0180] In general, the oral dosage of any compound of the present invention, or a pharmaceutically acceptable salt thereof, when administered to humans will depend on the nature of the compound and can be readily determined by one skilled in the art. The dosage can be, for example, about 0.001 mg to about 2000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day, about 100 mg to about 1500 mg per day, about 500 mg to about 1500 mg per day, From about 500 mg to about 2000 mg or any range derived therein.

[0181] In some embodiments, the pharmaceutical composition may further comprise additional compounds having antiproliferative activity. Depending on the mode of administration, the compound, or a pharmaceutically acceptable salt thereof, will be formulated into a suitable composition for delivery. Each compound in the combination therapy, or a pharmaceutically acceptable salt thereof, can be formulated in a variety of ways known in the art. For example, the first agent and the second agent in a combination therapy can be formulated together or separately. Desirably, the first and second agents are formulated together so that the agents are administered at or near the same time.

[0182] It is understood that the compounds and pharmaceutical compositions of the present invention may be formulated and used in combination therapy, that is, the compounds and pharmaceutical compositions may be formulated with one or more other desired therapeutic agents or medical procedures or concurrently with, prior to, or subsequent to the administration of the one or more other desired therapeutic agents or medical procedures. The particular combination of therapies (therapeutic agents or procedures) to be used in a combination regimen will take into account the compatibility of the desired therapeutic agents or procedures with the desired therapeutic effect to be achieved. It is also understood that the therapy employed may achieve the desired effect for the same disorder, or it may achieve a different effect (eg, control any adverse effects).

[0183] As described herein, the administration of each drug in the combination therapy can independently range from one to four times daily, for one day to one year, and even for the lifetime of the individual. Chronic / long-term administration is also applicable. Instructions

[0184] In some embodiments, the present invention discloses a method of treating a disease or condition characterized by aberrant Ras activity caused by a Ras mutant. In some embodiments, the disease or disorder is cancer.

[0185] Accordingly, there is also provided a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a compound comprising such a compound or salt. Pharmaceutical composition. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendix cancer, melanoma, acute myelogenous leukemia, small bowel cancer, ampullary cancer, germ cell cancer, Cervical cancer, cancer of unknown primary site, endometrial cancer, esophagogastric cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, liver and gallbladder cancer or bladder cancer. In some embodiments, the cancer is appendix cancer, endometrial cancer or melanoma. Also provided is a method for treating Ras protein-related disorders in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such a compound or salt things.

[0186] 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 are useful in the treatment of various 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 their salts, pharmaceutical compositions comprising such compounds or salts, and methods include, but are not limited to, tumor types such as: astrocytic, breast, cervix, colon Carcinomas and sarcomas of the rectum, endometrium, esophagus, stomach, head and neck, hepatocytes, larynx, lung, oral cavity, ovary, prostate and thyroid. Other cancers include, for example: heart, e.g. sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung, e.g. bronchogenic carcinoma (squamous cell , undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal, e.g. esophageal (squamous carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, 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); genitourinary tract, eg: kidney (adenocarcinoma, Wilm's tumor (Wilms tumor), lymphoma , leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma) , sarcomas, mesenchymal cell carcinomas, fibromas, fibroadenomas, adenomatoid tumors, lipomas); liver, e.g. hepatocellular carcinoma (liver cell carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, Adenoma, hemangioma; Biliary tract, eg, gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone, eg, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma (Ewing's sarcoma) sarcoma), malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (exostoses of osteochondral), benign enchondroma, chondroblastoma, chondromyxoma fibroma, osteoid osteoma, and giant cell tumor; nervous system, e.g., skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, colloid neoplastic disease), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglia Cytoma, schwannomas, retinoblastoma, congenital tumors), neurofibroma of the spinal cord, neurofibromatosis type 1, meningioma, glioma, sarcoma); gynecology, e.g. uterus (endometrial cancer , uterine cancer, endometrial cancer), cervix (cervical cancer, cervical precancerous atypical hyperplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), Granular-theca cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma tumor), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematopoietic system, e.g. blood (myelogenous leukemia (acute and chronic), acute leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin, Examples: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland, eg, neuroblastoma tumor.

[0187] In some embodiments, the Ras protein is wild-type (RasWT). Accordingly, in some embodiments, compounds of the invention are used in methods of treating a patient with a RasWT-containing cancer (eg, K-RasWT, H-RasWT, or N-RasWT). In some embodiments, the Ras protein is Ras amplified (eg, K-Rasamp). Accordingly, in some embodiments, compounds of the invention are used in a method of treating a patient with a Rasamp (K-Rasamp, H-Rasamp or N-Rasamp) containing cancer. In some embodiments, the cancer comprises a Ras mutation, such as a Ras mutation described herein. In some embodiments, the mutant line is selected from: (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F , Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L or G13V, and combinations thereof; (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C , K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N or G12R, and combinations thereof; (c) the following N-Ras mutants: Q61R, Q61K, G12D , Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T, or any combination thereof; combination of one. In some embodiments, the cancer comprises a K-Ras mutation selected from the group consisting of G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61H, Q61K, and Q61L. In some embodiments, the cancer comprises an N-Ras mutation selected from the group consisting of G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer comprises an H-Ras mutation selected from the group consisting of Q61H and Q61L. In some embodiments, the cancer comprises a Ras mutation 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, compounds of the invention inhibit multiple Ras mutants. For example, compounds can inhibit both K-Ras G12C and K-Ras G13C. Compounds can inhibit both N-Ras G12C and K-Ras G12C. Compounds can inhibit both N-Ras G12C and K-Ras G12C. In some embodiments, the compound inhibits both K-Ras G12C and K-Ras G12D. In some embodiments, the compound inhibits both K-Ras G12V and K-Ras G12C. In some embodiments, the compound inhibits both K-Ras G12V and K-Ras G12S. In some embodiments, compounds of the invention inhibit RasWT as well as one or more additional Ras mutations (e.g., K, H, or N-RasWT 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-RasWT and H-Ras Q61R, G13R, Q61K, G12S, or K, H or N-RasWT 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) . In some embodiments, compounds of the invention inhibit Rasamp as well as one or more additional Ras mutations (e.g., K-, H-, or N-Rasamp 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-Rasamp and H-Ras Q61R, G13R, or K-, H- Or N-Rasamp 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).

[0188] Methods for detecting Ras mutations are known in the art. Such approaches include, but are not limited to, direct sequencing and the use of high-sensitivity diagnostic assays (using CE-IVD markers), such as Domagala et al., Pol J Pathol 3: 145-164 (2012), which is incorporated herein by reference in its entirety Methods described in, including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; See also eg WO 2020 / 106640.

[0189] In some embodiments, the cancer is non-small cell lung cancer and the Ras mutation comprises 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 comprises 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 comprises 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 comprises an N-Ras mutation, such as N-Ras G12D. In some embodiments, the cancer is melanoma and the Ras mutation comprises 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-Rasamp. In any of the foregoing, if not specifically stated, the compound may also inhibit RasWT (eg, K-, H-, or N-RasWT) or Rasamp (eg, K-, H-, or N-Rasamp).

[0190] In some embodiments, the cancer comprises a Ras mutation and a STK11LOF, KEAP1, EPHA5, or NF1 mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and a STK11 LOF mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and a STK11 LOF mutation. In some embodiments, the cancer comprises a K-Ras G13C Ras mutation and a STK11LOF, KEAP1, EPHA5, or NF1 mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises a K-Ras G12V mutation. In some embodiments, the cancer is colorectal cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12D mutation. In some embodiments, the cancer is pancreatic cancer and comprises a K-Ras G12V mutation. In some embodiments, the cancer is endometrial cancer and comprises a K-Ras G12C mutation. In some embodiments, the cancer is gastric cancer and comprises a K-Ras G12C mutation. In any of the foregoing, compounds may also inhibit RasWT (eg, K-, H-, or N-RasWT) or Rasamp (eg, K-, H-, or N-Rasamp).

[0191] Also provided is a method of inhibiting Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Also provided is a method of inhibiting RAF-Ras binding comprising contacting the cell with an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. The cell can be a cancer cell. The cancer cells may be of any type of cancer described herein. The cells can be in vivo or in vitro. combination therapy

[0192] The methods of the invention may include the compounds of the invention alone or in combination with one or more additional therapies (eg, non-drug treatments or therapeutic agents). When administered alone, the dosage of one or more of these additional therapies (eg, non-drug treatments or therapeutic agents) may be reduced relative to the standard dosage. For example, doses can be determined empirically based on drug combinations and permutations or can be inferred by isoradiometric analysis (eg, Black et al., Neurology 65:S3-S6 (2005)).

[0193] The compounds of the invention may be administered before, after or concurrently with one or more of these additional therapies. When combined, the dose of the compound of the invention and the dose of the one or more additional therapies (eg, non-drug treatments or therapeutic agents) provide a therapeutic effect (eg, a synergistic or additive therapeutic effect). A compound of the invention and an additional therapy, such as an anticancer agent, can be administered together, such as in a single pharmaceutical composition, or separately, and when administered separately, the administration can occur simultaneously or sequentially. Such sequential administrations may be close or far apart in time.

[0194] In some embodiments, the additional therapy is the administration of a side effect limiting agent (eg, an agent intended to reduce the occurrence or severity of side effects of treatment). For example, in some embodiments, compounds of the invention may also be used in combination with therapeutic agents for the treatment of nausea. Examples of agents that may be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or Its pharmaceutically acceptable salt.

[0195] In some embodiments, the one or more additional therapies include non-drug treatments (eg, surgery or radiation therapy). In some embodiments, the one or more additional therapies include a therapeutic agent (eg, a compound or biologic that is an anti-angiogenic, signal transduction inhibitor, anti-proliferative, glycolysis inhibitor, or autophagy inhibitor). In some embodiments, the one or more additional therapies include non-drug treatments such as surgery or radiation therapy and therapeutic agents such as anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors or Compounds or biological agents of autophagy inhibitors). In other embodiments, the one or more additional therapies include two therapeutic agents. In yet 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.

[0196] In this Combination Therapies section, all references are incorporated by reference with respect to the agents described, whether or not expressly stated as such. non-drug therapy

[0197] Examples of non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (eg, surgical resection of tumor tissue), and T cell recipient transfer (ACT) therapy.

[0198] In some embodiments, the compounds of the present invention may be used as adjunctive therapy after surgery. In some embodiments, compounds of the invention may be used as preoperative neoadjuvant therapy.

[0199] Radiation therapy is useful for inhibiting abnormal cell growth or treating hyperproliferative disorders, such as cancer, in an individual, eg, a mammal (eg, a human). Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered by one or a combination of several methods, including but not limited to external beam therapy, internal radiation therapy, implant radiation, stereotaxic radiosurgery, whole body radiation therapy, radiation therapy, and permanent or transient implant brachytherapy . As used herein, the term "brachytherapy" refers to radiation therapy delivered by insertion of spatially confined radioactive material in the body at or near the site of a tumor or other proliferative tissue disease. The term is intended, but not limited to, to include exposure to radioactive isotopes such as At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu radioactive isotopes). Suitable radioactive sources for use as cell conditioning agents of the present 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 hormones, beta particles, gamma radiation or other therapeutic rays. The radioactive material may also be a fluid made from any radionuclide solution, such as a solution of I-125 or I-131, or a radioactive fluid may be made using a suitable fluid containing small particles of a solid radionuclide such as Au-198 or Y-90. Fluid slurry preparation. In addition, radionuclides can be embedded in gels or radioactive microspheres.

[0200] In some embodiments, the compounds of the present invention can sensitize abnormal cells to radiation therapy for the purpose of killing or inhibiting the growth of such cells. Accordingly, the invention further relates to a method for sensitizing abnormal cells in a mammal to radiation therapy, the method comprising administering to the mammal an amount of a compound of the invention effective to sensitize the abnormal cells to radiation therapy . The amount of the compound in the method can be determined according to the manner used to determine the effective amount of the compound described herein. In some embodiments, compounds of the invention are useful as adjuvant therapy following radiation therapy or as neoadjuvant therapy prior to radiation therapy.

[0201] In some embodiments, the non-drug therapy is T cell recipient transfer (ACT) therapy. In some embodiments, the T cell line activates T cells. The T cells can 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 CAR into T cells. A source of T cells is obtained from an individual prior to expansion and genetic modification of the T cells. 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 a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the invention, various T cell lines available in the art may be used. In some embodiments, the T cells are autologous T cells. Before or after T cells have been genetically modified to express a desired protein, such as a CAR, such T cells can generally be activated and expanded using methods such as those described in, for example, the following US 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; 6,867,041. therapeutic agent

[0202] A therapeutic agent may be a compound useful in the treatment of cancer or its associated symptoms.

[0203] For example, the therapeutic agent can be a steroid. Accordingly, in some embodiments, the one or more additional therapies include steroids. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone , cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone ( diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, Flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, flupermesolone acetate (fluperolone acetate), fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide ( halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrison (medrysone), meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone ( prednisolone), 25-diethylaminoacetic acid prednisolone, prednisolone sodium phosphate, prednisone, prednival, prednylidene, Lime rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and their salts or derivatives.

[0204] Additional examples of therapeutic agents that may be used in combination therapy with the compounds of the present invention include compounds described in the following patents: U.S. Patent Nos. No. 5,770,599, No. 5,747,498, No. 5,990,141, No. 6,235,764 and No. 8,623,885, and 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.

