RAS inhibitors

Abstract

The present disclosure features macrocyclic compounds capable of inhibiting Ras proteins, as well as pharmaceutical compositions and protein complexes thereof, and their use in cancer treatment.

Description

Technical field

[0001] Cross-reference to related applications 62 / 930,355, filed November 4, 2019; 62 / 951,652, filed December 20, 2019; 63 / 000,357; and 63 / 043,588, filed Jun. 24, 2020, all of which are hereby incorporated by reference in their entirety. . [Background technology]

[0002] The vast majority of small molecule drugs act by binding to functionally important pockets on the target protein, thereby regulating the activity of that protein. For example, cholesterol-lowering drugs known as statins bind to the enzymatic active site of HMG-CoA reductase, thus preventing the enzyme from engaging its substrates. The fact that many such drug / target interaction pairs are known is misleading to some extent, and given the reasonable amount of time, effort, and resources, small molecule modulators are likely to However, it may lead one to believe that it can be found for most proteins. This is far from the truth. Current estimates are that only about 10% of all human proteins are targetable by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18:674-699 (2019). Another 90% are now considered refractory or refractory to small molecule drug discovery as described above. Such targets are commonly referred to as "undruggable". These undruggable targets comprise vast and abundant underutilized reservoirs of clinically important human proteins. Therefore, there is a great deal of interest in discovering novel molecular modalities that can control the function of such undruggable targets.

[0003] The literature is well documented that Ras proteins (K-Ras, H-Ras, and N-Ras) play essential roles in various human cancers and are therefore suitable targets for anti-cancer therapeutics. has been established in In fact, mutations in the Ras protein account for approximately 30% of all human cancers in the United States, many of which are fatal. Dysregulation of Ras proteins by activating mutations, overexpression, or upstream expression is common in human tumors, and activating mutations in Ras are frequently found in human cancers. For example, activating mutations in codon 12 in the Ras protein inhibit both the GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, turning the population of Ras mutant proteins "on" (GTP (Bound) state (Ras(ON)), resulting in oncogenic MAPK signaling. In particular, Ras exhibits picomolar affinity for GTP, allowing Ras to be activated even in the presence of low concentrations of this nucleotide. Mutations in codon 13 of Ras (eg, G13D) and mutations in codon 61 (eg, Q61K) are also responsible for oncogenic activity in some cancers.

[0004] Despite extensive drug discovery efforts directed against Ras in recent decades, no drugs that directly target Ras have yet been approved. Further efforts are needed to identify additional drugs against cancers driven by various Ras mutations. [Outline of the Invention]

[0005] RAS inhibitors are provided herein. The approach described here involves two intracellular proteins that do not interact with synthetic ligands under normal physiological conditions: a protein of interest (e.g., Ras), and a cytosolic chaperone that is widely expressed in cells. Requires formation of a high-affinity ternary complex or conjugate with (presenter protein) (eg, cyclophilin A). More specifically, in some embodiments, the inhibitors of Ras described herein exhibit a high affinity interaction between the Ras protein and the ubiquitously expressed cytosolic chaperone Cyclophilin A (CYPA). including novel binding pocket cytosols in Ras by driving the formation of sex tricomplexes or conjugates. While not wishing to be bound by theory, one way in which the compounds and complexes, or conjugates of the invention, affect the inhibitory effect on Ras is to interact between Ras and downstream effector molecules such as RAF and PI3K. It is the formation of a steric occlusion of the interaction site at , which the inventors believe is necessary for the development of the oncogenic signal.

[0006] Thus, in some embodiments, this disclosure features a compound of Structural Formula I, or a pharmaceutically acceptable salt thereof: [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-10 It binds to the carbon atom of the member heteroarylene. ] and B does not exist or -CH(R 9 )-, >C=CR 9 R. 9’ , or >CR 9 R. 9’ [Wherein, carbon is -N(R 11 )C(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 It is attached to the carbonyl carbon of the heteroarylene. ] and G is any permuted C 1 -C 4 Alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, -C(O)O-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], -C(O)NH-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], arbitrarily permuted C 1 -C 4 heteroalkylene or 3- to 8-membered heteroarylene, L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, haloacetal, or alkynyl sulfone; X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH and X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 is CH, CH 2 , or N, and Y 6 is C(O), CH, CH 2 , or N, and R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R. 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl, R. 2 is absent, hydrogen, optionally substituted C 1 -C 6alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl or in combination with the carbon to which they are attached to form a carbonyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is H, F, optionally permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or R. 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R. 9’ is hydrogen or optionally substituted C 1 -C 6 is alkyl, or R. 9 and R 9’ are combined with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, R. 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, R. 10a is hydrogen or halo, R. 11 is hydrogen or C 1 -C 3 is an alkyl, and R. 21 is hydrogen or C 1 -C 3 Alkyl (eg, methyl). ].

[0007] Also provided are pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] Further provided is a conjugate comprising the structure of Formula IV, or a salt thereof: M-L-P Formula IV [wherein L is a linker, P is a monovalent organic moiety, M has the structure of Formula V. ]. [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B does not exist or -CH(R 9 )-, >C=CR 9 R. 9’ , or >CR 9 R. 9’ [Wherein, carbon is -N(R 11 )C(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 It is attached to the carbonyl carbon of the heteroarylene. ] and G is any permuted C 1 -C 4 Alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, -C(O)O-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], -C(O)NH-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], arbitrarily permuted C 1 -C 4 heteroalkylene or 3- to 8-membered heteroarylene, X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH and X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 is CH, CH 2 , or N, and Y 6 is C(O), CH, CH 2 , or N, and R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R. 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl, R. 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl or in combination with the carbon to which they are attached to form a carbonyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is H, F, optionally permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or R. 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R. 9’ is hydrogen or optionally substituted C 1 -C 6 is alkyl, or R. 9 and R 9’ are combined with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, R. 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, R. 10a is hydrogen or halo, R. 11 is hydrogen or C 1 -C 3 is an alkyl, and R. 21 is H or C 1 -C 3 is alkyl. ] A method of treating cancer in a subject in need of cancer treatment, said method comprising administering to said subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. The above method is also provided, comprising:

[0009] In some embodiments, a method of treating a Ras protein-related disease in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of the invention; or a pharmaceutically acceptable salt thereof.

[0010] Further provided is a method of inhibiting Ras protein in a cell, said method comprising contacting said cell with an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. do.

[0011] It is specifically contemplated that any limitations discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. Further, 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 produce or utilize any compound or composition of the invention. can do. [Brief description of the drawing]

[0012] [Fig. 1A] Matched pair analysis of the potency of a particular compound of the invention (Formula BB) (dots on the right) and the corresponding compound of Formula AA (dots on the left) is shown in two different cell-based assays. In context H is replaced by (S)Me. The y-axis shows the pERK EC50 (Fig. 1A) or CTG IC50 (Fig. 1B) measured in the H358 cell line. [Fig. 1B] Matched pair analysis of the potency of a particular compound of the invention (Formula BB) (dots on the right) and the corresponding compound of Formula AA (dots on the left) is shown in two different cell-based assays. In context H is replaced by (S)Me. The y-axis shows the pERK EC50 (Fig. 1A) or CTG IC50 (Fig. 1B) measured in the H358 cell line.

Figure 2

[0013] Definitions and chemical terms In this application, unless the context clearly indicates otherwise, (i) the term "a (a)" means "one or more" and (ii) means alternative expressions only; Although used to mean "and / or" unless the alternatives are expressly indicated to be mutually exclusive, this disclosure refers to only alternatives and to "and / or." to support the definitions, and (iii) the terms "comprising" and "including" are presented by themselves or in conjunction with one or more additional components or steps It is understood to include an itemized component or step regardless, and (iv) where a range is indicated, endpoints are included.

[0014] As used herein, the term "about" is used to indicate that a value includes the standard deviation of error of the device or method used to determine the value. In certain embodiments, the term "about" refers to a stated value, unless otherwise stated or clear from the context (e.g., where such number may exceed 100% of the possible values). 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9% in either direction (above or below) , 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less.

[0015] As used herein, the term “adjacent,” in the context of describing adjacent atoms, means divalent atoms that are directly covalently attached.

[0016] As used herein, "compounds of the invention" and similar terms refer to the compounds of Formula I and sub-formulas thereof, and the compounds of Tables 1 and 2, whether or not explicitly stated. compounds, as well as salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers thereof. means a Ras inhibitor as described in

[0017] The term "wild-type" means an entity that has a structure or activity that is found in nature in a "normal" (paired with a mutant, disease, alteration, etc.) state or context. Those skilled in the art will appreciate that wild-type genes and polypeptides often exist in multiple different forms (eg, alleles).

[0018] Certain compounds described herein may have one or more different isomeric (e.g. stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g. deuterium) forms. It will be understood by those skilled in the art that one or more atoms can be present in a form substituted with different isotopes of that atom, such as hydrogen substituted with . Unless otherwise indicated, or apparent from context, a depicted structure may be understood to represent any such isomeric or isotopic forms, individually or in combination.

[0019] Compounds described herein can be asymmetric (eg, possess one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the disclosure containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials, such as by resolution of racemic mixtures or stereoselection methods, are known in the art. Many geometric isomers of olefins, C=N double bonds, etc. may also exist in the compounds described in this disclosure and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are contemplated and may be isolated as a mixture of isomers or as separated isomeric forms.

[0020] In some embodiments, one or more compounds described herein can exist in different tautomeric forms. References to such compounds include all such tautomeric forms, unless expressly excluded, as is clear from the context. In some embodiments, tautomeric forms arise from the exchange of a single bond with an adjacent double bond and the accompanying proton shift. In certain embodiments, a tautomeric form can be a prototropic tautomer, which is an isomeric protonation state that has the same empirical formula and overall charge as a reference form. Examples of moieties with prototropic tautomeric forms are ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and 1H- and 3H-imidazole, 1H-, 2H -, and 4H-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole are cyclic forms in which the protons can occupy more than one position in the heterocyclic system. In some embodiments, tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms arise from acetal interconversions.

[0021] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the invention include: 2 H. 3 H. 11 C. 13 C. 14 C. 13 N, 15 N, 15 O 17 O 18 O 32 P. 33 P. 35 S, 18 F. 36 Cl, 123 I, and 125 and isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as I. Isotope-labeled compounds (e.g., 3 H and 14 C-labeled compounds) may be useful in compound or substrate tissue distribution assays. tritium labels (i.e. 3 H), and carbon-14 (i.e. 14 C) Isotopes can be useful because of their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e. 2 Substitutions such as H) are more metabolically stable and may result in certain therapeutic advantages (eg, longer in vivo half-life or lower dosage requirements). In some embodiments, one or more hydrogen atoms are 2 H or 3 replaced by H or one or more carbon atoms are 13 C or 14 replaced by C-enriched carbon. 15 O 13 N, 11 C and 18Positron emitting isotopes such as F are useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents following procedures analogous to those disclosed for the compounds of the invention described herein. can be prepared by

[0022] As is known in the art, many chemical moieties can be in a variety of different solid forms, such as amorphous or crystalline forms (eg, polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be utilized in any such form, including any solid form. In some embodiments, compounds described or illustrated herein may be provided or utilized in hydrate or solvate form.

[0023] At various places in the present specification, substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that this disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term "C 1 -C 6 "Alkyl" specifically means methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 alkyl, and C 6 Alkyl is intended to be disclosed separately. Further, when a compound contains multiple positions where substituents are disclosed in groups or ranges, the disclosure includes subcombinations of each and every individual element at each position unless otherwise specified. It is intended to cover individual compounds as well as groups of compounds (eg, genera and subgenera).

[0024] The term "optionally substituted X" (e.g., optionally substituted alkyl) is used to refer to "X, wherein X is optionally substituted" (e.g., "alkyl, said alkyl being optionally substituted is intended to be equivalent to ''). The feature "X" (eg, alkyl) per se is not intended to be meant to be optional. As described herein, certain compounds of interest may contain one or more "optionally substituted" moieties. Generally, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are preferred substituents, such as those described herein. It means substituted by either a group or groups. Unless otherwise stated, an "optionally substituted" group can have a suitable substituent at each suitable position of the group. Also, when more than one position in any given structure can be substituted with more than one substituent selected from the specified groups, the substituents may be the same or different at each position. It can be either. For example, the term "arbitrarily permuted C 1 -C 6 Alkyl-C 2 -C 9 In "heteroaryl", the alkyl portion, the heteroaryl portion, or both may be optionally substituted. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically compatible compounds. The term "stable," as used herein, refers to the production, detection, and, in certain embodiments, recovery, purification, and use of compounds for one or more of the purposes disclosed herein. It means a compound that does not change substantially when subjected to the conditions foreseen of its use.

[0025] Suitable monovalent substituents at substitutable carbon atoms of "optionally substituted" groups are independently deuterium, halogen, -(CH 2 ) 0 - 4 R°, -(CH 2 ) 0 - 4 OR°, -O(CH 2 ) 0 - 4 R. ° , -O-(CH 2 ) 0 - 4 C(O)OR°, -(CH 2 ) 0 - 4 CH(OR°) 2 , -(CH 2 ) 0 - 4 SR°, -(CH 2 ) 0 - 4 Ph[R° may be substituted. ], -(CH 2 ) 0 - 4 O(CH 2 ) 0 - 1 Ph[R° may be substituted. ], -CH=CHPh[R° may be substituted. ], -(CH 2 ) 0 - 4 O(CH 2 ) 0 - 1 -pyridyl[R° may be substituted. ], 4- to 8-membered saturated or unsaturated heterocycloalkyl (e.g., pyridyl), 3- to 8-membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), -NO 2 , -CN, -N 3 , -(CH 2 ) 0 - 4 N(R°) 2 , -(CH 2 ) 0 - 4 N(R°)C(O)R°, -N(R°)C(S)R°;-(CH 2 ) 0 - 4 N(R°)C(O)NR° 2 ;-N(R°)C(S)NR° 2 ;-(CH 2 ) 0 - 4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR° 2 ;-N(R°)N(R°)C(O)OR°;-(CH 2 ) 0 - 4 C(O)R°;-C(S)R°;-(CH 2 ) 0 - 4 C(O)OR°;-(CH 2 ) 0 - 4 -C(O)-N(R o ) 2 ;-(CH 2 ) 0 - 4 -C(O)-N(R o )-S(O) 2 -R o ;-C(NCN)NR° 2 ;-(CH 2 ) 0 - 4 C(O)SR°;-(CH 2 ) 0 - 4 C(O)OSiR° 3 ;-(CH 2 ) 0 - 4 OC(O)R°;-OC(O)(CH 2 ) 0 - 4 SR°;-SC(S)SR°;-(CH 2 ) 0 - 4 SC(O)R°;-(CH 2 ) 0 - 4 C(O)NR° 2 ;-C(S)NR° 2 ;-C(S)SR°;-(CH 2 ) 0 - 4 OC(O)NR° 2 ;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH 2 C(O)R°;-C(NOR°)R°;-(CH 2 ) 0 - 4 SSR°;-(CH 2 ) 0 - 4 S(O) 2 R°;-(CH 2 ) 0 - 4 S(O) 2 OR°;-(CH 2 ) 0 - 4 OS(O) 2 R°;-S(O) 2 NR° 2 ;-(CH 2 ) 0 - 4 S(O)R°;-N(R°)S(O) 2 NR° 2 ;-N(R°)S(O) 2 R°;-N(OR°)R°;-C(NOR°)NR° 2 ;-C(NH)NR° 2 ;-P(O) 2 R°;-P(O)R° 2 ;-P(O)(OR°) 2 ;-OP(O)R° 2 ;-OP(O)(OR°) 2 ;-OP(O)(OR°)R°,-SiR° 3 ;-(C 1 - 4 straight-chain or branched-chain alkylene) O-N(R°) 2 ; or -(C 1 - 4 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, -C 1 - 6 aliphatic, -CH 2 Ph, -O(CH2 ) 0 - 1 Ph, -CH 2 -(5- to 6-membered heteroaryl ring) or 3- to 6-membered, saturated, partially unsaturated, having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an aryl ring, or regardless of the above definition, two independently occurring R°, together with the atom(s) intervening, are independently selected from nitrogen, oxygen, or sulfur. to form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms, which may be substituted as defined below. .