[0205] The therapeutic agent may be a biological agent (eg, an interleukin (eg, an interferon or an interleukin, such as IL-2)) for the treatment of cancer or its associated symptoms. In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein or functional fragment thereof). Antibody-drug conjugates are also included.

[0206] The therapeutic agent can be a T cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (eg, a monospecific antibody, such as a monoclonal antibody). The antibody can 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, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (eg, an inhibitory antibody or a small molecule inhibitor) (eg, an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (eg, an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PDL-1 inhibitor or antagonist (eg, an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PDL-2 inhibitor or antagonist (eg, an inhibitory antibody or Fc fusion or small molecule inhibitor) (eg, a PDL-2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B Inhibitors or antagonists of -7 family ligands or combinations thereof (eg inhibitory antibodies or small molecule inhibitors). In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody such as avelumab (avelumab), durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene) or Preusser, M . et al. (2015) Nat. Rev. Neurol. The checkpoint inhibitors disclosed in, including but not limited to ipilimumab (ipilimumab), tremelimumab (tremelimumab), nivolumab, pembrolizumab anti, AMP224, AMP514 / MEDI0680, BMS936559, MED14736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9 and KW-6002.

[0207] The therapeutic agent may be an anti-TIGIT antibody such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A or OMP-313M32 (etigilimab).

[0208] The therapeutic agent can be an agent that treats cancer or its related symptoms (eg, cytotoxic agents, non-peptide small molecules, or other compounds useful in the treatment of cancer or its related symptoms, collectively referred to as "anticancer agents"). Anticancer agents can be, for example, chemotherapeutic or targeted therapeutic agents.

[0209] Anticancer agents include mitotic inhibitors, intercalative antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folate analogs , pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination Complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogues . Other anticancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel ( doxetaxel). In some embodiments, the one or more additional therapies include two or more anticancer agents. The two or more anticancer agents may be used in a mixed solution for combined administration or separate administration. Suitable dosing regimens for combination anticancer agents are known in the art and described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355 (9209 ): 1041-1047 (2000).

[0210] Other non-limiting examples of anticancer agents include Gleevec® (Imatinib Mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib) ); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents such as thiotepa and cyclophosphamide; Busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimine and methylmelamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine amines; polyacetylenes (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin ( bryostatin ); callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycin (especially candocin 1 and candocin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189 and CB1-TM1); eleutherobin ; pancratistatin; sarcodictyn A; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholphosamide (cholophosphamide), estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, Xinen Novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine ( carmustine ), chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as enediynes Antibiotics (e.g., calicheamicin, such as calicheamicin γ11 and calicheamicin ω11 (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dannamycin ( dynemicin ), such as dynomycin A; bisphosphonates, such as clodronate; esperamicin; neocarzinostatin chromophore and related chromophores Alkyne antibiotic chromophore, aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, actinomycin Cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins ), dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (adriamycin) (doxorubicin), N-morpholinodoxorubicin, cyano(N-morpholino)doxorubicin, (2-pyrrolinyl-doxorubicin, deoxydoxorubicin Bicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (such as mitomycin C ), mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, triiron Adriamycin (quelamycin), rhodorubicin (rodorubicin), streptonigrin (streptonigrin), streptozocin (streptozocin), tubercidin (tubercidin), ubenimex (ubenimex), netastatin (zinostatin), zorubicin (zorubicin); antimetabolites, such as methotrexate (methotrexate) and 5-fluorouracil (5-FU); pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as amcitabine (ancitabine), azacitidine, 6-thiazopyrimidine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enoxa enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testosterone testolactone; anti-epinephrines such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisan bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate ; epothilone, such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids , such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; Pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; (2-ethylhydrazine; procarbazine (procarbazine); PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes such as T-2 toxin, Verrucospora Verracurin A, roridin A and anguidine; urethane; vindesine; dacarbazine; mannomustine ( mannomustine); mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphine Amides; Thiotepa; taxoids such as Taxol® (paclitaxel), Abraxane® (polyoxyethylene hydrogenated castor oil-free, albumin-engineered nanoparticle formulation of paclitaxel) and Taxotere ® (docetaxel); chloranbucil; tamoxifen (Nolvadex™); raloxifene; aromatase-inhibiting 4(5)-imidazole; Hydroxytamoxifen; Trioxifene; Keoxifene; LY 117018; Onapristone; Toremifene (Fareston®); Flutamide ), nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar® gemcitabine; 6 - thioguanine; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide ) (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Navelbine® (vinorelbine); Novantrone; Teniposide ; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (eg CPT-11); topoisomerization Enzyme inhibitors RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperamicins; capecitabine (eg Xeloda®); pharmaceutically acceptable salts.

[0211] Additional non-limiting examples of anticancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximabv (Erbitux®) , rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicine, abagovomab, acridine carboxamide, adelaide adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, alvocidib, 3-amine Pyridine-2-carbaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastic agents (e.g., cell cycle non-specific antineoplastic agents, and others as described herein) antineoplastic agents), antineoplastic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine ), BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), sponge-induced cancer Calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod (imiquimod), indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, thiothrone ( lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN - 38. Salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur -tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, 2-chloroethylamine, troxacitabine , uramustine, vadimezan, vinflunine, ZD6126 and zosuquidar.

[0212] Other non-limiting examples of anticancer agents include natural products such as vinca alkaloids (such as vinblastine, vincristine, and vinorelbine), epipodophyllotoxins (such as etoposide and teniposide), glycosides), antibiotics (such as dactinomycin / actinomycin D), daunomycin, and idarubicin), anthracyclines, mitoxantrone, bleomycins , plicamycin (mithramycin), mitomycin, enzymes such as L-asparaginase, which systemically metabolize L-asparagine and remove Paragamide cells), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (such as methamethamine, cyclophosphamide and analogs melphalan (melphalan) and chlorambucil), ethylene oxide Amines and methylmelamines (e.g. (hexamethylmelamine and thiotepa), CDK inhibitors (e.g. CDK4 / 6 inhibitors such as abemaciclib, ribociclib, palbociclib ( palbociclib), seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638 and SCH727965), alkyl sulfonates (such as white sulfame), nitrosoureas (such as carmustine (BCNU) and analogs, and streptozocin), trazenes-dacarbazinine (DTIC), antiproliferative / Anti-mitotic antimetabolites (such as folic acid analogs), pyrimidine analogs (such as fluorouracil, aziridine, and cytarabine), purine analogs and related inhibitors (such as mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (such as anastrozole, exemestane, and letrozole), and platinum coordination complexes (such as cisplatin and carboxylate Platinum), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (eg, trichostatin, sodium butyrate, Apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215 and panobinostat )), mTOR inhibitors (eg, vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5 ) inhibitors (e.g. Array 520), DNA binding agents (e.g. Zalypsis®), PI3K inhibitors such as PI3K delta inhibitors (e.g. GS-1101 and TGR-1202), (PI3K delta and gamma inhibitors (e.g. Cal- 130), copanlisib, alpelisib, and idelalisib; multikinase inhibitors (such as TG02 and sorafenib), hormones (such as estrogen and hormone Agonists such as luteinizing hormone releasing hormone (LHRH) agonists (eg goserelin, leuprolide and triptorelin), BAFF neutralizing antibodies (eg LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g. CNT0328), telomerase inhibitors (e.g. GRN 163L), Aurora kinase inhibitors (e.g. MLN8237), cell surface monoclonal antibodies (e.g. anti-CD38 (HUMAX-CD38) ), anti-CS1 (e.g. elotuzumab), HSP90 inhibitors (e.g. 17 AAG and KOS 953), P13K / Akt inhibitors (e.g. perifosine), Akt inhibitors (e.g. GSK-2141795), PKC inhibitors (e.g. enzastaurin), FTIs (e.g. Zarnestra™), anti-CD138 (e.g. BT062), Torcl / 2 specific kinase inhibitors (e.g. INK128), ER / UPR targets Antitropic agents (such as MKC-3946), cFMS inhibitors (such as ARRY-382), JAK1 / 2 inhibitors (such as CYT387), PARP inhibitors (such as olaparib and veliparib (ABT-888 )) and BCL-2 antagonists.

[0213] In some embodiments, the anticancer agent is selected from the group consisting of methamethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafil Ni (sorafenib) or any of the aforementioned analogs or derivatives variants.

[0214] 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®); small molecule tyrosine kinase inhibitors such as gefitinib Iressa®, Erlotinib (Tarceva®), Pilitinib, CP-654577, CP-724714, Canertinib (CI 1033), HKI-272, Lapatinib Lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, JNJ-26483327, and JNJ-26483327.

[0215] In some embodiments, 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.

[0216] In some embodiments, the anticancer agent is an inhibitor of receptor tyrosine kinase (RTK) / growth factor receptor downstream members (e.g., a SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630 , JAB-3068, RLY-1971), SOS1 inhibitors (eg, BI-1701963, BI-3406), Raf inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, AKT inhibitors, or mTOR inhibition In some embodiments, the anticancer agent is JAB-3312. In some embodiments, the anticancer agent is an additional Ras inhibitor (such as AMG 510, MRTX1257, MRTX849, ARS-853, ARS-1620, ARS-3248 (or JNJ-74699157), LY3499446) or Ras vaccine or another treatment mode designed to directly or indirectly reduce the carcinogenic activity of Ras. Can be combined with the Ras inhibitor of the present invention Further examples of combined Ras inhibitors are provided in the following patents (which are incorporated herein by reference in their entirety): WO 2020050890, WO 2020047192, WO 2020035031, WO 2020028706, WO 2019241157, WO 2019232419, WO 2019217691, WO 201 9217307, WO 2019215203, WO 2019213526, WO 2019213516, WO 2019155399, WO 2019150305, WO 2019110751, WO 2019099524, WO 2019051291, WO 2018218070, WO 201 8217651, WO 2018218071, WO 2018218069, WO 2018206539, WO 2018143315, WO 2018140600, WO 2018140599, WO 2018140598, WO 2018140514, WO 2018140513, WO 2018140512, WO 2018119183, WO 2018112420, WO 2018068017, WO 2018064510, WO 2017201161, WO 2017172979, WO 20 17100546, WO 2017087528, WO 2017058807, WO 2017058805, WO 2017058728, WO 2017058902, WO 2017058792, WO 2017058768 , WO 2017058915, WO 2017015562, WO 2016168540, WO 2016164675, WO 2016049568, WO 2016049524, WO 2015054572, WO 2014152588, WO 2014143659 and WO 2013155223.

[0217] In some embodiments, a therapeutic agent that can be combined with a compound of the invention is a MAP kinase (MAPK) pathway inhibitor (or "MAPK inhibitor"). MAPK inhibitors include but are not limited to one or more MAPK inhibitors described in Cancers (Basel) 2015 September; 7(3): 1758–1784. For example, the MAPK inhibitor can be selected from one or more of the following: trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132; Vemurafenib, Pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; ) (RDEA 119 / BAY 86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (Roche, described in PLoS One. 25 Nov 2014; 9(11)) and GSK1120212 (or JTP-74057, described in Clin Cancer Res. 2011 Mar 1; 17(5):989-1000). The MAPK inhibitor can be PLX8394, LXH254, GDC-5573 or LY3009120.

[0218] In some embodiments, the anticancer agent is a disruptor or a RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway inhibitor. PI3K / AKT inhibitors may include, but are not limited to, one or more PI3K / AKT inhibitors described in Cancers (Basel) September 2015; 7(3): 1758-1784. For example, the PI3K / AKT inhibitor can be selected from one or more of the following: NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103;

[0219] In some embodiments, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0220] In some embodiments, 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 embodiments, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0221] IGF-1R inhibitors include linsitinib or a pharmaceutically acceptable salt thereof.

[0222] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNA. 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 natural ligand activation of EGFR. Non-limiting examples of antibody-based EGFR inhibitors include 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 EGFR inhibition described in Yang et al., Cancer Res.1999, 59:1236-1243 agent. The EGFR inhibitor may be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra) or Mab C225 (ATCC Accession No. HB-8508) or an antibody or antibody fragment having binding specificity therefor.

[0223] Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®) and lapatinib (TykerB®). See, eg, 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, 30 4( 5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). Other non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, and all pharmaceutically acceptable salts of such EGFR inhibitors: EP 0520722; EP 0566226; WO96 / 33980 ; US Patent No. 5,747,498; WO96 / 30347; EP 0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; 70; WO97 / 13771; WO98 / 02437; WO98 / 02438; WO97 / 32881; DE 19629652; WO98 / 33798; 4895;WO96 / 31510; wo98 / 14449; wo98 / 14450; wo98 / 14451; wo95 / 09847; wo97 / 19065; wo98 / 17662; US Patent 5,789,427; US Patent No. 5,650,415; US Patent No. 5,656,643; WO99 / 3 3 3; 5146; wo99 / 35132; WO99 / 07701; and WO92 / 20642. Other non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family consists of HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3) and HER (ERBB4).

[0224] 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 group consisting of class I MEK1 mutations: D67N, P124L, P124S, and L177V. In some embodiments, the MEK mutation is a class II MEK1 mutation selected from: ΔE51-Q58, ΔF53-Q58, E203K, L177M, C121S, F53L, K57E, Q56P, and K57N.