[0026] Suitable monovalent substituents on R° (or a ring formed by using two independently occurring R° together with the atoms in between) are independently halogen, —(CH 2 ) 0 - 2 R. ● ,-(halo R ● ), -(CH 2 ) 0 - 2 OH, -(CH 2 ) 0 - 2 OR ● , -(CH 2 ) 0 - 2 CH(OR ● ) 2 , -O (halo R ● ), -CN, -N 3 , -(CH 2 ) 0 - 2 C(O)R ● , -(CH 2 ) 0 - 2 C(O)OH, -(CH 2 ) 0 - 2 C(O)OR ● , -(CH 2 ) 0 - 2 SR ● , -(CH 2 ) 0 - 2 SH, -(CH 2 ) 0 - 2 NH 2 , -(CH 2 ) 0 - 2 NHR ● , -(CH 2 ) 0 - 2 NR ● 2 , -NO 2 , -SiR ● 3 , -OSiR ● 3 , -C(O)SR ● , -(C 1 - 4 straight or branched alkylene)C(O)OR ● , or -SSR ● where each R ● is unsubstituted or, where preceded by "halo", is substituted only by one or more halogens and independently, C 1 - 4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 - 1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on the saturated carbon atoms of R° include =O and =S.

[0027] Suitable divalent substituents on saturated carbon atoms of "optionally substituted" groups include: =O, =S, =NNR * 2 , = NNHC(O)R * , =NNHC(O)OR * , =NNHS(O) 2 R. * ,=NR * , =NOR * , -O(C(R * 2 )) 2 - 3 O-, or -S(C(R * 2 )) 2 - 3 S-, where each independently present R * is a hydrogen, C which can be substituted as defined below 1 - 6 selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur . Suitable divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2 ) 2 - 3 O-, where each independently present R * is a hydrogen, C which can be substituted as defined below 1 - 6 selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur .

[0028] R. * Suitable substituents on the aliphatic group of include -R ● , (halo R ● ), -OH, -OR ● , -OR ● , -O (halo R ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR 2 , or -NO 2 where each R ● is unsubstituted or, where preceded by "halo", is substituted only by one or more halogens and independently, C 1 - 4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 - 1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] Suitable substituents on the substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2 , -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH 2 C(O)R † , -S(O) 2 R. † , -S(O) 2 NR † 2 , -C(S)NR † 2 , -C(NH)NR † 2 , or -N(R † )S(O) 2 R. † where each R † is independently hydrogen, C 1 - 6 aliphatic, unsubstituted -OPh, or unsubstituted 3-6 membered saturated, partially unsaturated, or -OPh having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; being an aryl ring or, regardless of the above definitions, two independently occurring R † is an unsubstituted 3- to 12-membered saturated, partially unsaturated heteroatom having, together with the intervening atom(s), 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; , or form an aryl mono- or bicyclic ring.

[0030] R. † Suitable substituents on the aliphatic groups of are independently halogen, -R, -(haloR ● ), -OH, ● -OR ● , -O (halo R ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 where each R ● is unsubstituted or, where preceded by "halo", is substituted only by one or more halogens and independently, C 1 -C 4 aliphatic, -CH 2 Ph, -O(CH 2 ) 0 - 1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R. † Suitable divalent substituents on the saturated carbon atoms of include =O and =S.

[0031] As used herein, the term "acetyl" refers to the group -C(O)CH 3 means

[0032] As used herein, the term "alkoxy" means -O-C 1 -C 20Alkyl means the alkoxy group is attached to the rest of the compound through the oxygen atom.

[0033] As used herein, the term “alkyl” refers to a saturated, straight or branched monovalent carbon containing 1-20 (eg, 1-10, or 1-6) carbons. means a hydrogen group. In some embodiments, alkyl groups are unbranched (ie, straight chain), and in some embodiments, alkyl groups are branched. Alkyl groups are exemplified by, but not limited to, methyl, ethyl, n- and isopropyl, n-, sec-, iso- and tert-butyl, and neopentyl.

[0034] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon radical derived from a straight or branched chain saturated hydrocarbon by removing two hydrogen atoms, methylene, ethylene , isopropylene, and the like. The term "C x -C y "Alkylene" refers to an alkylene group having x to y carbons. Exemplary values ​​for x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14. , 16, 18, or 20 (e.g., C 1 -C 6 , C 1 -C 10 , C 2 -C 20 , C 2 -C 6 , C 2 -C 10 , or C 2 -C 20 alkylene). In some embodiments, the alkylene can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.

[0035] As used herein, the term “alkenyl,” unless otherwise specified, means 2-20 carbons containing one or more carbon-carbon double bonds (eg, 2-6, or 2-10 (1 carbons) monovalent straight or branched chain group, exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl includes both cis and trans isomers. As used herein, the term “alkenylene,” unless otherwise specified, means 2-20 carbons containing one or more carbon-carbon double bonds (eg, 2-6, or 2-10 (1 carbons), represents a divalent straight or branched chain group.

[0036] As used herein, the term “alkynyl” refers to 2-20 carbon atoms (eg, 2-4, 2-6, or 2-10 carbons) containing a carbon-carbon triple bond. , represents a monovalent straight or branched chain radical, exemplified by ethynyl and 1-propynyl.

[0037] As used herein, the term "alkynylsulfone" refers to the structure [formation] [wherein R is any chemically suitable substituent as described herein. ] represents a group containing

[0038] As used herein, the term "amino" means -N(R † ) 2 , e.g., -NH 2 and -N(CH 3 ) 2 represents

[0039] As used herein, the term "aminoalkyl" represents an alkyl moiety substituted on one or more carbon atoms with one or more amino moieties.

[0040] As used herein, the term "amino acid" refers to side chains, amino groups, and acidic groups (e.g., -CO 2 H or -SO 3 H), the amino acid is attached to the parent molecular group through a side chain, amino group, or acid group (eg, side chain). As used herein, the term "amino acid" in its broadest sense means any compound or substance that can be incorporated into a polypeptide chain, eg, by forming one or more peptide bonds. In some embodiments, the amino acid has the general structure H 2 It has N-C(H)(R)-COOH. In some embodiments, amino acids are naturally occurring amino acids. In some embodiments, the amino acids are synthetic amino acids, in some embodiments the amino acids are D-amino acids, and in some embodiments the amino acids are L-amino acids. By "standard amino acid" is meant 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, glutamine, glycine, histidine, optionally substituted hydroxyl norvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline. , pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0041] As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system formed by carbon atoms in which the ring attached to the pendant group is aromatic is. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl and anthracenyl. An aryl ring can be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms can be optionally substituted.

[0042] As used herein, the term "C 0 ” represents a bond. For example, the term -N(C(O)-(C 0 -C 5 Part of alkylene-H)- is -N(C(O)-(C 0 Includes alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0043] As used herein, the terms "carbocyclic" and "carbocyclyl" mean a monovalent, optionally substituted C3-12 monocyclic, bicyclic, or tricyclic cyclic structure. , which may optionally be bridged, fused or spirocyclic, all rings are formed by carbon atoms and at least one ring is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decalinyl and the like. A carbocyclic ring can be attached to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms can be optionally substituted.

[0044] As used herein, the term "carbonyl" represents a C(O) group, which can also be represented as C=O.

[0045] As used herein, the term "carboxyl" means -CO 2 H, (C=O)(OH), COOH, or C(O)OH, or the unprotonated corresponding group.

[0046] As used herein, the term "cyano" represents a -CN group.

[0047] As used herein, the term “cycloalkyl” refers to a monovalent saturated cyclic hydrocarbon group, which, unless otherwise specified, may be bridged, fused, or have from 3 to 8 carbons. exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0048] As used herein, the term “cycloalkenyl” refers to a monovalent non-aromatic saturated cyclic hydrocarbon radical, which, unless otherwise specified, may be bridged, fused, or 3-8 carbons and contains one or more carbon-carbon double bonds.

[0049] As used herein, the term "diastereomers" means stereoisomers that are not mirror images of each other and are not superimposable.

[0050] As used herein, "enantiomer" means at least 80% (i.e., at least 90% of one enantiomer and up to 10% of the other enantiomer), preferably at least 90%, and more preferably, It refers to each individual optically active form of a compound of the invention having an optical purity or enantiomeric excess (measured by standard methods in the art) of at least 98%.

[0051] The term "guanidyl" refers to the structure [formation] [wherein each R is independently any of the chemically suitable substituents described herein. ] means a group having

[0052] As used herein, the term "guanidinoalkylalkyl" represents an alkyl moiety substituted on one or more carbon atoms with one or more guanidyl moieties.

[0053] As used herein, the term "haloacetyl" means an acetyl group in which at least one hydrogen has been replaced with a halogen.

[0054] As used herein, the term "haloalkyl" represents an alkyl moiety in which one or more carbon atoms have been replaced with one or more same or different halogen moieties.

[0055] As used herein, the term "halogen" represents a halogen selected from bromine, chlorine, iodine or fluorine.

[0056] As used herein, the term "heteroalkyl" refers to an "alkyl" group (as defined herein) in which at least one carbon atom is replaced with a heteroatom (e.g., an O, N, or S atom). ). Heteroatoms can occur in the middle or at the ends of the radical.

[0057] As used herein, the term "heteroaryl" refers to monovalent monocyclic or polycyclic ring structures containing at least one complete aromatic ring. That is, they contain 4n+2 π electrons in a monocyclic or polycyclic ring system and at least one ring heteroatom selected from N, O or S in the aromatic ring. do. Exemplary unsubstituted heteroaryl groups are those of 1-12 (eg, 1-11, 1-10, 1-9, 2-12, 2-11, 2-10, or 2-9) carbons. is. The term "heteroaryl" refers to bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings are fused to one or more aryl or carbocyclic rings such as a phenyl ring or a cyclohexane ring. including. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl. A heteroaryl ring can be attached to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms can be optionally substituted. In some embodiments, the heteroaryl is substituted with 1, 2, 3, or 4 substituents.

[0058] As used herein, the term "heterocycloalkyl" denotes a monovalent monocyclic, bicyclic or polycyclic ring system, which may be bridged, fused or spirocyclic. , at least one ring is non-aromatic, the non-aromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. Exemplary unsubstituted heterocycloalkyl groups are 1-12 (eg, 1-11, 1-10, 1-9, 2-12, 2-11, 2-10, or 2-9) carbons. It is a thing. The term "heterocycloalkyl" also refers to heterocyclic compounds having bridged polycyclic structures in which one or more carbon or heteroatoms bridge two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group. . The term "heterocycloalkyl" means that any of the above heterocyclic rings may be one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings such as aryl, cyclohexane, cyclohexene, cyclo Includes bicyclic, tricyclic, and tetracyclic groups fused to a pentane, cyclopentene, pyridine, or pyrrolidine ring. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine and decahydronaphthyridinyl. A heterocycloalkyl ring can be attached to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms can be optionally substituted.

[0059] As used herein, the term "hydroxy" refers to the -OH group.

[0060] As used herein, the term "hydroxyalkyl" represents an alkyl moiety substituted on one or more carbon atoms with one or more -OH moieties.

[0061] As used herein, "isomer" means any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the invention. The compounds of the invention may have one or more chiral centers or double bonds and are therefore stereoisomers, such as double bond isomers (i.e. geometric E / Z isomers), or diastereomers (e.g. , are recognized to exist as enantiomers (i.e. (+) or (-), or cis / trans isomers).According to the present invention, the chemical structures described herein and, therefore, the compounds of the present invention. Compounds are represented in all corresponding stereoisomers, i.e., in stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure), as well as enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures of the compounds of the invention are generally prepared by well-known methods such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, compound as chiral salt complexes. or by crystallization of the compound in a chiral solvent, it can be resolved into its constituent enantiomers or stereoisomers, which can be separated into stereoisomers by well-known asymmetric synthetic methods. can also be obtained from chemically or enantiomerically pure intermediates, reagents, and catalysts.

[0062] As used herein, the term "linker" refers to a compound such that the resulting compound is capable of achieving an IC50 of 2 uM or less in the Examples below and the Ras-RAF Disruption Assay Protocol provided herein. , in compounds of formula I, means the divalent organic moiety that connects moiety B to moiety W.

[0063] The purpose of this biochemical assay was to measure the ability of a test compound to facilitate ternary complex formation between a nucleotide-loaded Ras isoform and cyclophilin A, the resulting ternary complex being , BRAF RBD Abolishes binding to the construct and inhibits Ras signaling through the RAF effector.

[0064] 0.002% Tween20, 0.1% BSA, 100 mM NaCl and 5 mM MgCl in assay buffer containing 25 mM HEPES (pH 7.3) 2 , untagged cyclophilin A, His6-K-RasGMPPNP (or other Ras variants), and GST-BRAF RBD are combined in a 384-well assay plate at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. Compounds are present in plate wells as a 10-point 3-fold dilution series, starting at a final concentration of 30 μM. After incubation for 3 hours at 25° C., a mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was added to assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and reactions were incubated for an additional 1.5 hours. The TR-FRET signal is read on a microplate reader (excitation 320 nm, emission 665 / 615 nm). Compounds that promote disruption of the Ras:RAF complex are identified as those that induce a decrease in the TR-FRET ratio relative to DMSO control wells.

[0065] In some embodiments, the linker contains 20 or fewer linear atoms. In some embodiments, the linker contains 15 or fewer linear atoms. In some embodiments, the linker contains 10 or fewer linear atoms. In some embodiments, the linker has a molecular weight of less than 500g / mol. In some embodiments, the linker has a molecular weight of less than 400g / mol. In some embodiments, the linker has a molecular weight of less than 300g / mol. In some embodiments, the linker has a molecular weight of less than 200g / mol. In some embodiments, the linker has a molecular weight of less than 100g / mol. In some embodiments, the linker has a molecular weight of less than 50 g / mol.

[0066] 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, a "monovalent organic moiety" is less than 500 g / mol. In some embodiments, a "monovalent organic moiety" ranges from 500 g / mol to 500 kDa.

[0067] As used herein, the term "stereoisomer" refers to all the different isomeric forms and structural forms that a compound may have (e.g., compounds of any of the formulas described herein ), in particular all possible stereochemical and structural isomeric forms of the basic molecular structure, including all diastereomers, enantiomers or conformers, including atropisomers. Some compounds of the invention may exist in different tautomeric forms, all of the latter being included within the scope of the invention.

[0068] As used herein, the term "sulfonyl" refers to -S(O) 2 - represents a group.

[0069] As used herein, the term "thiocarbonyl" means a -C(S)- group.

[0070] As used herein, the term "vinyl ketone" means a group containing a carbonyl group directly attached to a carbon-carbon double bond.

[0071] As used herein, the term "vinylsulfone" means a group containing a sulfonyl group directly attached to a carbon-carbon double bond.

[0072] As used herein, the term "ynone" refers to the structure [formation] [wherein R is any optional chemically suitable substituent described herein. ] represents a group containing

[0073] Certain compounds described herein may be in any of a variety of forms, such as salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, etc. A person of ordinary skill in the art reading this disclosure will understand that it can be provided or utilized in In some embodiments, a reference to a particular compound may relate to a particular form of that compound. In some embodiments, a reference to a particular compound may relate to that compound in any form. In some embodiments, for example, a single stereoisomeric preparation of a compound can be considered a form of the compound that is different from a racemic mixture of the compound; A preparation containing a structural isomer of a double bond ((Z) or (E)) may be considered a different form than the salt form of the other structural isomer of the double bond ((E) or (Z)), and a preparation in which one or more atoms are of a different isotope than that present in the reference preparation is considered to be in a different form. can be considered.

[0074] (detailed description) Compound

[0075] RAS inhibitors are provided herein. The approach described here involves two intracellular proteins that do not interact with synthetic ligands under normal physiological conditions: a protein of interest (e.g., Ras), and a cytosolic chaperone that is widely expressed in cells. Requires formation of a high-affinity ternary complex or conjugate with (presenter protein) (eg, cyclophilin A). More specifically, in some embodiments, the inhibitors of Ras described herein exhibit a high affinity interaction between the Ras protein and the ubiquitously expressed cytosolic chaperone Cyclophilin A (CYPA). including novel binding pocket cytosols in Ras by driving the formation of sex tricomplexes or conjugates. Without wishing to be bound by theory, one way in which the compounds and complexes or conjugates of the present invention affect the inhibitory effect on Ras is to interact between Ras and downstream effector molecules such as RAF. It is the formation of a steric occlusion of the interaction site, which the inventors believe is necessary for the development of the oncogenic signal.