[0225] PI3K inhibitors include but are not limited to wortmannin; 17-hydroxy wortmannin analogues described in WO06 / 044453; 4-[2-(1H-indazol-4-yl) -6-[[4-(Methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as Pitilixi( pictilisib) or GDC-0941 and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl )-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235 and described in WO06 / 122806); (S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-(N-morpholino)thieno[3,2-d]pyrimidine- 6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H -l-benzopyran-4-one (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinopyrido[3',2':4,5]furo [3,2-d]pyrimidin-2-yl]phenol hydrochloride (purchased from Axon Medchem); PIK 75 (2-methyl-5-nitro-2-[(6-bromoimidazo[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-hydroxyl-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 ); 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.

[0226] AKT inhibitors include but are not limited to Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem.J. 2005, 385(Pt. 2): 399-408); Akt-1-1,2 ( Inhibition of Akl and 2) (Barnett et al., Biochem.J. 2005, 385(Pt. 2): 399-408); API-59CJ-Ome (eg Jin et al., Br. J. Cancer 2004, 91:1808- 12); 1-H-imidazo[4,5-c]pyridyl compounds (eg WO 05 / 011700); indole-3-carbinol and derivatives thereof (eg US Pat. No. 6,656,963; Sarkar and Li J Nutr .2004, 134(12 Suppl):3493S-3498S); Perifosine (e.g. interferes with Akt membrane localization; Dasmahapatra et al., Clin. Cancer Res. 2004, 10(15):5242-52); Phosphatidylinositol Ether lipid analogs (eg 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. People, Cancer Res. 2004, 64:4394-9).

[0227] mTOR inhibitors include but are not limited to ATP competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO94 / 09010); Deforolimus (also known as deforolimus or AP23573); rapamycin analogs (rapalogs), 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-table- (tetrazolyl)-rapamycin (also known as ABT578); 32-deoxyrapamycin; 16-pentynyloxy-32(S)-dihydrorapamycin; described in WO05 / 005434 Derivatives disclosed in US Patent Nos. 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 / 1111 30. WO94 Derivatives disclosed in / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807 and WO2018204416; and phosphorus-containing rapamycin derivatives (such as WO05 / 016252 ). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see eg WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552.

[0228] BRAF inhibitors that may be used in combination with the compounds of the present invention include, for example, vemurafenib, dabrafenib and encorafenib. BRAF may comprise class 3 BRAF mutations. In some embodiments, the class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; D594G; D594A; D594H; F595L; G596D; G596R; and A762E.

[0229] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance to not only traditional chemotherapy but also targeted therapeutics including BCL-2 inhibitors such as ABT-263.

[0230] In some embodiments, the additional therapeutic agent is a SHP2 inhibitor. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to various 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 an inactive, autoinhibitory configuration stabilized by a binding network involving residues from the N-SH2 and PTP domains. Stimulation with, for example, cytokines or growth factors acting through receptor tyrosine kinases (RTKs) results in exposure of the catalytic site, resulting in enzymatic activation of SHP2.

[0231] SHP2 is involved in signaling via the RAS-mitogen-activated protein kinase (MAPK), ie, JAK-STAT or phosphoinositide 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 myelomonocytosis Leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, and cancers of the breast, lung, and colon. Some of these mutations destabilize the auto-inhibitory conformation of SHP2 and promote auto-activation or enhanced growth factor-driven activation of SHP2. Therefore, SHP2 represents a particularly interesting target for the development of novel therapies for the treatment of various diseases, including cancer. Combinations of SHP2 inhibitors (e.g. RMC-4550 or SHP099) and RAS pathway inhibitors (e.g. MEK inhibitors) have been shown to inhibit various cancer cell lines (e.g. pancreatic, lung, ovarian and breast) in vitro of proliferation. Therefore, combination therapy involving SHP2 inhibitors and RAS pathway inhibitors may be a general strategy for preventing tumor drug resistance in various malignancies.

[0232] 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; WO20162034 05; WO2016203406; WO2011022440; WO2017156397; WO2017079723; WO2017211303; WO2012041524; WO2017211303; WO2019051084; WO2017211303; ; WO2014176488; WO2017100279; WO2019051469; US8637684; WO2007117699; 191328; WO2016196591; WO2017078499; WO2017210134; WO2018013597; WO2018129402; WO2018130928; WO20181309928; WO2018136264; WO2018136265; WO2018160731; WO2018172984;

[0233] 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, eg, a non-covalent allosteric inhibitor. In some embodiments, the SHP2 inhibitor is a covalent SHP2 inhibitor, such as an inhibitor that targets 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.

[0234] 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 agent. In some embodiments, the additional therapeutic agent is selected from the group consisting of a MEK inhibitor, a SHP2 inhibitor, and a PD-L1 inhibitor. See, eg, 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 inhibitors of the invention are used in combination with MEK inhibitors and SOS1 inhibitors. In some embodiments, the Ras inhibitors of the present invention are used in combination with PDL-1 inhibitors and SOS1 inhibitors. In some embodiments, the Ras inhibitors of the present invention are used in combination with PDL-1 inhibitors and SHP2 inhibitors. In some embodiments, the Ras inhibitors of the invention are used in combination with MEK inhibitors and SHP2 inhibitors. In some embodiments, the cancer is colorectal cancer and the treatment comprises administering a combination of a Ras inhibitor of the invention and a second or third therapeutic agent.

[0235] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0236] Immunotherapies include but are not limited to monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T cells (e.g. CAR-T cells), bispecific antibodies (e.g. BiTEs) And anti-PD-1 agent, anti-PDL-1 agent, anti-CTLA4 agent, anti-LAG1 agent and anti-OX40 agent.

[0237] Immunomodulators (IMiDs) are a class of immunomodulatory drugs (drugs that modulate the immune response) that contain imide groups. IMiD drugs include thalidomide and its analogs (lenalidomide, pomalidomide and apremilast).

[0238] Exemplary anti-PD-1 antibodies and methods of use thereof 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 herein.

[0239] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (eg, bivalent anti-GITR antibodies), such as those described in U.S. Patent No. 6,111,090, U.S. Patent No. 8,586,023, WO2010 / 003118, and WO2011 / 090754 or such as US Patent No. 7,025,962, EP 1947183, US Patent No. 7,812,135; US Patent No. 8,388,967; US Patent No. 8,591,886; 54 , WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451 and WO2011 / 051726.

[0240] Another example of a therapeutic agent that may 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, antibodies, antigen-binding domains, radionuclear species, and combinations and conjugates thereof synthesized in vitro. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally can be used to inhibit or stimulate their targets (such as receptor or enzyme activation or inhibition), and thereby promote cell death or make cells growth arrest. In some embodiments, the one or more additional therapies include anti-angiogenic agents.

[0241] Anti-angiogenic agents may 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, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab ( 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, and US Patent Nos. 5,863,949 and 5,861,5 No. 10 in. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no MMP-1 inhibitory activity. More preferably compared to other matrix metalloproteases (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) are inhibitors that selectively inhibit MMP-2 or AMP-9. Some specific examples of MMP inhibitors are AG-3340, RO 32-3555 and RS 13-0830.

[0242] Other exemplary anti-angiogenic agents include kinase domain KDR (kinase domain receptor) inhibitors (such as antibodies and antigen binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (such as specific Antibodies or antigen binding domains that bind VEGF (e.g. bevacizumab or soluble VEGF receptor or its ligand binding domain), such as VEGF-TRAP™, and anti-VEGF receptor agents (e.g. specifically bind to VEGF receptor Antibody or antigen-binding region of EGFR), EGFR inhibitors (such as antibodies or antigen-binding regions that specifically bind to EGFR), such as Vectibix® (panitumumab), Erlotinib (Tarceva®), anti-Angl and anti-Ang2 agents (such as antibodies or antigen-binding regions that specifically bind to Angl and Ang2 or their receptors, such as Tie2 / Tek), and anti-Tie2 kinase inhibitors (such as antibodies or antigen-binding regions that specifically bind to Tie2 kinase district). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (such as specifically binding antibodies or antigen binding domains, or Soluble TWEAK receptor antagonists; see US6,727,225), ADAM disintegrin domains that antagonize the binding of integrins to their ligands (US 2002 / 0042368), specifically binding anti-eph receptor or anti-pterin antibodies or antigens Binding regions (U.S. Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124 and their patent family members), and anti-PDGF-BB antagonists (such as specifically binding antibodies or Antigen binding region), and an antibody or antigen binding region that specifically binds to PDGF-BB ligand, and a PDGFR kinase inhibitor (such as an antibody or antigen binding region that specifically binds to PDGFR kinase). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium (Gilead Sciences, USA); Alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); Ilomastat (Arriva, USA, US5892112); Emaxanib (Pfizer, USA , US 5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); ) (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 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070); ARGENT Technologies (Ariad, USA); -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); Mitastatin (Metastatin) (EntreMed, USA); Serpin (maspin) (Sosei, Japan); 2-methoxyestradiol (Oncology Sciences Corporation, USA) ; ER-68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02233610) ; platelet factor 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); Lengitide (Merck KGaA, German; 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 Childrens Hospital, USA); ATN 161 (Attenuon, USA); 2-methoxyestradiol (Boston Childrens Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); Tissue factor pathway inhibitor (EntreMed, USA); pegatanib (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); SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); Motuporamine C (Motuporamine C) (British Columbia University, Canada); CDP 791 (Celltech Group, UK); Atiprimod (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); Kinase plasminogen activator inhibitor (Dendreon, USA); oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); Angusidine (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); Endo-2-methoxyestradiol; anginex (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA ); tumor necrosis factor-α inhibitors; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Childrens 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); Combretastatin 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); (Genaera, USA); RPI 4610 (Sirna, USA); Heparanase Inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); 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); Protein-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); , USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thromboplastin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA). .

[0243] Other examples of therapeutic agents that may be used in combination with the compounds of the invention include agents (e.g., antibodies, antigen binding domains, or soluble receptors) that specifically bind to and inhibit the activity of growth factors, such as hepatocyte growth factor (HGF, also Antagonists known as Scatter Factor), and antibodies or antigen binding domains that specifically bind the receptor c-Met.

[0244] Another example of a therapeutic agent that can be used in combination with the compounds of the invention is an autophagy inhibitor. Autophagy inhibitors include but are not limited to chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1 (bafilomycin A1), 5-amino-4-imidazolamide riboside (AICAR ), soft sponge acid, autophagy-inhibitory 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 vincrin alkali. In addition, antisense RNA or siRNA that inhibit the expression of proteins, including but not limited to ATG5 (involved in autophagy), can also be used. In some embodiments, the one or more additional therapies include an autophagy inhibitor.

[0245] Another example of a therapeutic agent that may be used in combination with the compounds of the present invention is an antineoplastic agent. In some embodiments, the one or more additional therapies include antineoplastic agents. Non-limiting examples of antineoplastic agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, altretinoin, hexamethylmelamine , amifostine, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim ), arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, simox Interleukin (celmoleukin), cetrorelix (cetrorelix), cladribine (cladribine), clotrimazole (clotrimazole), cytarabine ocfosfate (cytarabine ocfosfate), DA 3030 (Dong-A), daclid Daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, Doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon α, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, etiflorine ( emitefur), epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole ( fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine (gemcitabine), gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin (heptaplatin), human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid (ibandronic acid), idarubicin (idarubicin), imiquimod (imiquimod), interferon alpha, natural interferon alpha , 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 beta-lb, interferon gamma, natural interferon gamma-la, interferon gamma-lb), interleukin-1 beta, iobenguane, irinotecan, irsogladine ), lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, interferon-alpha, leuproxine Relin, levamisole + fluorouracil, liarazole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsine Alcohol (melarsoprol), metoclopramide (metoclopramide), mifepristone (mifepristone), miltefosine (miltefosine), mirimostim (mirimostim), mismatch double-stranded RNA, mitoguanidine hydrazone, di Bromodulcitol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, neda Platinum, nilutamide, noscapine, novel erythropoietin, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, paclitaxel Pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil , Birubicin, rabbit anti-thymocyte polyclonal antibody, pegylated interferon α-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment , rhenium etidronate Re 186 , RII isotretinamide (retinamide), rituximab (rituximab), romotide (romourtide), samarium lexidronam (153 Sm) (samarium lexidronam), sand Sargramostim, sizofiran, sobuzoxane, sonermin, strontium chloride-89, suramin, tasonermin, other Tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymofasin ( thymalfasin), thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, trastuzumab Treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, natural tumor necrosis factor alpha, ubenimex, bladder cancer vaccine, Maruyama vaccine , melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer, or zoledronate Acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), decitabine , dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide (fenretinide ), filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granules Macrophage colony stimulating factor (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), pleomorphic epithelial mucin-yttrium 90 MAb (Antisoma) , marimastat, menogaril, mitomomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, Nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), Lu rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdenum thaliblastine, thrombopoietin, tin ethyletiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University) , melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital), or valspodar.