[0076] Without being bound by theory, it is presently believed that both covalent and non-covalent interactions of compounds of the invention with Ras and chaperone proteins (e.g., cyclophilin A) may contribute to inhibition of Ras activity. The inventors assume that In some embodiments, a compound of the invention forms a covalent adduct with a side chain of a Ras protein (eg, the mercapto (group) sulfhydryl side chain of a cysteine ​​at position 12 or 13 of a mutant Ras protein). Covalent adducts can also be formed with other side chains of Ras. Additionally, or alternatively, non-covalent interactions may be acted upon: such as van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, and combinations thereof, according to the present invention. may contribute to their ability to form complexes and act as RAS inhibitors. Accordingly, various Ras proteins can be inhibited by the compounds of the invention (e.g., K-Ras, N-Ras, H-Ras at positions 12, 13, and 61, and mutants thereof, e.g., G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, and others described herein).

[0077] Methods for measuring covalent adduct formation are known in the art. One way to measure covalent adduct formation is to perform a "cross-linking" assay, such as under the following conditions (Note - the protocol below is for cross-linking of K-Ras G12C (GMP-PNP) to compounds of the invention. (This protocol can also be performed with other Ras proteins or nucleotides).

[0078] The purpose of this biochemical assay is to measure the ability of test compounds to covalently label nucleotide-loaded K-Ras isoforms. 75 mM NaCl, 1 mM MgCl in assay buffer containing 12.5 mM HEPES (pH 7.4) 2 , 1 mM BME, 5 μM Cyclophilin A and 2 μM test compound, 5 μM GMP-PNP-loaded K-Ras(1-169)G12C stock solution is diluted 10-fold to give a final concentration of 0.5 μM. Final sample volume is 100 μL.

[0079] Samples are incubated at 25° C. for periods of up to 24 hours before being quenched by the addition of 10 μL of 5% formic acid. After centrifugation of the quenched sample at 15000 rpm for 15 min in a benchtop centrifuge, 10 μL aliquots are injected onto a reverse-phase C4 column and eluted into the mass spectrometer with increasing acetonitrile gradient in the mobile phase. . Raw data analysis can be performed using Waters MassLynx MS software, and percent binding is calculated from the deconvoluted protein peaks for labeled and unlabeled K-Ras.

[0080] Accordingly, provided herein are compounds having the structure of Formula I, or a pharmaceutically acceptable salt thereof: [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-10 It binds to the carbon atom of the member heteroarylene. ] and B does not exist or -CH(R 9 )-, >C=CR 9 R. 9’ , or >CR 9 R. 9’ [Wherein, carbon is -N(R 11 )C(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 It is attached to the carbonyl carbon of the heteroarylene. ] and G is any permuted C 1 -C 4 Alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, -C(O)O-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], -C(O)NH-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], arbitrarily permuted C 1 -C 4 heteroalkylene or 3- to 8-membered heteroarylene, L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, haloacetal, or alkynyl sulfone; X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 is CH, CH 2 , or N, and Y 6 is C(O), CH, CH 2 , or N, and R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R. 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl, R. 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7’ R. 8’ ;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl or in combination with the carbon to which they are attached to form a carbonyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is H, F, optionally permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or R. 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R. 9’ is hydrogen or optionally substituted C 1 -C 6 is alkyl, or R. 9 and R 9’ are combined with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, R. 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, R. 10a is hydrogen or halo, R. 11 is hydrogen or C 1 -C 3 is an alkyl, and R. 21 is hydrogen or C 1 -C 3 Alkyl (eg, methyl). ].

[0081] In some embodiments, R 9 is H, optionally permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl.

[0082] In some embodiments, R 21 is hydrogen.

[0083] In some embodiments, provided herein are compounds having the structure of Formula Ia, or a pharmaceutically acceptable salt thereof: [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-10 It binds to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )- or >C=CR 9 R. 9’ [Wherein, carbon is -N(R 11)C(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 Binds to the carbonyl carbon of the heteroarylene. ] and G is any permuted C 1 -C 4 Alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, -C(O)O-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], -C(O)NH-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], arbitrarily permuted C 1 -C 4 heteroalkylene or 3- to 8-membered heteroarylene, L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, haloacetal, or alkynyl sulfone; X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 is CH, CH 2 , or N, and Y 6 is C(O), CH, CH 2 , or N, and R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R. 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl, R. 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl or in combination with the carbon to which they are attached to form a carbonyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or R. 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R. 9’ is hydrogen or optionally substituted C 1 -C 6 is an alkyl, R. 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, R. 10a is hydrogen or halo, and R. 11 is hydrogen or C 1 -C 3 is alkyl. ].

[0084] In some embodiments, the disclosure features a compound of structural formula Ib, or a pharmaceutically acceptable salt thereof: [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )-[where carbon is -N(R 11 )C(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 It is attached to the carbonyl carbon of the heteroarylene. ] and G is any permuted C 1 -C 4 Alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, -C(O)O-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], -C(O)NH-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], arbitrarily permuted C 1 -C 4 heteroalkylene or 3- to 8-membered heteroarylene, L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, haloacetal, or alkynyl sulfone; X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH and X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 and Y 6 is independently CH or N, R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R. 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, and R. 11 is hydrogen or C 1 -C 3 is alkyl. ].

[0085] In some embodiments of the compounds of the invention, G is an optionally substituted C 1 -C 4 It is heteroalkylene.

[0086] In some embodiments, compounds are provided having the structure of Formula Ic, or a pharmaceutically acceptable salt thereof: [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )-[where carbon is -N(R 11 )C(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 It is attached to the carbonyl carbon of the heteroarylene. ] and L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; X 2 is O or NH and X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 and Y 6 is independently CH or N, R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R. 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, and R. 11 is hydrogen or C 1 -C 3 is alkyl. ].

[0087] In some embodiments of the compounds of the invention, X 2 is NH. In some embodiments, X 3 is CH. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is C 1 -C 3 is alkyl. In some embodiments, R 11 is methyl.

[0088] In some embodiments, the compounds of the invention have the structure of Formula Id, or a pharmaceutically acceptable salt thereof: [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 and Y 6 is independently CH or N, R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R. 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, and R. 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is alkyl. ].

[0089] In some embodiments of the compounds of the invention, X 1 is an arbitrarily permuted C 1 -C 2 is alkylene. In some embodiments, X 1 is methylene. In some embodiments, X 1 is C 1 -C 6 methylene substituted with alkyl or halogen. In some embodiments, X 1 is -CH(Br)-. In some embodiments, X 1 is -CH(CH 3 )-. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C optionally substituted with halogen 1 -C 4 is alkyl. In some embodiments, R 5 is methyl. In some embodiments, Y 4 is C. In some embodiments, R 4 is hydrogen. In some embodiments, Y 5 is CH.

[0090] In some embodiments, Y 6 is CH. In some embodiments, Y 1 is C. In some embodiments, Y 2 is C. In some embodiments, Y 3 is N. In some embodiments, R 3 does not exist. In some embodiments, Y 7 is C.

[0091] In some embodiments, the compounds of the invention have the structure of Formula Ie, or a pharmaceutically acceptable salt thereof: [formation] [In the formula, A is -N (H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R. 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, and R. 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is alkyl. ].

[0092] In some embodiments of the compounds of the invention, R 6 is hydrogen. In some embodiments, R 2 is hydrogen, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl. In some embodiments, R 2 is an arbitrarily permuted C 1 -C 6 is alkyl. In some embodiments, R 2 is fluoroalkyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 Ha-CH 2 CF 3 is. In some embodiments, R 2 is C 2 -C 6 is alkynyl. In some embodiments, R 2 is -CHC≡CH. In some embodiments, R 2 Ha-CH 2 C≡CCH 3 is. In some embodiments, R 7 is an arbitrarily permuted C 1 -C 3 is alkyl. In some embodiments, R 7 is C 1 -C 3 is alkyl. In some embodiments, R 8 is an arbitrarily permuted C 1 -C 3 is alkyl. In some embodiments, R 8 is C 1 -C 3 is alkyl.

[0093] In some embodiments, the compounds of the invention have the structure of Formula If, or a pharmaceutically acceptable salt thereof: [formation] [In the formula, A is -N (H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R. 2 is C 1 -C 6 alkyl or 3- to 6-membered cycloalkyl, R. 7 is C 1 -C 3 is an alkyl, R. 8 is C 1 -C 3 is an alkyl, and R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl. ].

[0094] In some embodiments of the compounds of the invention, R 1 is optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 6-membered cycloalkenyl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R 1 is optionally substituted 6-membered aryl, optionally substituted 6-membered cycloalkenyl, or optionally substituted 6-membered heteroaryl.

[0095] In some embodiments of the compounds of the invention, R 1 teeth, [formation] or a stereoisomer thereof (eg, an atropisomer). In some embodiments of the compounds of the invention, R 1 teeth [formation] or a stereoisomer thereof (eg, an atropisomer). In some embodiments of the compounds of the invention, R 1 teeth [formation] is.

[0096] In some embodiments, the compounds of the invention have the structure of Formula Ig, or a pharmaceutically acceptable salt thereof: [formation] [In the formula, A is -N (H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; R. 2 is C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl or 3- to 6-membered cycloalkyl, R. 7 is C 1 -C 3 is an alkyl, R. 8 is C 1 -C 3 is an alkyl, and R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, X e and X f is independently N or CH, and R. 12 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl or optionally substituted 3- to 6-membered heterocycloalkylene. ]. In some embodiments of the compounds of the invention, X e is N and X f is CH. In some embodiments, X e is CH and X f is N.

[0097] In some embodiments of the compounds of the invention, R 12 is an arbitrarily permuted C 1 -C 6 is heteroalkyl. In some embodiments, R 12 teeth, [formation] is. In some embodiments, R 12 teeth [formation] is.

[0098] In some embodiments, the compounds of the invention have the structure of Formula VI, or a pharmaceutically acceptable salt thereof: [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol), or optionally It binds to the carbon atom of the 5- to 10-membered heteroarylene substituted with . ] and B does not exist or -CH(R 9 )-, >C=CR 9 R. 9’ , or >CR 9 R. 9’ [Wherein, carbon is -N(R 11 )C(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 It is attached to the carbonyl carbon of the heteroarylene. ] and G is any permuted C 1 -C 4 Alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, -C(O)O-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], -C(O)NH-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], arbitrarily permuted C 1 -C 4 heteroalkylene or 3- to 8-membered heteroarylene, L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, haloacetal, or alkynyl sulfone; X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH and X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 is CH, CH 2 , or N, and Y 6 is C(O), CH, CH 2 , or N, and R. 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl or in combination with the carbon to which they are attached to form a carbonyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is H, F, optionally permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or R. 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R. 9’ is hydrogen or optionally substituted C 1 -C 6 is alkyl, or R. 9 and R 9’ are combined with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, R. 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, R. 10a is hydrogen or halo, R. 11 is hydrogen or C 1 -C 3 is an alkyl, R. 21 is hydrogen or C 1 -C 3 is alkyl (e.g., methyl), and X e and X f is independently N or CH. ].

[0099] In some embodiments, the compounds of the invention have the structure of Formula VIa, or a pharmaceutically acceptable salt thereof: [formation] [Wherein, A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol) , or optionally substituted 5- to 6-membered heteroarylene, B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH and n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, R. 2 is C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl or 3- to 6-membered cycloalkyl, R. 7 is C 1 -C 3 is an alkyl, R. 8 is C 1 -C 3 is an alkyl, and R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, X e and X f is independently N or CH, R. 11 is hydrogen or C 1 -C 3 is an alkyl, and R. 21 is hydrogen or C 1 -C 3 is alkyl. ].

[0100] In some embodiments of the compounds of the invention, X e is N and X f is CH. In some embodiments, X e is CH and X f is N.

[0101] In some embodiments, the compounds of the invention have the structure of Formula VIb, or a pharmaceutically acceptable salt thereof: [formation] [Wherein, A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol) , or optionally substituted 5- to 6-membered heteroarylene, B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or L is absent or is a linker, W is a cross-linking group including vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone. ]. In some embodiments of the compounds of the invention, A is an optionally substituted 6-membered arylene.

[0102] In some embodiments, the compounds of the invention have the structure of formula VIc (corresponding to formula BB in Figures 1A and 1B), or a pharmaceutically acceptable salt thereof: [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol), or optionally It binds to the carbon atom of the 5- to 10-membered heteroarylene substituted with . ] and B does not exist or -CH(R 9 )-, >C=CR 9 R. 9’ , or >CR 9 R. 9’ [Wherein, carbon is -N(R 11 )C(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 It is attached to the carbonyl carbon of the heteroarylene. ] and G is any permuted C 1 -C 4 Alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, -C(O)O-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], -C(O)NH-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], arbitrarily permuted C 1 -C 4 heteroalkylene or 3- to 8-membered heteroarylene, L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, haloacetal, or alkynyl sulfone; X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH and X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 is CH, CH 2 , or N, and Y 6 is C(O), CH, CH 2 , or N, and R. 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl or in combination with the carbon to which they are attached to form a carbonyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is H, F, optionally permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or R. 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R. 9’ is hydrogen or optionally substituted C 1 -C 6 is alkyl, or R. 9 and R 9’are combined with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, R. 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, R. 10a is hydrogen or halo, R. 11 is hydrogen or C 1 -C 3 is an alkyl, and R. 21 is hydrogen or C 1 -C 3 Alkyl (eg, methyl). ].

[0103] In some embodiments, A is the structure [formation] , where R 13 is hydrogen, halo, hydroxy, amino, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl and R 13a is hydrogen or halo. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 and R 13a are each hydrogen. In some embodiments, R 13 is hydroxy, methyl, fluoro, or difluoromethyl.

[0104] In some embodiments, A is an optionally substituted 5-6 membered arylene. In some embodiments, A is [formation] is.

[0105] In some embodiments, A is optionally substituted C 1 -C 4 It is heteroalkylene. In some embodiments, A is [formation] is. In some embodiments, A is an optionally substituted 3-6 membered heterocycloalkylene. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is.

[0106] In some embodiments of the compounds of the invention, B is -CHR 9 -is. In some embodiments, R 9 is H, F, optionally permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl. In some embodiments, R 9 teeth, [formation] is. In some embodiments, R 9 teeth, [formation] is. In some embodiments, R 9 is H, optionally permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl.

[0107] In some embodiments of the compounds of the invention, B is an optionally substituted 6-membered arylene. In some embodiments, B is a 6-membered arylene. In some embodiments, B is [formation] is.

[0108] In some embodiments of the compounds of the invention, R 7 is methyl.

[0109] In some embodiments of the compounds of the invention, R 8 is methyl.

[0110] In some embodiments, R 21 is hydrogen.

[0111] In some embodiments of the compounds of the invention, the linker is the structure of Formula II: A. 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Formula II [In the formula, A 1 is the bond between the linker and B; A 2 is the bond between W and the linker; B 1 , B 2 , B 3 , and B 4 are each independently an arbitrarily permuted C 1 -C 2 Alkylene, optionally substituted C 1 -C 3 heteroalkylene, O, S, and NR N is selected from;R N is hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted C 1 -C 7 is heteroalkyl; C 1 and C 2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; D 1 is an arbitrarily permuted C 1 -C 10 Alkylene, optionally substituted C 2 -C 10 alkenylene, optionally substituted C 2 -C 10 alkynylene, optionally substituted 3-14 membered heterocycloalkylene, optionally substituted 5-10 membered heteroarylene, optionally substituted 3-8 membered cycloalkylene, optionally substituted 6-10 member arylene, optionally substituted C 2 -C 10 polyethylene glycolene or optionally substituted C 1 -C 10 heteroalkylene, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -to-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 is a chemical bond that binds to ]. In some embodiments, the linker is acyclic. In some embodiments, the linker has the structure of Formula IIa: [formation] [In the formula, X a does not exist or is N, and R. 14 is absent, hydrogen, or optionally substituted C 1 -C 6 is an alkyl, and L. 2 does not exist or -SO 2 -, arbitrarily permuted C 1 -C 4 alkylene or optionally substituted C 1 -C 4 heteroalkylene and X a , R 14 , or L 2at least one of ]. In some embodiments, the linker has the structure: [formation]

[0112] In some embodiments, the linker is or includes a cyclic moiety. In some embodiments, the linker has the structure of Formula IIb: [formation] [Where o is 0 or 1, R. 15 is hydrogen or optionally substituted C 1 -C 6 alkyl, optionally substituted 3-8 membered cycloalkylene, or optionally substituted 3-8 membered heterocycloalkylene, X 4 is absent or arbitrarily permuted C 1 -C 4 Alkylene, O, NCH 3 , or any permuted C 1 -C 4 is a heteroalkylene, Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to is a 10-membered heteroarylene, and L. 3 does not exist or -SO 2 -, arbitrarily permuted C 1 -C 4 Alkylene, or optionally substituted C 1 -C 4 It is heteroalkylene. ].