[0246] Additional examples of therapeutic agents that may be used in combination with the compounds of the present invention include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, and Known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; (dacetuzumab); muromonab-CD3; ipilumumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP 224; adalimumab (Humira®); ado-trastuzumab emtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab ( Simulect®); belimumab (Benlysta®); basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (Adcetris®); canakinumab (Ilaris®); certolizumab pegol (Cimzia®); daclizumab (Zenapax®); Anti-(daratumumab) (Darzalex®); denosumab (Prolia®); eculizumab (Soliris®); efalizumab (Raptiva®); Gemtuzumab ozogamicin (Mylotarg®); golimumab (Simponi®); ibritumomab tiuxetan (Zevalin®); infliximab (infliximab) (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); Anti (ofatumumab) (Arzerra®); omalizumab (Xolair®); palivizumab (Synagis®); pertuzumab (Perjeta®); Monoclonal antibodies (Perjeta®); ranibizumab (Lucentis®); raxibacumab (Abthrax®); tocilizumab (Actemra®); (tositumomab); tositumomab-i-131; tositumomab and tositumomab-i-131 (Bexxar®); ustekinumab (Stelara®); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0247] Depending on the condition being treated, the compounds described herein may be used in combination with the agents disclosed herein or other suitable agents. Accordingly, in some embodiments, one or more compounds of the disclosure will be co-administered with other therapies described herein. When used in combination therapy, the compounds described herein can be administered with the second agent simultaneously or separately. Such combination administration can include simultaneous administration of both agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any agent described herein can be formulated together in the same dosage form and administered at the same time. Alternatively, the compounds of the invention and any of the therapies described herein can be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, a compound of the disclosure may be administered first followed by any therapy described herein, or vice versa. In some embodiments of separate administration regimens, the compounds of the invention and any of the therapies described herein are administered minutes apart, or hours apart, or days apart.

[0248] In some embodiments of any of the methods described herein, the first therapy (eg, a compound of the invention) and the one or more additional therapies are administered simultaneously or sequentially in either order. The first therapeutic agent can be immediately before, 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 after administration of the one or more additional therapies , 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 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.

[0249] The invention also features a kit comprising (a) a pharmaceutical composition comprising an agent described herein (eg, a compound of the invention) and (b) with instructions for performing any of the methods described herein packaging insert. In some embodiments, the kit includes (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the invention), (b) one or more additional therapies (e.g., a non-drug treatment or therapeutic agent), and (c) A package insert with instructions for performing any of the methods described herein.

[0250] Since one aspect of the invention encompasses the treatment of a disease or its associated symptoms with combinations of pharmaceutically active compounds that may be administered separately, the invention further relates to combining individual pharmaceutical compositions in kit form. The kit may comprise two separate pharmaceutical compositions: a compound of the invention and one or more additional therapies. The kit may comprise containers for containing the individual components, such as dispensing bottles or dispensing foil packs. Additional examples of containers include syringes, boxes and bags. In some embodiments, the kit can include directions for the use of the individual components. When the individual components are preferably administered in different dosage forms (e.g., oral or parenteral), when administered at different dosage intervals, or when the prescribing healthcare practitioner wishes to adjust the individual components of the combination, This kit form is particularly advantageous. Example of numbering

[0251] [1] A compound or a pharmaceutically acceptable salt thereof, which has the structure of Formula I: Formula I wherein the dotted lines represent zero, one, two, three or four non-adjacent double bonds; A is -N(H or CH3)C(O)-(CH2)-, wherein the amine nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; optionally Substituted 3-6 membered heterocycloalkyl; optionally substituted 6-membered aryl; or optionally substituted 5-10 membered heteroaryl; B is -CH(R9)- or >C = CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene ; optionally substituted 6-membered aryl; or 5 to 6-membered heteroaryl; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenylene; Substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O)NH-CH(R6)-, wherein C Bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3 to 8 membered heteroaryl; L is absent or is a linker; W is a crosslinking group, which contains carbonization Diimine, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid , borates, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enose; X1 It is an optionally substituted C1-C2 alkylene group, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano, Optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O) ) N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkane Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R1 is cyano, Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, optionally substituted Optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl, or R1 and R2 are combined with the atoms to which they are attached Form an optionally substituted 3 to 14 membered heterocycloalkyl; R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2 - C6 alkynyl, 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 R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 14 membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxyl or C1-C4 alkoxy R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms they are attached to form as appropriate Substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R8 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 3-8 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 R7 and R8 are combined with the carbon atom to which they are attached to form C=CR7 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; R7a and R8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or carbonyl combined with the carbon to which they are attached; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' 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 R7' and R8' combined with the carbon atom to which they are attached form an optionally substituted 3 to 6 membered Cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted Substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl, or R9 and L combined with the atoms to which they are attached form an optionally substituted 3 to 14 membered heterocycloalkyl ; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl.

[0252] [2] The compound of paragraph [1] or a pharmaceutically acceptable salt thereof, wherein G is an optionally substituted C1-C4 heteroalkylene.

[0253] [3] The compound of paragraph [1] or [2], or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ia: Formula Ia wherein the dotted line represents zero, one, two, three Or four non-adjacent double bonds; A series -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bound to the carbon atom of -CH(R10)-; to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered aryl; or optionally substituted 5 to 6 membered heteroaryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered cycloalkylene Heterocycloalkyl; optionally substituted 6-membered aryl; or 5 to 6-membered heteroaryl; L does not exist or is a linker; W is a crosslinking group, which includes carbodiimide, oxazole phylloline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester, N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enose; X2 is O or NH; X3 N or CH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 Alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R' )2; each R' is independently H or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 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 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; R3 is absent, or R2 and R3 are taken together with the atoms to which they are attached to form an optionally substituted 3- to 8-membered ring Alkyl or optionally substituted 3 to 14 membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano or methyl optionally substituted with 1 to 3 halogens; R5 is hydrogen, optionally halogen Substituted C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkane or R6 and R7 are combined with the carbon atoms they are connected to form an optionally substituted 3 to 6 membered cycloalkyl or an optionally substituted 3 to 7 membered heterocycloalkyl; R8 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 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 R7 and R8 are combined with the carbon atoms they are connected to form C=CR7'R8'; 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; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' 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 Substituted 6- to 10-membered aryl, or R7' and R8' are combined with the carbon atoms to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkane R is 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 cycloalkyl; R10 is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; and R11 is hydrogen or C1-C3 alkyl.

[0254] [4] The compound according to any one of paragraphs [1] to [3], or a pharmaceutically acceptable salt thereof, wherein X2 is NH.

[0255] [5] The compound according to any one of paragraphs [1] to [4], or a pharmaceutically acceptable salt thereof, wherein X3 is CH.

[0256] [6] The compound according to any one of paragraphs [1] to [5], or a pharmaceutically acceptable salt thereof, wherein R11 is hydrogen.

[0257] [7] The compound according to any one of paragraphs [1] to [5], or a pharmaceutically acceptable salt thereof, wherein R11 is a C1-C3 alkyl group.

[0258] [8] The compound of paragraph [7] or a pharmaceutically acceptable salt thereof, wherein R11 is methyl. [9] The compound according to any one of paragraphs [1] to [6], or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula Ib: Formula Ib wherein the dotted line represents zero, one, two One, three or four non-adjacent double bonds; A series -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bound to the carbon atom of -CH(R10)-; as the case may be Substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkyl; optionally substituted 6 membered aryl; or optionally substituted 5 to 6 membered hetero Aryl; B is -CH(R9)-, 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 cycloalkylene Heterocycloalkyl; optionally substituted 6-membered aryl; or 5 to 6-membered heteroaryl; L does not exist or is a linker; W is a crosslinking group, which includes carbodiimide, oxazole phylloline, thiazoline, chloroethyl urea, chloroethyl thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester, N -ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enose; n is 0, 1 or 2 ; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C( O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or A substituted C1-C4 alkyl group; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 and Y6 are independently CH or N; R1 is cyano, depending on the circumstances Substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 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 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 Substituted 5 or 6 membered heteroaryl; R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 14 membered Heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano or methyl optionally substituted by 1 to 3 halogens; R5 is hydrogen, C1-C4 alkyl optionally substituted by halogen, cyano, hydroxyl Or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or the carbon atom to which R6 and R7 are attached Combined to form optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R8 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 3-8 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 a combination of R7 and R8 and the carbon atoms to which they are attached Together form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; optionally substituted 3 to 6 or optionally substituted 3 to 7 membered heterocycloalkyl; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' 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 R7' And R8' is combined with the carbon atom to which it is attached to form an optionally substituted 3 to 6 membered cycloalkyl or an optionally substituted 3 to 7 membered heterocycloalkyl; R9 is an optionally substituted C1-C6 Alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, or optionally substituted 3 to 7 membered heterocycloalkyl; and R10 is hydrogen, hydroxyl, C1 -C3 alkoxy or C1-C3 alkyl.

[0260]

[10] The compound according to any one of paragraphs [1] to [9], or a pharmaceutically acceptable salt thereof, wherein X1 is an optionally substituted C1-C2 alkylene group.

[0261]

[11] The compound of paragraph

[10] or a pharmaceutically acceptable salt thereof, wherein X1 is methylene.

[0262]

[12] The compound of any one of paragraphs [1] to

[11] , or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen.

[0263]

[13] The compound according to any one of paragraphs [1] to

[11] , or a pharmaceutically acceptable salt thereof, wherein R5 is C1-C4 alkyl optionally substituted with halogen.

[0264]

[14] The compound of paragraph

[13] or a pharmaceutically acceptable salt thereof, wherein R5 is methyl.

[0265]

[15] The compound according to any one of paragraphs [1] to

[14] , wherein Y4 is C, or a pharmaceutically acceptable salt thereof.

[0266]

[16] The compound of any one of paragraphs [1] to

[15] , or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.

[0267]

[17] The compound according to any one of paragraphs [1] to

[16] , or a pharmaceutically acceptable salt thereof, wherein Y5 is CH.

[0268]

[18] The compound according to any one of paragraphs [1] to

[17] , or a pharmaceutically acceptable salt thereof, wherein Y6 is CH.

[0269]

[19] The compound according to any one of paragraphs [1] to

[18] , wherein Y1 is C, or a pharmaceutically acceptable salt thereof.

[0270]

[20] The compound of any one of paragraphs [1] to

[19] , or a pharmaceutically acceptable salt thereof, wherein Y2 is C.

[0271]

[21] The compound of any one of paragraphs [1] to

[20] , or a pharmaceutically acceptable salt thereof, wherein Y3 is N.

[0272]

[22] The compound of any one of paragraphs [1] to

[21] , or a pharmaceutically acceptable salt thereof, wherein R3 is absent.

[0273]

[23] The compound according to any one of paragraphs [1] to

[22] , wherein Y7 is C, or a pharmaceutically acceptable salt thereof.

[274]

[24] The compound of any one of paragraphs [1] to [6] or [9] to

[23] , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ic: Formula Ic Wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; Optionally substituted 3-6 membered heterocycloalkyl; optionally substituted 6-membered aryl; or optionally substituted 5-6 membered heteroaryl; B is -CH(R9)-, where the carbon is bound to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered Extended aryl; or 5 to 6 membered heteroaryl; L does not exist or is a linker; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl Thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester, N-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enose; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted 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 Optionally substituted 6 to 10 membered aryl or optionally substituted 5 to 10 membered heteroaryl; R2 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; R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form optionally substituted 3 to 8 membered cycloalkyl or optionally substituted 3 to 14 membered heterocycloalkyl; R5 is hydrogen, optionally C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl substituted by halogen; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1- C3 alkyl, or R6 and R7 combined with the carbon atom they are connected to form an optionally substituted 3 to 6 membered cycloalkyl or an optionally substituted 3 to 7 membered heterocycloalkyl; R8 is hydrogen, halogen , hydroxy, 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 R7 and R8 are combined with the carbon atoms they are connected to form C=CR7'R8'; 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; R7' is hydrogen, halogen or optionally substituted C1-C3 alkane R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 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 Optionally substituted 6 to 10 membered aryl, or R7' and R8' are combined with the carbon atom to which they are attached to form optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered hetero Cycloalkyl; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, or optionally substituted 3 to 7 and R10 is hydrogen, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl.

[0275]

[25] The compound of any one of paragraphs [1] to

[24] , or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen.

[0276]

[26] The compound according to any one of paragraphs [1] to

[25] , or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen, cyano, optionally substituted C1-C6 alkyl, Optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 6 membered heterocycloalkyl.

[0277]

[27] The compound of paragraph

[26] or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted C1-C6 alkyl.

[0278]

[28] The compound of paragraph

[27] , or a pharmaceutically acceptable salt thereof, wherein R2 is ethyl.

[0279]

[29] The compound according to any one of paragraphs [1] to

[28] , or a pharmaceutically acceptable salt thereof, wherein R7 is optionally substituted C1-C3 alkyl.

[0280]

[30] The compound of paragraph

[29] or a pharmaceutically acceptable salt thereof, wherein R7 is C1-C3 alkyl.

[0281]

[31] The compound according to any one of paragraphs [1] to

[30] , or a pharmaceutically acceptable salt thereof, wherein R8 is optionally substituted C1-C3 alkyl.

[0282]

[32] The compound of paragraph

[31] or a pharmaceutically acceptable salt thereof, wherein R8 is C1-C3 alkyl.

[0283]

[33] The compound according to any one of paragraphs [1] to

[32] , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Id: Formula Id wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 A membered heterocycloalkyl group; an optionally substituted 6-membered aryl group; or an optionally substituted 5-6 membered heteroaryl group; B is -CH(R9)-, wherein the carbon is bonded to -NHC(O )- at the carbonyl carbon; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkyl; optionally substituted 6 membered aryl; or 5 to 6 Member extended heteroaryl; L does not exist or is a linker; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, carbamate chloride Ethyl ester, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or alkenyl sugars; R1 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl , optionally substituted 3 to 6 membered cycloalkyl, optionally substituted 3 to 6 membered cycloalkenyl, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered Aryl or optionally substituted 5 to 10 membered heteroaryl; R2 is C1-C6 alkyl or 3 to 6 membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl .

[0284]

[34] The compound according to any one of paragraphs [1] to

[33] , or a pharmaceutically acceptable salt thereof, wherein R1 is a 5- to 10-membered heteroaryl group.

[0285]

[35] The compound of paragraph

[34] , or a pharmaceutically acceptable salt thereof, wherein R1 is an optionally substituted 6-membered aryl or an optionally substituted 6-membered heteroaryl.

[0286]

[36] The compound according to any one of paragraphs [1] to

[35] , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ie: Formula Ie wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 A membered heterocycloalkyl group; an optionally substituted 6-membered aryl group; or an optionally substituted 5-6 membered heteroaryl group; B is -CH(R9)-, wherein the carbon is bonded to -NHC(O )- at the carbonyl carbon; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkyl; optionally substituted 6 membered aryl; or 5 to 6 Member extended heteroaryl; L does not exist or is a linker; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl thiourea, carbamate chloride Ethyl ester, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxides, oxazolium or enose; R2 is C1-C6 alkyl or 3 to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1 -C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl; Xe and Xf are independently N or CH; and R12 is optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl, or optionally substituted 3 to 7 membered heterocycloalkyl.

[0287]

[37] The compound of paragraph

[36] , or a pharmaceutically acceptable salt thereof, wherein Xe is N and Xf is CH.

[0288]

[38] The compound of paragraph

[36] , or a pharmaceutically acceptable salt thereof, wherein Xe is CH and Xf is N.

[0289]

[39] The compound according to any one of paragraphs

[36] to

[38] , or a pharmaceutically acceptable salt thereof, wherein R12 is optionally substituted C1-C6 heteroalkyl.

[0290]

[40] The compound according to any one of paragraphs

[36] to

[39] , or a pharmaceutically acceptable salt thereof, wherein R12 is , or.

[0291]

[41] The compound of paragraph [1] or [2], or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula VI: Formula VI wherein the dotted line represents zero, one, two, three Or four non-adjacent double bonds; A series -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bound to the carbon atom of -CH(R10)-; to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkyl; optionally substituted 6 membered aryl; or optionally substituted 5 to 10 membered heteroaryl; B is -CH(R9)- or >C=CR9R9', where the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered aryl; or 5 to 6 membered heteroaryl; G is optionally substituted C1-C4 alkylene; optionally substituted C1-C4 alkenylene; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8)-; -C(O) NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4 heteroalkylene; or 3 to 8 membered heteroaryl; L does not exist or is a linker; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aza Cyclopropane, trifluoromethyl ketone, boronic acid, borate esters, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxy Compound, oxazolium or alkenyl sugar; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0,1 Or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H Or optionally substituted C1-C4 alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH , CH2 or N; R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, 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; R3 is absent, or R2 and R3 are combined with the atoms they are connected to form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 14 membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano Or optionally methyl substituted by 1 to 3 halogens; R5 is hydrogen, optionally halogen substituted C1-C4 alkyl, cyano, hydroxyl or C1-C4 alkoxy, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3-6 membered cycloalkyl Or optionally substituted 3 to 7 membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally 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 R7 and R8 are combined with the carbon atom to which they are attached to form C=CR7'R8'; 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 hetero Cycloalkyl; R7a and R8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or a combination of the carbons to which they are attached to form a carbonyl; R7' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkene radical, 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 heterocycloalkyl, Aryl or optionally substituted 6 to 10 membered aryl, or R7' and R8' combined with the carbon atom to which they are attached form a optionally substituted 3 to 6 membered cycloalkyl or an optionally substituted 3 to 7-membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or Optionally substituted 3 to 7-membered heterocycloalkyl, or R9 and L are combined with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl; R9' is hydrogen or optionally substituted C1-C6 alkyl; R10 is hydrogen, halo, hydroxyl, C1-C3 alkoxy or C1-C3 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; R34 is hydrogen or C1-C3 alkyl; and Xe and Xf are independently N or CH.

[0292]

[42] The compound of paragraph

[41] , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula VIa: Formula VIa wherein A is an optionally substituted 3 to 6 membered cycloalkylene , optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 membered aryl or optionally substituted 5 to 6 membered heteroaryl; B is -CH(R9)-, where the carbon is bound to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered Extended aryl; or 5 to 6 membered heteroaryl; L does not exist or is a linker; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl Thiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester, N-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline (EEDQ), iso-EEDQ or other EEDQ derivatives, epoxides, oxazolium or enose; X1 is optionally substituted C1-C2 alkylene, NR, O or S (O)n; X2 is O or NH; n is 0, 1 or 2; R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally Substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S( O)2N(R')2; each R' is independently H or optionally substituted C1-C4 alkyl; R2 is C1-C6 alkyl or 3 to 6-membered cycloalkyl; R7 is C1-C3 alkane R8 is C1-C3 alkyl; and R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl or optionally substituted Xe and Xf are independently N or CH; R11 is hydrogen or C1-C3 alkyl; and R21 is hydrogen or C1-C3 alkyl.

[0293]

[43] The compound of paragraph

[41] or

[42] , or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula VIb: Formula VIb wherein A is optionally substituted with 3 to 6 members Cycloalkylene, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 membered aryl or optionally substituted 5 to 6 membered heteroaryl; B is -CH( R9)-, 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 heterocycloalkylene; optionally substituted Substituted 6-membered aryl; or 5 to 6-membered heteroaryl; L does not exist or is a linker; W is a cross-linking group, which includes carbodiimide, oxazoline, thiazoline, and ethyl chloride Urea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester, N-ethoxycarbonyl-2- Ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or enose; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, or optionally substituted 3 to 7 membered heterocycloalkyl; and Xe and Xf are independently N or CH.

[0294]

[44] The compound according to any one of paragraphs [1] to

[43] , or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 6-membered aryl group.

[0295]

[45] The compound of paragraph

[44] , or a pharmaceutically acceptable salt thereof, wherein A has the following structure: wherein R13 is hydrogen, hydroxyl, amino, optionally substituted C1-C6 alkyl or Optionally substituted C1-C6 heteroalkyl.

[0296]

[46] The compound of paragraph

[45] , or a pharmaceutically acceptable salt thereof, wherein R13 is hydrogen.

[0297]

[47] The compound of paragraph

[45] or a pharmaceutically acceptable salt thereof, wherein R13 is hydroxyl.

[0298]

[48] The compound according to any one of paragraphs [1] to

[47] , or a pharmaceutically acceptable salt thereof, wherein B is -CHR9-.

[0299]

[49] The compound of paragraph

[48] or a pharmaceutically acceptable salt thereof, wherein R9 is optionally substituted C1-C6 alkyl or optionally substituted 3-6 membered cycloalkyl.

[0300]

[50] The compound of paragraph

[49] or a pharmaceutically acceptable salt thereof, wherein R9 is , or.

[0301]

[51] The compound of paragraph

[50] or a pharmaceutically acceptable salt thereof, wherein R9 is.

[0302]

[52] The compound according to any one of paragraphs [1] to

[47] , or a pharmaceutically acceptable salt thereof, wherein B is an optionally substituted 6-membered aryl group.

[0303]

[53] The compound of paragraph

[52] or a pharmaceutically acceptable salt thereof, wherein B is a 6-membered aryl group.

[0304]

[54] The compound of paragraph

[53] or a pharmaceutically acceptable salt thereof, wherein B is: .

[0305]

[55] The compound according to any one of paragraphs [1] to

[54] , or a pharmaceutically acceptable salt thereof, wherein R7 is methyl.

[0306]

[56] The compound according to any one of paragraphs [1] to

[55] , or a pharmaceutically acceptable salt thereof, wherein R8 is methyl.

[0307]

[57] The compound according to any one of paragraphs [1] to

[56] or a pharmaceutically acceptable salt thereof, wherein the linker has a structure of formula II: A1-(B1)f-(C1) g-(B2)h-(D1)-(B3)i-(C2)j-(B4)k-A2 Formula II wherein A1 is the bond between the linker and B; A2 is the link between W and the linker A bond between bodies; B1, B2, B3 and B4 are each independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S and NRN; RN is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3 to 14 membered heterocycloalkyl, Optionally substituted 6-10 membered aryl or optionally substituted C1-C7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h , i, j and k are each independently 0 or 1; and D1 is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkylene Alkynyl, optionally substituted 3 to 14 membered heterocycloalkyl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 3 to 8 membered cycloalkylene, optionally substituted 6 to 10-membered aryl, optionally substituted C2-C10 polyethylene glycol or optionally substituted C1-C10 heteroalkyl, or A1-(B1)f-(C1)g- (B2)h- bond to -(B3)i-(C2)j-(B4)k-A2.

[0308]

[58] The compound according to any one of paragraphs [1] to

[57] , or a pharmaceutically acceptable salt thereof, wherein the linkage system is acyclic.

[0309]

[59] The compound of paragraph

[58] , or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of Formula IIa: Formula IIa wherein Xa is absent or N; R14 is absent, hydrogen or Optionally substituted C1-C6 alkyl; and L2 is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted C1-C4 heteroalkylene, wherein Xa, R14 or at least one of L2 is absent.

[0310]

[60] The compound of paragraph

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

[0311]

[61] The compound according to any one of paragraphs [1] to

[57] , or a pharmaceutically acceptable salt thereof, wherein the linkage system may contain a cyclic group.

[0312]

[62] The compound of any one of paragraphs [1] to

[57] or

[61] , or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of Formula IIb: Formula IIb wherein o is 0 or 1; R15 is hydrogen or optionally substituted C1-C6 alkyl; Cy is optionally substituted 3 to 8 membered cycloalkyl, optionally substituted 3 to 8 membered heterocycloalkyl, Optionally substituted 6-10 membered arylylene or optionally substituted 5 to 10 membered heteroaryl; and L3 is absent, -SO2-, optionally substituted C1-C4 alkylene or optionally substituted In the case of substituted C1-C4 heteroalkylene.

[0313]

[63] The compound of paragraph

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

[0314]

[64] The compound of any one of paragraphs [1] to

[63] , or a pharmaceutically acceptable salt thereof, wherein W comprises carbodiimide.

[0315]

[65] The compound of paragraph

[64] , or a pharmaceutically acceptable salt thereof, wherein W has the structure of formula IIIa: Formula IIIa wherein R14 is optionally substituted C1-C6 alkyl, optionally substituted Substituted C1-C6 heteroalkyl, optionally substituted 3 to 8 membered cycloalkyl, optionally substituted 6 to 10 membered aryl, optionally substituted 3 to 14 membered heterocycloalkyl or optionally substituted Substituted 5 to 10 membered heteroaryl.

[0316]

[66] The compound of paragraph

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

[0317]

[67] The compound of any one of paragraphs [1] to

[63] , or a pharmaceutically acceptable salt thereof, wherein W comprises oxazoline or thiazoline.

[0318]

[68] The compound of paragraph

[67] , or a pharmaceutically acceptable salt thereof, wherein W has the structure of formula IIIb: Formula IIb wherein X1 is O or S; X2 is absent or NR19; R15, R16 , R17 and R18 are independently hydrogen or optionally substituted C1-C6 alkyl; and R19 is hydrogen, C(O) (optionally substituted C1-C6 alkyl), optionally substituted C1-C6 Alkyl, optionally substituted 6 to 10 membered aryl, optionally substituted 3 to 14 membered heterocycloalkyl, or optionally substituted 5 to 10 membered heteroaryl.

[0319]

[69] The compound of paragraph

[68] or a pharmaceutically acceptable salt thereof, wherein W is.

[0320]

[70] The compound of any one of paragraphs [1] to

[63] , or a pharmaceutically acceptable salt thereof, wherein W comprises chloroethylurea, chloroethylthiourea, chloroethyl carbamate ester or chloroethyl thiocarbamate.

[0321]

[71] The compound of paragraph

[70] or a pharmaceutically acceptable salt thereof, wherein W has the structure of formula IIIc: formula IIIc wherein X3 is O or S; X4 is O, S, NR26; R21, R22, R23, R24 and R26 are independently hydrogen or optionally substituted C1-C6 alkyl; and R25 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6 to 10 membered aryl . Optionally substituted 3 to 14 membered heterocycloalkyl or optionally substituted 5 to 10 membered heteroaryl.

[0322]

[72] The compound of paragraph

[71] or a pharmaceutically acceptable salt thereof, wherein W is.

[0323]

[73] The compound of any one of paragraphs [1] to

[63] , or a pharmaceutically acceptable salt thereof, wherein W comprises aziridine.

[0324]

[74] The compound of paragraph

[73] , or a pharmaceutically acceptable salt thereof, wherein W has the structure of formula IIId1, formula IIId2, formula IIId3 or formula IIId4: formula IIId1 formula IIId2 formula IIId3 formula IIId4 wherein X5 Is absent or NR30; Y is absent or C(O), C(S), S(O), SO2 or optionally substituted C1-C3 alkylene; R27 is hydrogen, -C(O)R32 , -C(O)OR32, -SO2R33, -SOR33, optionally substituted C1-C6 alkyl, optionally substituted 6 to 10 membered aryl, optionally substituted 3 to 14 membered heterocycloalkyl or optionally substituted 5- to 10-membered heteroaryl; R28 and R29 are independently hydrogen, CN, C(O)R31, CO2R31, C(O)R31R31, optionally substituted C1-C6 alkyl, optionally Optionally substituted 3 to 10 membered cycloalkyl, optionally substituted 6 to 10 membered aryl, optionally substituted 3 to 14 membered heterocycloalkyl or optionally substituted 5 to 10 membered heteroaryl each R31 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6 to 10 membered aryl, optionally substituted 3 to 14 membered heterocycloalkyl, or optionally substituted 5 to 10 membered heterocycloalkyl; 10 membered heteroaryl; R30 is hydrogen or optionally substituted C1-C6 alkyl; and R32 and R33 are independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 6 to 10 members Aryl, optionally substituted 3 to 14 membered heterocycloalkyl or optionally substituted 5 to 10 membered heteroaryl.