[0113] In some embodiments, the linker has the structure of Formula IIb-1: [formation] [Where o is 0 or 1, R. 15 is hydrogen or optionally substituted C 1 -C 6 alkyl, optionally substituted 3-8 membered cycloalkylene, or optionally substituted 3-8 membered heterocycloalkylene, Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to is a 10-membered heteroarylene, and L. 3 does not exist or -SO 2 -, arbitrarily permuted C 1 -C 4 Alkylene, or optionally substituted C 1 -C 4 It is heteroalkylene. ].

[0114] In some embodiments, the linker has the structure of Formula IIc: [formation] [In the formula, R 15 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene, and R. 15a , R 15b , R 15c , R 15d , R 15e , R 15f , and R 15g is independently hydrogen, halo, hydroxy, cyano, amino, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 is alkoxy; or, R 15b and R 15d are combined with the carbon to which they are attached to form an optionally substituted 3- to 8-membered cycloalkylene or an optionally substituted 3- to 8-membered heterocycloalkylene. ]. In some embodiments, the linker has the structure: [formation] [formation]

[0115] In some embodiments, the linker has the structure: [formation] [formation] [formation] [formation]

[0116] In some embodiments, the linker has the structure [formation] have

[0117] In some embodiments, the linker has the structure [formation] have In some embodiments of the compounds of the invention, W is a cross-linking group comprising a vinyl ketone. In some embodiments, W has the structure of Formula IIIa: [formation] [In the formula, R 16a , R 16b , and R 16c is independently hydrogen, -CN, halogen, or -OH, -O-C 1 -C 3 Alkyl, -NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , or -C optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl 1 -C 3 is alkyl. ]. In some embodiments, W is [formation] is. In some embodiments, W is a bridging group that includes an inone. In some embodiments, W has the structure of Formula IIIb: [formation] [In the formula, R 17 is hydrogen; -OH, -O-C 1 -C 3 Alkyl, -NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 or -C optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl 1 -C 3 alkyl; or 4- to 7-membered saturated heterocycloalkyl. ]. In some embodiments, W is [formation] [formation] is. In some embodiments, W is [formation] is.

[0118] In some embodiments, W is a cross-linking group comprising vinyl sulfone. In some embodiments, W has the structure of Formula IIIc: [formation] [In the formula, R 18a , R 18b , and R 18c is independently hydrogen, -CN, or -OH, -O-C 1 -C 3 Alkyl, -NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2, or -C optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl 1 -C 3 is alkyl. ]. In some embodiments, W is [formation] is. In some embodiments, W is a bridging group comprising an alkynylsulfone. In some embodiments, W has the structure of Formula IIId: [formation] [In the formula, R 19 is hydrogen; -OH, -O-C 1 -C 3 Alkyl, -NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 or -C optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl 1 -C 3 alkyl; or 4- to 7-membered saturated heterocycloalkyl. ]. In some embodiments, W is [formation] is. In some embodiments, W has the structure of Formula IIIe: [formation] [In the formula, X e is a halogen, and R. 20 is hydrogen; -OH, -O-C 1 -C 3 Alkyl, -NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , or -C optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl 1 -C 3 is alkyl. ]. In some embodiments, W is haloacetal. In some embodiments W is not a haloacetal.

[0119] In some embodiments, the compounds of the invention are selected from Table 1, or are pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the compounds of the invention are selected from Table 1, or are pharmaceutically acceptable salts or atropisomers thereof.

[0120] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22] [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28] [Table 1-29] [Table 1-30] [Table 1-31] [Table 1-32] [Table 1-33] [Table 1-34] [Table 1-35] [Table 1-36] [Table 1-37] [Table 1-38] [Table 1-39] [Table 1-40] [Table 1-41] [Table 1-42] [Table 1-43] [Table 1-44] [Table 1-45] [Table 1-46] [Table 1-47] [Table 1-48] [Table 1-49] [Table 1-50] [Table 1-51] [Table 1-52] [Table 1-53] [Table 1-54] [Table 1-55] [Table 1-56] [Table 1-57] [Table 1-58] [Table 1-59] [Table 1-60] [Table 1-61] [Table 1-62] [Table 1-63] [Table 1-64] [Table 1-65] [Table 1-66] [Table 1-67] [Table 1-68] [Table 1-69] [Table 1-70] [Table 1-71] [Table 1-72] [Table 1-73] [Table 1-74] [Table 1-75] [Table 1-76] [Table 1-77] [Table 1-78] [Table 1-79] [Table 1-80] [Table 1-81] [Table 1-82] [Table 1-83] [Table 1-84] [Table 1-85] [Table 1-86] [Table 1-87] [Table 1-88] [Table 1-89] [Table 1-90] [Table 1-91] [Table 1-92] [Table 1-93] [Table 1-94] [Table 1-95] [Table 1-96] [Table 1-97] [Table 1-98] [Table 1-99]

[0121] [Table 1-100] [Table 1-101] [Table 1-102] [Table 1-103] [Table 1-104] [Table 1-105] [Table 1-106] [Table 1-107] [Table 1-108] [Table 1-109] [Table 1-110] [Table 1-111] [Table 1-112] [Table 1-113] [Table 1-114] [Table 1-115] [Table 1-116] [Table 1-117] [Table 1-118] [Table 1-119] [Table 1-120] [Table 1-121] [Table 1-122] [Table 1-123] [Table 1-124] [Table 1-125] [Table 1-126] [Table 1-127] [Table 1-128] [Table 1-129] [Table 1-130] [Table 1-131] [Table 1-132] [Table 1-133] [Table 1-134] [Table 1-135] [Table 1-136] [Table 1-137] [Table 1-138] [Table 1-139] [Table 1-140] [Table 1-141] [Table 1-142] [Table 1-143] [Table 1-144] [Table 1-145] [Table 1-146] [Table 1-147] [Table 1-148] [Table 1-149] [Table 1-150]

[0122] [Table 1-151] [Table 1-152] [Table 1-153] [Table 1-154] [Table 1-155] [Table 1-156] [Table 1-157] [Table 1-158] [Table 1-159] [Table 1-160] [Table 1-161] [Table 1-162] [Table 1-163] [Table 1-164] [Table 1-165] [Table 1-166] [Table 1-167] [Table 1-168] [Table 1-169] [Table 1-170] [Table 1-171] [Table 1-172] [Table 1-173] [Table 1-174] [Table 1-175] [Table 1-176] [Table 1-177] [Table 1-178] [Table 1-179] [Table 1-180] [Table 1-181] [Table 1-182] [Table 1-183] [Table 1-184] [Table 1-185] [Table 1-186]

[0123] In some embodiments, compounds of Table 2, or pharmaceutically acceptable salts thereof, are provided. In some embodiments, the compounds of the invention are selected from Table 2, or are pharmaceutically acceptable salts or atropisomers thereof.

[0124] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18] [Table 2-19] [Table 2-20] [Table 2-21] [Table 2-22] [Table 2-23] [Table 2-24] [Table 2-25] [Table 2-26] [Table 2-27] [Table 2-28] [Table 2-29] [Table 2-30] [Table 2-31] [Table 2-32] [Table 2-33] [Table 2-34] [Table 2-35] [Table 2-36] [Table 2-37] [Table 2-38] [Table 2-39] [Table 2-40] [Table 2-41] [Table 2-42] [Table 2-43] [Table 2-44] [Table 2-45] [Table 2-46] [Table 2-47] [Table 2-48] [Table 2-49] [Table 2-50] [Table 2-51] [Table 2-52] [Table 2-53] [Table 2-54] [Table 2-55] [Table 2-56] [Table 2-57] [Table 2-58] [Table 2-59] [Table 2-60] [Table 2-61] [Table 2-62] [Table 2-63] [Table 2-64] [Table 2-65] [Table 2-66] [Table 2-67] [Table 2-68] [Table 2-69]

[0125] In some embodiments, the compounds of the invention are or act as prodrugs, eg, for administration to a cell or subject in need thereof.