[0325]

[75] The compound of paragraph

[73] or

[74] , or a pharmaceutically acceptable salt thereof, wherein W is: ,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,or.

[0326]

[76] The compound of any one of paragraphs [1] to

[63] , or a pharmaceutically acceptable salt thereof, wherein W comprises an epoxide.

[0327]

[77] The compound of paragraph

[76] or a pharmaceutically acceptable salt thereof, wherein W is , , or.

[0328]

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

[0329]

[79] A pharmaceutical composition comprising the compound according to any one of paragraphs [1] to

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

[0330]

[80] A conjugate or salt thereof comprising the structure of Formula IV: M-L-P Formula IV wherein L is a linker; P is a monovalent organic moiety; and M has the structure of Formula V: Formula V wherein the dotted line represents zero , one, two, three or four non-adjacent double bonds; A series -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bound to the carbon of -CH(R10)- atom; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered arylylene; or optionally substituted 5 to 6 membered heterocycloalkylene; 6-membered heteroaryl; B is -CH(R9)- or >C=CR9R9', wherein the carbon is bonded to the carbonyl carbon of -N(R11)C(O)-; optionally substituted 3 to 6-membered Cycloalkyl; optionally substituted 3 to 6 membered heterocycloalkyl; optionally substituted 6 membered aryl; or 5 to 6 membered heteroaryl; G is optionally substituted C1-C4 Alkylene; optionally substituted C1-C4 alkenylene; optionally substituted C1-C4 heteroalkylene; -C(O)O-CH(R6)-, wherein C is bonded to -C(R7R8 ) -; -C(O)NH-CH(R6)-, wherein C is bonded to -C(R7R8)-; optionally substituted C1-C4heteroalkyl; or 3 to 8 membered heteroaryl; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; X3 is N or CH; n is 0, 1 or 2; R is hydrogen, cyano , optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C( O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1-C4 Alkyl; Y1 is C, CH or N; Y2, Y3, Y4 and Y7 are independently C or N; Y5 is CH, CH2 or N; Y6 is C(O), CH, CH2 or N; R1 is cyano , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered cycloalkenyl, Optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl, or optionally substituted 5 to 10 membered heteroaryl, or R1 and R2 are combined with the atoms to which they are attached together form an optionally substituted 3 to 14 membered heterocycloalkyl; R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, 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; R3 is absent, or R2 and R3 are combined with the atoms to which they are attached to form an optionally substituted 3 to 8 membered cycloalkyl or an optionally substituted 3 to 14 membered heterocycloalkyl; R4 is absent, hydrogen, halogen, cyano or optionally methyl substituted by 1 to 3 halogens; R5 is hydrogen, optionally halogen substituted C1-C4 alkyl, cyano, hydroxy or C1-C4 alkane Oxygen, cyclopropyl or cyclobutyl; R6 is hydrogen or methyl; R7 is hydrogen, halogen or optionally substituted C1-C3 alkyl, or R6 and R7 are combined with the carbon atoms they are attached to form an optional 3 to 6 membered cycloalkyl which is optionally substituted or 3 to 7 membered heterocycloalkyl which is optionally substituted; R8 is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally Optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 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 R7 and R8 are combined with the carbon atoms to which they are attached to form C= CR7 'R8'; 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; R7a and R8a are independently hydrogen, halo, optionally substituted C1-C3 alkyl, or a combination of the carbon to which it is attached to form a carbonyl group; R7 ' is hydrogen, halogen or optionally substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkane radical, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3 to 8 membered cycloalkyl, optionally substituted 3 to 14 membered heterocycloalkyl , an optionally substituted 5 to 10 membered heteroaryl group or an optionally substituted 6 to 10 membered aryl group, or R7' and R8' are combined with the carbon atoms to which they are attached to form an optionally substituted 3 to 6 membered heteroaryl group Cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally Substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl, or R9 and L combined with the atoms to which they are attached form an optionally substituted 3 to 14 membered heterocycloalkane R9' is hydrogen or optionally substituted C1-C6 alkyl; R10a is hydrogen or halo; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl.

[0331]

[81] The combination of paragraph

[80] or a salt thereof, wherein M has the structure of formula Vc: formula Vc wherein A is an optionally substituted 3 to 6 membered cycloalkylene, optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 membered aryl or optionally substituted 5 to 6 membered heteroaryl; B is -CH(R9)-, wherein carbon is bonded to -NHC The carbonyl carbon of (O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered arylylene; or 5 to 6-membered heteroaryl; X1 is optionally substituted C1-C2 alkylene, NR, O or S(O)n; X2 is O or NH; n is 0, 1 or 2; R is hydrogen, Cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R' or S(O)2N(R')2; each R' is independently H or optionally substituted C1 -C4 alkyl; Xe and Xf are independently N or CH; R2 is C1-C6 alkyl or 3 to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl; and R9 is Optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl or optionally substituted 3 to 7 membered heterocycloalkyl; R11 is hydrogen or C1-C3 alkyl; and R34 is hydrogen or C1-C3 alkyl. In some embodiments of the compounds of the invention, Xe is N and Xf is CH. In some embodiments, Xe is CH and Xf is N.

[0332]

[82] The combination of paragraph

[80] or

[81] , or a salt thereof, wherein M has the structure of formula Vd: Formula Vd wherein A is an optionally substituted 3 to 6 membered cycloalkylene, optionally Optionally substituted 3 to 6 membered heterocycloalkyl, optionally substituted 6 membered aryl or optionally substituted 5 to 6 membered heteroaryl; B is -CH(R9)-, where carbon Bonded to the carbonyl carbon of -NHC(O)-; optionally substituted 3 to 6 membered cycloalkylene; optionally substituted 3 to 6 membered heterocycloalkylene; optionally substituted 6 membered arylene or 5 to 6 membered heteroaryl groups; L does not exist or is a linker; W is a crosslinking group, which includes carbodiimide, oxazoline, thiazoline, chloroethyl urea, chloroethyl sulfide Urea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, boric acid ester, N-ethoxycarbonyl-2-ethoxy-1, 2-Dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazolium or alkenyl sugars; R9 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6 membered cycloalkyl, or optionally substituted 3 to 7 membered heterocycloalkyl; and Xe and Xf are independently N or CH.

[0333]

[83] The conjugate or salt thereof according to any one of paragraphs

[80] to

[82] , wherein the linker has the structure of formula II: A1-(B1)f-(C1)g-(B2 )h-(D1)-(B3)i-(C2)j-(B4)k-A2 Formula II wherein A1 is the bond between the linker and B; A2 is the link between P and the linker Bond; B1, B2, B3 and B4 are each independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S and NRN; RN is hydrogen, optionally Optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3 to 14 membered heterocycloalkyl, optionally substituted 6 to 10 membered aryl or optionally substituted C1-C7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl or phosphoryl; f, g, h, i, j and k are each independently 0 or 1; and D1 is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynylene, optionally substituted C2-C10 alkynyl, optionally Optionally substituted 3 to 14 membered heterocycloalkylene, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 3 to 8 membered cycloalkylene, optionally substituted 6 to 10 membered Member aryl, optionally substituted C2-C10 polyethylene glycol or optionally substituted C1-C10 heteroalkyl, or A1-(B1)f-(C1)g-(B2)h - a bond to -(B3)i-(C2)j-(B4)k-A2.

[0334]

[84] The conjugate of any one of paragraphs

[80] to

[83] , or a salt thereof, wherein the monovalent organic moiety is a protein.

[0335]

[85] The conjugate of paragraph

[84] or a salt thereof, wherein the protein is a Ras protein.

[0336]

[86] The conjugate of paragraph

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

[0337]

[87] The conjugate or salt thereof according to any one of paragraphs

[80] to

[86] , wherein the linker is bound to the monovalent organic moiety via a bond to the carboxyl group of the amino acid residue of the monovalent organic moiety organic part.

[0338]

[88] A method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of any one of paragraphs [1] to

[78] , or a pharmaceutically acceptable or the pharmaceutical composition of paragraph

[79] .

[0339]

[89] The method of paragraph

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

[0340]

[90] The method of paragraph

[88] or

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

[0341]

[91] The method of paragraph

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

[0342]

[92] A method of treating a Ras protein-associated disorder in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of the compound of any one of paragraphs [1] to

[78] or its pharmaceutical above acceptable salt or pharmaceutical composition as in paragraph

[79] .

[0343]

[93] A method of inhibiting Ras protein in a cell, the method comprising subjecting the cell to an effective amount of the compound of any one of paragraphs [1] to

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

[79] .

[0344]

[94] The method of paragraph

[92] or

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

[0345]

[95] The method of paragraph

[93] or

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

[0346]

[96] The method of paragraph

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

[0347]

[97] The method or use of any one of paragraphs

[88] to

[96] , wherein the method further comprises administering an additional anticancer therapy.

[0348]

[98] The method of paragraph

[97] , wherein the additional anticancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor , PI3K inhibitors, PTEN inhibitors, AKT inhibitors, mTORC1 inhibitors, BRAF inhibitors, PD-L1 inhibitors, PD-1 inhibitors, CDK4 / 6 inhibitors, HER2 inhibitors, or combinations thereof.

[0349]

[99] The method of paragraph

[97] or

[98] , wherein the additional anticancer therapy is a SHP2 inhibitor. example

[0350] The disclosure is further illustrated by the following examples and synthetic examples, which should not be construed to limit the scope or spirit of the disclosure to the specific procedures described herein. It should be understood that the examples provided are intended to illustrate certain embodiments and are not intended to thereby limit the scope of the disclosure. It should also be understood that resort can also be made to various other embodiments, modifications and equivalents thereof, which will occur to those skilled in the art without departing from the spirit of the disclosure or the scope of the appended claims. chemical synthesis

[0351] The following examples and definitions used elsewhere herein are as follows: CH 2 Cl 2 , DCM Methylene chloride, dichloromethane CH 3 CN, MeCN Acetonitrile CuI Copper(I) iodide DIPEA Diisopropylethylamine DMF N,N-Dimethylformamide EtOAc ethyl acetate h Hour h 2 o water HCl hydrochloric acid K 3 PO 4 Potassium phosphate (tribasic) MeOH Methanol Na 2 SO 4 sodium sulfate NMP N-Methylpyrrolidone Pd(dppf)Cl 2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) instrument

[0352] Mass spectral data collection was performed using a Shimadzu LCMS-2020 or Waters Acquity UPLC with QDa detector or SQ detector 2. Samples were injected in liquid phase onto a C-18 reverse phase column to remove assay buffer and prepare samples for mass spectrometry. Compounds were eluted from the column using an acetonitrile gradient and fed into the mass analyzer. Initial data analysis was performed with Shimadzu LabSolutions or Waters MassLynx. NMR data were collected with a Bruker AVANCE III HD 400MHz or Bruker Ascend 500MHz instrument and raw data were analyzed using TopSpin or Mestrelab Mnova. Synthetic intermediate Intermediate 1. Synthesis of 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-3-yl )-2,2-Dimethylpropan-1-ol Step 1: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy base)-2,2-dimethylpropan-1-one

[0353] 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionyl chloride (65 g, 137 mmol, crude product) was prepared at 0° C. under N2 atmosphere To the mixture in DCM (120 mL) was slowly added 1M SnCl4 in DCM (137 mL, 137 mmol). The mixture was stirred at 0 °C for 30 minutes, then a solution of 5-bromo-1H-indole (26.8 g, 137 mmol) in DCM (40 mL) was added dropwise. The mixture was stirred at 0 °C for 45 min, then diluted with EtOAc (300 mL), washed with brine (4 x 100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy yl)-2,2-dimethylpropan-1-one (55 g, 75% yield). LCMS (ESI) m / z: [M+Na] calcd. for C29H32BrNO2SiNa 556.1; found 556.3. Step 2: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1- ketone

[0354] Under N Atmosphere, to 1-(5-bromo-1H-indol-3-yl)-3-((tertiary butyldiphenylsilyl)oxyl group)-2 at 0°C, To a mixture of 2-dimethylpropan-1-one (50 g, 93.6 mmol) in THF (100 mL) was added LiBH4 (6.1 g, 281 mmol). The mixture was heated to 60 °C and stirred for 20 h, then MeOH (10 mL) and EtOAc (100 mL) were added and the mixture was washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (50 mL), cooled to 10 °C and dihydropyridine (9.5 g, 37.4 mmol) and TsOH•H2O (890 mg, 4.7 mmol) were added. The mixture was stirred at 10° C. for 2 hours, filtered, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 1-(5-bromo-1H-indol-3-yl)-3-( (tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (41 g, 84% yield). LCMS (ESI) m / z: Calcd. [M + H] for C29H34BrNOSi: 519.2; found 520.1; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.75 - 7.68 (m, 5H), 7.46 - 7.35 (m, 6H), 7.23 - 7.19 (m, 2H), 6.87 (d,J= 2.1 Hz, 1H), 3.40 (s, 2H), 2.72 (s, 2H), 1.14 (s, 9H), 0.89 (s, 6H). Step 3: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole

[0355] At room temperature, to 1-(5-bromo-1H-indol-3-yl)-3-((tertiary butyldiphenylsilyl)oxy)-2,2-dimethyl To a mixture of propan-1-one (1.5 g, 2.9 mmol) and I2 (731 mg, 2.9 mmol) in THF (15 mL) was added AgOTf (888 mg, 3.5 mmol). The mixture was stirred at room temperature for 2 h, then diluted with EtOAc (200 mL) and washed with saturated Na2S2O3 (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2 as a solid. -Dimethylpropyl)-2-iodo-1H-indole (900 mg, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 7.68 (d,J= 1.3 Hz, 1H), 7.64 - 7.62 (m, 4H), 7.46 - 7.43 (m, 6H), 7.24 - 7.22 (d, 1H), 7.14 - 7.12 (dd, J= 8.6, 1.6 Hz, 1H), 3.48 (s, 2H), 2.63 (s, 2H), 1.08 (s, 9H), 0.88 (s, 6H) . Step 4: Synthesis of (1S)-1-(3-bromopyridin-2-yl)ethanol

[0356] To a stirred mixture of HCOOH (66.3 g, 1.44 mol) in Et3N (1002 mL, 7.2 mol) was added portionwise at 0° C. under Ar atmosphere (4S,5S)-2-chloro-2 -Methyl-1-(4-methylbenzenesulfonyl)-4,5-diphenyl-1,3-diaza-2-rutheniumcyclopentane isopropyltoluene (3.9 g, 6.0 mmol) . The mixture was heated to 40°C and stirred for 15 minutes, then cooled to room temperature and l-(3-bromopyridin-2-yl)ethanone (120 g, 600 mmol) was added in portions. The mixture was heated to 40°C and stirred for an additional 2 hours, then the solvent was concentrated under reduced pressure. Brine (2 L) was added to the residue, the mixture was extracted with EtOAc (4 x 700 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give (1S)-1-(3-bromopyridin-2-yl)ethanol (100 g, 74% yield) as an oil. LCMS (ESI) m / z: [M+H] calculated for C7H8BrNO: 201.98; found 201.9. Step 5: Synthesis of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine

[0357] To a stirred mixture of (1S)-1-(3-bromopyridin-2-yl)ethanol (100 g, 495 mmol) in DMF (1 L) was added NaH in portions at 0°C. 60% dispersion in oil (14.25 g, 594 mmol). The mixture was stirred at 0°C for 1 hour. MeI (140.5 g, 990 mmol) was added dropwise at 0 °C and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was cooled to 0 °C and saturated NH4Cl (5 L) was added. The mixture was extracted with EtOAc (3 x 1.5 L), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (90 g, 75% yield) as an oil . LCMS (ESI) m / z: [M+H] calcd for C8H10BrNO: 215.99; found 215.9. Step 6: Synthesis of 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)pyridine

[0358] To a stirred mixture of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (90 g, 417 mmol) in toluene (900 mL) at room temperature under Ar atmosphere To this was added bis(pinacol)diboron (127 g, 500 mmol), KOAc (81.8 g, 833 mmol) and Pd(dppf)Cl2 (30.5 g, 41.7 mmol). The mixture was heated to 100°C and stirred for 3 hours. The filtrate was concentrated under reduced pressure and the residue was purified by Al2O3 column chromatography to give 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100 g, 63% yield). LCMS (ESI) m / z: [M+H] calcd for C14H22BNO3: 264.17; found 264.1. Step 7: Synthesis of 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2-[2-[(1S)- 1-methoxyethyl]pyridin-3-yl]-1H-indole

[0359] Under Ar atmosphere, at room temperature to 5-bromo-3-[3-[(tertiary butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2- Iodo-1H-indole (140 g, 217 mmol) and 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2 To a stirred mixture of -dioxaborolan-2-yl)pyridine (100 g, 380 mmol) in 1,4-dioxane (1.4 L) was added K2CO3 (74.8 g, 541 mmol) in portions ), Pd(dppf)Cl2 (15.9 g, 21.7 mmol) and H2O (280 mL). The mixture was heated to 85 °C and stirred for 4 h, then cooled, H2O (5 L) was added and the mixture was extracted with EtOAc (3 x 2 L). The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2 as a solid. -Dimethylpropyl]-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-1H-indole (71 g, 45% yield). LCMS (ESI) m / z: [M+H] calculated for C37H43BrN2O2Si: 655.23; found 655.1. Step 8: Synthesis of 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-1-ethyl-2-[2- [(1S)-1-methoxyethyl]pyridin-3-yl]indole

[0360] Under N Atmosphere, to 5-bromo-3-[3-[(tertiary butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2 at 0°C -[2-[(1S)-1-Methoxyethyl]pyridin-3-yl]-1H-indole (71 g, 108 mmol) was added in portions to a stirred mixture in DMF (0.8 L) Cs2CO3 (70.6 g, 217 mmol) and EtI (33.8 g, 217 mmol). The mixture was warmed to room temperature and stirred for 16 h, then H2O (4 L) was added and the mixture was extracted with EtOAc (3 x 1.5 L). The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain 5-bromo-3-[3-[(tert-butyld...

Claims

1. A compound having the structure of formula Ic, or a pharmaceutically acceptable salt thereof.

1. Wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; substituted 3 to 6-membered cycloalkyl; substituted 3 to 6-membered heterocycloalkyl; substituted 6-membered aryl; or substituted 5 to 6-membered heteroaryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; substituted 3 to 6-membered cycloalkyl; substituted 3 to 6-membered heterocycloalkyl; substituted 6-membered aryl; or 5 to 6-membered heteroaryl; L is absent or is a linker having the structure of formula II: A1-(B1)f-(C1)g-(B2)h-( Formula II (D1)-(B3)i-(C2)j-(B4)k-A2, wherein A1 is the bond between the linker and B; A2 is the bond between W and the linker; B1, B2, B3, and B4 are each independently selected from, as appropriate, substituted C1-C2 alkyl, substituted C1-C3 heteroalkyl, O, S, and NRN; RN is hydrogen, substituted C1-C4 alkyl, substituted C2-C4 alkenyl, substituted C2-C4 ynyl, substituted 3 to 14 heterocyclic alkyl, substituted 6 to 10 aryl, or substituted C1-C7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or... Phosphoyl; f, g, h, i, j, and k are each independently 0 or 1; and D1 is, as appropriate, a substituted C1-C10 alkyl group, a substituted C2-C10 alkenyl group, a substituted C2-C10 alkyne group, a substituted 3 to 14 heterocyclic alkyl group, a substituted 5 to 10 heteroaryl group, a substituted 3 to 8 heterocyclic alkyl group, a substituted 6 to 10 heteroaryl group, a substituted C2-C10 polyethylene glycol group, or a substituted C1-C10 heteroalkyl group, or a chemical bond connecting A1-(B1)f-(C1)g-(B2)h- to -(B3)i-(C2)j-(B4)k-A2; W is an intercalated cross-linked ... The group comprises carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazoline or enolic acid; R1 is a cyano group, a C1-C6 alkyl group as appropriate, a C1-C6 heteroalkyl group as appropriate, a 3- to 6-membered cycloalkyl group as appropriate, a 3- to 6-membered cycloalkenyl group as appropriate, a 3- to 6-membered heterocycloalkyl group as appropriate, a 6- to 10-membered aryl group as appropriate, or a 5- to 10-membered heteroaryl group as appropriate;R2 is hydrogen, a C1-C6 alkyl group (subject to substitution), a C2-C6 alkenyl group (subject to substitution), a 3- to 6-membered cycloalkyl group (subject to substitution), a 3- to 7-membered heterocycloalkyl group (subject to substitution), a 6-membered aryl group (subject to substitution), or a 5- or 6-membered heteroaryl group (subject to substitution); R3 is absent, or R2 and R3 are combined with the atoms they are attached to to form a 3- to 8-membered cycloalkyl group (subject to substitution) or a 3- to 14-membered heterocycloalkyl group (subject to substitution); R5 is hydrogen, a C1-C4 alkyl group (subject to halogen substitution), a cyano, a hydroxyl, or a C1-C4 alkoxy, a cyclopropyl, or a cyclobutyl group (subject to substitution); R6 is hydrogen or methyl; R7 is hydrogen, a halogen, or a C1-C3 alkyl group (subject to substitution), or R6 and R7 are combined with the carbon atoms they are attached to to form a 3- to 8-membered cycloalkyl group (subject to substitution); Together they form, as appropriate, substituted 3 to 6-membered cycloalkyl or substituted 3 to 7-membered heterocycloalkyl; R8 is hydrogen, halogen, hydroxyl, cyano, substituted C1-C3 alkoxy, substituted C1-C3 alkyl, substituted C2-C6 alkenyl, substituted C2-C6 alkynyl, substituted 3 to 8-membered cycloalkyl, substituted 3 to 14-membered heterocycloalkyl, substituted 5 to 10-membered heteroaryl, or substituted 6 to 10-membered aryl, or R7 and R8 combined with the carbon atom to which they are attached to form C=CR7'R8'; C=N(OH); C=N(O-C1-C3 alkyl); C=O; C=S; C=NH; as appropriate, substituted Instead of 3 to 6-membered cycloalkyl; or, as appropriate, 3 to 7-membered heterocycloalkyl; R7' is hydrogen, halogen, or, as appropriate, substituted C1-C3 alkyl; R8' is hydrogen, halogen, hydroxyl, cyano, as appropriate, substituted C1-C3 alkoxy, as appropriate, substituted C1-C3 alkyl, as appropriate, substituted C2-C6 alkenyl, as appropriate, substituted C2-C6 alkynyl, as appropriate, substituted 3 to 8-membered cycloalkyl, as appropriate, substituted 3 to 14-membered heterocycloalkyl, as appropriate, substituted 5 to 10-membered heteroaryl, or, as appropriate, substituted 6 to 10-membered aryl, or R7' and R8' combined with the carbon atom to which they are attached to form, as appropriate, substituted 3 to 6-membered cycloalkyl or, as appropriate, substituted 3 to 7-membered heterocycloalkyl; R 9 series: C1-C6 alkyl, C1-C6 heteroalkyl, 3- to 6-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl, substituted as appropriate; R10 series: hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl; wherein the substituted group, when substituted, contains one, two, or three substituents independently selected from the group consisting of: deuterium; halogen; -(CH2)0-4Ro; -(CH2)0-4ORo; -O(CH2)0-4Ro; -O-(CH2)0-4C(O)ORo; -(CH2)0-4CH(ORo)2; -(CH2)0-4SRo; -(CH2)0-4Ph, which may be substituted with Ro;-(CH2)0-4O(CH2)0-1Ph, which can be substituted with Ro; -CH=CHPh, which can be substituted with Ro; -(CH2)0-4O(CH2)0-1-pyridyl, which can be substituted with Ro; 4 to 8-membered saturated or unsaturated heterocyclic alkyl; 3 to 8-membered saturated or unsaturated cycloalkyl; -NO2; -CN; -N3; ​​-(CH2)0-4N(Ro)2; -(CH2)0-4N(Ro)C(O)Ro; -N(Ro)C(S)Ro; -(CH2)0-4N(Ro)C(O)NRo2; -N(Ro)C(S)NRo2; -(CH2) 0-4N(Ro)C(O)ORo; -N(Ro)N(Ro)C(O)Ro; -N(Ro)N(Ro)C(O)NRo2; -N(Ro)N(Ro)C(O)ORo; -(CH2)0-4C(O)Ro; -C(S)Ro; -(CH2)0-4C (O)ORo; -(CH2)0-4-C(O)-N(Ro)2; -(CH2)0-4-C(O)-N(Ro)-S(O)2-Ro; -C(NCN)NRo2; -(CH2)0-4C(O)SRo; -(CH2)0-4C(O)OSiRo3 ;-(CH2)0-4OC(O)Ro;-OC(O)(CH2)0-4SRo;-SC(S)SRo;-(CH2)0-4SC(O)Ro;-(CH2)0-4C(O)NRo2;-C(S)NRo2;-C(S)SRo;-(CH2)0 -4OC(O)NRo2; -C(O)N(ORo)Ro; -C(O)C(O)Ro; -C(O)CH2C(O)Ro; -C(NORo)Ro; -(CH2)0-4SSRo; -(CH2)0-4S(O)2Ro; -(CH2)0-4S(O -2ORo; -(CH2)O-4OS(O)2Ro; -S(O)2NRo2; -(CH2)O-4S(O)Ro; -N(Ro)S(O)2NRo2; -N(Ro)S(O)2Ro; -N(ORo)Ro; -C(NORo)NRo2; -C(NH)NRo2; -P(O)2Ro; -P(O)Ro2; -P(O)(ORo)2; -OP(O)Ro2; -OP(O)(ORo)2; -OP(O)(ORo)Ro; -SiRo3; -(C1-C4 straight-chain or branched alkyl)ON(Ro)2;Or -(C1-C4 straight-chain or branched alkyl)C(O)ON(Ro)2, wherein each Ro may be substituted and independently as defined below: hydrogen, -C1-C6 aliphatic group, -CH2Ph, -O(CH2)0-1Ph, -CH2- (5 to 6-membered heteroaryl ring), or having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or notwithstanding the above definitions, but two independently existing Ros together with their inserted atoms form a 3 to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted; the substituted Ro group, or A ring formed by two independently existing Ro atoms and their inserted atoms, when substituted, contains one, two, or three substituents independently selected from the following: halogen, -(CH2)O-2R˙, -(halo R˙), -(CH2)O-2OH, -(CH2)O-2OR˙, -(CH2)O-2CH(OR˙)2, -O(halo R˙), -CN, -N3, -(CH2)O-2C(O)R˙, -(CH2)O-2C(O)OH, -(CH2)O-2C(O)OR˙, -(CH2)O-2SR˙, -(CH2)O-2SH, -(CH2)O-2NH2, -(CH2)O -2NHR˙, -(CH2)O-2NR˙2, -NO2, -SiR˙3, -OSiR˙3, -C(O)SR˙, -(C1-4 straight-chain or branched alkyl)C(O)OR˙ or -SSR˙, wherein each R˙ is unsubstituted or, if preceded by a "halogen group", substituted with only one or more halogens, and is independently selected from C1-C4 aliphatic groups, -CH2Ph, -O(CH2)O-1Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; suitable divalent substituents on the saturated carbon atom of Ro include =O and =S; the saturated group "substituted as appropriate" is saturated Suitable divalent substituents on carbon atoms 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-, wherein R* is selected from hydrogen each time it appears independently; C1-C6 aliphatic groups that may be substituted as defined below; or unsubstituted 5 to 6 saturated, partially unsaturated or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; or suitable divalent substituents attached to adjacent substituted carbons of groups "substituted as appropriate" include: -O(CR*2)2-3O-, wherein R* is selected from hydrogen each time it appears independently; a C1-C6 aliphatic group, which may be substituted as defined below; or an unsubstituted 5 to 6-member saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; suitable substituents on the aliphatic group of R* include halogens, -R˙, (halogen R˙), -OH, -OR˙, -O(halogen R˙), -CN, -C(O)OH, -C(O)OR˙, -NH2, -NHR˙, -NR˙2, or -NO2, wherein each R˙ is unsubstituted or, in the case of a "halogen" prefix, is substituted with only one or more halogens, and Independently C1-C4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph or having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, 5 to 6 saturated, partially unsaturated or aryl rings; suitable substituents on the substituted nitrogen of the group "substituted as appropriate" 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†; wherein each R† is independently hydrogen; C1-C6 aliphatic group The aliphatic group can be substituted as defined below; unsubstituted -OPh; or an unsubstituted 3 to 6-member saturated, partially unsaturated, or aryl ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur; or, despite the above definitions, two independently existing R†s together with their insert atoms form a 3 to 12-member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur; suitable substituents on the aliphatic group of R† are independently halogens, -R˙, -(haloR˙), -OH, -OR˙, -O(haloR˙), -CN, -C(O)OH, -C(O)OR˙, -NH2, -NHR -NR˙ or -NO2, wherein each R˙ is unsubstituted or, if preceded by a "halogen group", is substituted with only one or more halogens and is independently a C1-C4 aliphatic group, -CH2Ph, -O(CH2)0-1Ph or a 5- to 6-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, and as used herein, "heteroalkyl", "heterocyclic alkyl", "heteroaryl", "heteroaryl" on itself or as part of a substituent refers to a group containing one, two, three or four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula Id:

2. Wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; substituted 3 to 6-membered cycloalkyl; substituted 3 to 6-membered heterocycloalkyl; substituted 6-membered aryl; or substituted 5 to 6-membered heteroaryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; substituted 3 to 6-membered cycloalkyl; substituted 3 to 6-membered heterocycloalkyl; substituted 6-membered aryl; or 5 to 6-membered heteroaryl; L is absent or is a linker having the structure of formula II: A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i- (C2)j-(B4)k-A2 formula II, wherein A1 is the bond between the linker and B; A2 is the bond between W and the linker; B1, B2, B3 and B4 are each independently selected from, as appropriate, substituted C1-C2 alkyl, substituted C1-C3 heteroalkyl, O, S and NRN; RN is hydrogen, substituted C1-C4 alkyl, substituted C2-C4 alkenyl, substituted C2-C4 ynyl, substituted 3 to 14 heterocyclic alkyl, substituted 6 to 10 aryl or substituted C1-C7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonyluyl or phosphatyl; f, g, h, i, j and k are each independently 0 or 1; and D1 is, as appropriate, a substituted C1-C10 alkyl group, a substituted C2-C10 alkenyl group, a substituted C2-C10 alkynyl group, a substituted 3 to 14 heterocyclic alkyl group, a substituted 5 to 10 heteroaryl group, a substituted 3 to 8 heterocyclic alkyl group, a substituted 6 to 10 heteroaryl group, a substituted C2-C10 polyethylene glycol group, or a substituted C1-C10 heteroalkyl group, or a chemical bond connecting A1-(B1)f-(C1)g-(B2)h- to -(B3)i-(C2)j-(B4)k-A2; W is a crosslinking group comprising carbodiimide, oxazoline, thiazoline, chloroethylurea, or chloroethylthiourea. , ethyl carbamate, ethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazonium or enolic acid; R1 is cyano, substituted C1-C6 alkyl, substituted C1-C6 heteroalkyl, substituted 3- to 6-membered cycloalkyl, substituted 3- to 6-membered cycloalkenyl, substituted 3- to 6-membered heteroalkyl, substituted 6- to 10-membered aryl or substituted 5- to 10-membered heteroaryl; R2 is C1-C6 alkyl or 3- to 6-membered cycloalkyl; R7 is C1-C3 alkyl; R8 is C1-C3 alkyl;Furthermore, R9 can be any of the following: substituted C1-C6 alkyl groups, substituted C1-C6 heteroalkyl groups, substituted 3- to 6-membered cycloalkyl groups, or substituted 3- to 7-membered heteroalkyl groups, depending on the specific case.

3. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein R1 is a 5 to 10 heteroaryl group.

4. The compound of claim 3 or its pharmaceutically acceptable salt, wherein R1 is, where appropriate, a substituted 6-membered aryl or a substituted 6-membered heteroaryl.

5. A compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula Ie:

5. Wherein A is -N(H or CH3)C(O)-(CH2)-, wherein the amino nitrogen is bonded to the carbon atom of -CH(R10)-; substituted 3 to 6-membered cycloalkyl; substituted 3 to 6-membered heterocycloalkyl; substituted 6-membered aryl; or substituted 5 to 6-membered heteroaryl; B is -CH(R9)-, wherein the carbon is bonded to the carbonyl carbon of -NHC(O)-; substituted 3 to 6-membered cycloalkyl; substituted 3 to 6-membered heterocycloalkyl; substituted 6-membered aryl; or 5 to 6-membered heteroaryl; L is absent or is a linker having the structure of formula II: A1-(B1)f-(C1)g-(B2)h-(D1) Formula II: (B3)i-(C2)j-(B4)k-A2 where A1 is the bond between the linker and B; A2 is the bond between W and the linker; B1, B2, B3 and B4 are each independently selected from, as appropriate, substituted C1-C2 alkyl, substituted C1-C3 heteroalkyl, O, S and NRN; RN is hydrogen, substituted C1-C4 alkyl, substituted C2-C4 alkenyl, substituted C2-C4 alkynyl, substituted 3 to 14 heterocyclic alkyl, substituted 6 to 10 aryl or substituted C1-C7 heteroalkyl; C1 and C2 are each independently selected from carbonyl, thiocarbonyl, sulfonylurea or phosphatyl. f, g, h, i, j, and k are each independently 0 or 1; and D1 is, depending on the case, a substituted C1-C10 alkyl group, a substituted C2-C10 alkenyl group, a substituted C2-C10 alkynyl group, a substituted 3 to 14 heterocyclic alkyl group, a substituted 5 to 10 heteroaryl group, a substituted 3 to 8 heterocyclic alkyl group, a substituted 6 to 10 heteroaryl group, a substituted C2-C10 polyethylene glycol group, or a substituted C1-C10 heteroalkyl group, or a chemical bond connecting A1-(B1)f-(C1)g-(B2)h- to -(B3)i-(C2)j-(B4)k-A2; W is a crosslinking group, which includes Contains carbodiimide, oxazoline, thiazoline, chloroethylurea, chloroethylthiourea, chloroethyl carbamate, chloroethyl thiocarbamate, aziridine, trifluoromethyl ketone, boric acid, borate ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazoline, or enoxin; R2 is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; R7 is a C1-C3 alkyl; R8 is a C1-C3 alkyl; and R9 is, as appropriate, a substituted C1-C6 alkyl, a substituted C1-C6 heteroalkyl, a substituted 3- to 6-membered cycloalkyl, or a substituted 3- to 7-membered heteroalkyl; Xe and Xf are independently N or CH;Furthermore, R12 is, as appropriate, a substituted C1-C6 alkyl group, or, as appropriate, a substituted C1-C6 heteroalkyl group, or, as appropriate, a substituted 3- to 7-membered heterocyclic alkyl group.

6. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein A is a substituted 6-membered aryl group, as appropriate.

7. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein B is -CHR9-.

8. The compound of claim 7 or its pharmaceutically acceptable salt, wherein R9 is, where appropriate, a substituted C1-C6 alkyl or a substituted 3- to 6-membered cycloalkyl.

9. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein B is, where appropriate, a substituted 6-membered aryl group.

10. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the linking system is non-cyclic.

11. A compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of formula IIa:

11. Wherein the Xa series is absent or N; the R14 series is absent, hydrogen or, as appropriate, a substituted C1-C6 alkyl; and the L2 series is absent, -SO2-, or, as appropriate, a substituted C1-C4 heteroalkyl or, as appropriate, a substituted C1-C4 heteroalkyl, wherein at least one of Xa, R14 or L2 is absent.

12. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the linking system may contain a cyclic group.

13. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of formula IIb:

13. Wherein o is 0 or 1; R15 is hydrogen or, as appropriate, a substituted C1-C6 alkyl group; Cy is, as appropriate, a substituted 3 to 8-membered cycloalkyl group, a substituted 3 to 8-membered heterocycloalkyl group, a substituted 6 to 10-membered aryl group, or a substituted 5 to 10-membered heteroaryl group; and L3 is absent, -SO2-, a substituted C1-C4 alkyl group, or a substituted C1-C4 heteroalkyl group.

14. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein W contains carbodiimide.

15. A compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein W has the structure of formula IIIa:

15. Wherein R14 is a C1-C6 alkyl group, a C1-C6 heteroalkyl group, a 3- to 8-membered cycloalkyl group, a 6- to 10-membered aryl group, a 3- to 14-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group, which may be substituted as appropriate.

16. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein W contains oxazoline or thiazoline.

17. A compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein W has the structure of formula IIIb:

17. Wherein X1 is O or S; X2 is absent or NR19; R15, R16, R17 and R18 are independently hydrogen or, as appropriate, substituted C1-C6 alkyl; and R19 is hydrogen, C(O) (as appropriate, substituted C1-C6 alkyl), as appropriate, substituted C1-C6 alkyl, as appropriate, substituted 6 to 10 aryl, as appropriate, substituted 3 to 14 heterocyclic alkyl or, as appropriate, substituted 5 to 10 heteroaryl.

18. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein W comprises chloroethylurea, chloroethylthiourea, chloroethyl carbamate or chloroethyl thiocarbamate.

19. A compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein W has the structure of formula IIIc:

19. Wherein X3 is O or S; X4 is O, S, NR26; R21, R22, R23, R24 and R26 are independently hydrogen or, where appropriate, substituted C1-C6 alkyl; and R25 is hydrogen,, where appropriate, substituted C1-C6 alkyl,, where appropriate, substituted 6 to 10 aryl,, where appropriate, substituted 3 to 14 heterocyclic alkyl or, where appropriate, substituted 5 to 10 heteroaryl.

20. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein W comprises aziridine.

21. A compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein W has a structure of formula IIId1, IIId2, IIId3 or IIId4:

21. Wherein, X5 series is absent or NR30; Y series is absent or C(O), C(S), S(O), SO2 or, as appropriate, substituted C1-C3 alkyl; R27 series is hydrogen, -C(O)R32, -C(O)OR32, -SO2R33, -SOR33, as appropriate, substituted C1-C6 alkyl, as appropriate, substituted 6 to 10 aryl, as appropriate, substituted 3 to 14 heterocyclic alkyl or, as appropriate, substituted 5 to 10 heteroaryl; R28 and R29 are independently hydrogen, CN, C(O)R31, CO2R31, C(O)R31R31, as appropriate, substituted C1-C6 alkyl, as appropriate, substituted 3 R31 is independently hydrogen, C1-C6 alkyl, 6-10 aryl, 3-14 heterocyclic alkyl, or 5-10 heteroaryl; R30 is hydrogen or C1-C6 alkyl; and R32 and R33 are independently hydrogen, C1-C6 alkyl, 6-10 aryl, 3-14 heterocyclic alkyl, or 5-10 heteroaryl.

22. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein W comprises an epoxide.

23. If the compound in claim 1 or its pharmaceutically acceptable salt is selected from the group consisting of:

23. Or a medically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

25. Use of a compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 24 for the preparation of a pharmaceutical product for treating cancer in an individual, wherein the cancer comprises a Ras mutation.

26. As claimed in claim 25, wherein the cancer is pancreatic cancer, non-small cell lung cancer, colorectal cancer, or endometrial cancer.

27. As used in claim 25, wherein the Ras mutation is K-Ras G12D or K-Ras G13D.

28. Use of a compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 24 for the preparation of a pharmaceutical product for treating Ras protein-related diseases.

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