[0126] In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0127] Further provided is a conjugate comprising the structure of Formula IV, or a salt thereof: M-L-P Formula IV [wherein L is a linker, P is a monovalent organic moiety, M has the structure of formula Va. ] [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B does not exist or -CH(R 9 )-, >C=CR 9 R. 9’ , or >CR 9 R. 9’ [Wherein, carbon is -N(R 11 )C(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 It is attached to the carbonyl carbon of the heteroarylene. ] and G is any permuted C 1 -C 4 Alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, -C(O)O-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], -C(O)NH-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], arbitrarily permuted C 1 -C 4 heteroalkylene or 3- to 8-membered heteroarylene, X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH and X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 is CH, CH 2 , or N, and Y 6 is C(O), CH, CH 2 , or N, and R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R. 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl, R. 2is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl or in combination with the carbon to which they are attached to form a carbonyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is H, optionally permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or R. 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R. 9’ is hydrogen or optionally substituted C 1 -C 6 is alkyl, or R. 9 and R 9’ are combined with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, R. 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, R. 10a is hydrogen or halo, and R. 11 is hydrogen or C 1 -C 3 is alkyl. ].

[0128] In some embodiments, the conjugate, or salt thereof, comprises the structure of Formula IV: M-L-P Formula IV [wherein L is a linker, P is a monovalent organic moiety, M has the structure of Formula Vb. ] [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )- or >C=CR 9 R. 9’ [Wherein, carbon is -N(R 11 )C(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 Binds to the carbonyl carbon of the heteroarylene. ] and G is any permuted C 1 -C 4 Alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, -C(O)O-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], -C(O)NH-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], arbitrarily permuted C 1 -C 4 heteroalkylene or 3- to 8-membered heteroarylene, X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH, X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 is CH, CH 2 , or N, and Y 6is C(O), CH, CH 2 , or N, and R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R. 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl, R. 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl or in combination with the carbon to which they are attached to form a carbonyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or R. 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R. 9’ is hydrogen or optionally substituted C 1 -C 6 is an alkyl, R. 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, R. 10a is hydrogen or halo, and R. 11 is hydrogen or C 1 -C 3 is alkyl. ].

[0129] 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, M has the structure of Formula V. ] [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )-[where carbon is -N(R 11 )C(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 It is attached to the carbonyl carbon of the heteroarylene. ] and G is any permuted C 1 -C 4 Alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, -C(O)O-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], -C(O)NH-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], arbitrarily permuted C 1 -C 4 heteroalkylene or 3- to 8-membered heteroarylene, X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH and X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 and Y 6 is independently CH or N, R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R. 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, and R. 11 is hydrogen or C 1 -C 3 is alkyl. ].

[0130] In some embodiments, compounds of the invention have the structure of Formula IV: M-L-P Formula IV [wherein L is a linker, P is a monovalent organic moiety, M has the structure of formula Vd. ] [formation] [Wherein, A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol) , or optionally substituted 5- to 6-membered heteroarylene, B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH and n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, R. 2 is C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl or 3- to 6-membered cycloalkyl, R. 7 is C 1 -C 3 is an alkyl, R. 8 is C 1 -C 3 is an alkyl, and R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, X e and X f is independently N or CH, R. 11 is hydrogen or C 1 -C 3 is an alkyl, and R. 21 is hydrogen or C 1 -C 3 is alkyl. ].

[0131] In some embodiments of the compounds of the invention, X e is N and X f is CH. In some embodiments, X e is CH and X f is N.

[0132] In some embodiments, compounds of the invention have the structure of Formula IV: M-L-P Formula IV [wherein L is a linker, P is a monovalent organic moiety, M has the structure of formula Ve. ] [formation] [Wherein, A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene (e.g., phenyl or phenol) , or optionally substituted 5- to 6-membered heteroarylene, B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl. ].

[0133] In some embodiments of the conjugates of the invention, the linker has the structure of Formula II: A. 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Formula II [In the formula, A 1 is the bond between the linker and B; A 2 is the bond between P and the linker; B 1 , B 2 , B 3 , and B 4 are each independently an arbitrarily permuted C 1 -C 2 Alkylene, optionally substituted C 1 -C 3 heteroalkylene, O, S, and NR N is selected from;R N is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted C 1 -C 7 is heteroalkyl; C 1 and C 2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; D 1 is an arbitrarily permuted C 1 -C 10 Alkylene, optionally substituted C 2 -C 10 alkenylene, optionally substituted C 2 -C 10 alkynylene, optionally substituted 3-14 membered heterocycloalkylene, optionally substituted 5-10 membered heteroarylene, optionally substituted 3-8 membered cycloalkylene, optionally substituted 6-10 member arylene, optionally substituted C 2 -C 10 polyethylene glycolene or optionally substituted C 1 -C 10 heteroalkylene, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -to-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 is a chemical bond that binds to ].

[0134] In some embodiments of the conjugates of the invention, the monovalent organic moiety is a protein, such as Ras protein. In some embodiments, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras proteins are described herein. In some embodiments, the linker is attached to the monovalent organic moiety via attachment to a sulfhydryl group of an amino acid residue of the monovalent organic moiety. In some embodiments, the linker is attached to the monovalent organic moiety via attachment to the carboxyl group of the amino acid residue of the monovalent organic moiety.

[0135] A method of treating cancer in a subject in need of cancer treatment, said method comprising administering to said subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. The above method is further provided, comprising: The cancer can be, for example, pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myelogenous leukemia, multiple myeloma, thyroid cancer, myelodysplastic syndrome, or small squamous follicular carcinoma. In some embodiments, the cancer comprises a Ras mutation, such as K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G12C, N-Ras G12C, or N-Ras G13C. Other Ras mutations are described herein.

[0136] A method of treating a Ras protein-related disease in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable compound thereof. Further provided is the above method comprising administering a salt of

[0137] Further provided is a method of inhibiting Ras protein in a cell, said method comprising contacting said cell with an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. do. For example, the Ras protein is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G13C, N-Ras G12C, or N-Ras G13C. Other Ras proteins are described herein. The cells may be pancreatic cancer cells, colorectal cancer cells, non-small cell lung cancer cells, acute myelogenous leukemia cells, multiple myeloma cells, thyroid cancer cells, myelodysplastic syndrome cells, or small squamous carcinoma follicular cancer cells. Can be cancer cells. Other cancer types are described herein. Cells may be in vivo or in vitro.

[0138] For compounds of the invention, one stereoisomer may show better inhibition than another. For example, one atropisomer may show inhibition while another atropisomer may show little or no inhibition.

[0139] In some embodiments, the methods or uses described herein further comprise administering an additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy is a HER2 inhibitor, 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, or combinations thereof. In some embodiments, the additional anti-cancer therapy is a SHP2 inhibitor. Other additional anti-cancer therapies are described herein.

[0140] synthesis method The compounds described herein can be made from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic processes.

[0141] The compounds of the invention can be prepared by any number of methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods illustrated in the schemes below, along with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. . These methods include, but are not limited to, those described in the schemes below.

[0142] Scheme 1. General Synthesis of Macrocyclic Esters [formation]

[0143] A general synthesis of macrocyclic esters is outlined in Scheme 1. An appropriately substituted aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (1) was converted to a protected 3-(5- Palladium-Mediated Coupling, Alkylation, and Deprotection Starting from Bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol and an Appropriately Substituted Boronic Acid It can be prepared in three steps including reactions.

[0144] Protecting methyl-amino-hexahydropyridazine-3-carboxylate-boronic ester (2), iridium-catalyzed boration, and methylmethyl (S)-hexahydropyridazine-3-carboxylate containing 3 It can be prepared in a process.

[0145] Coupling of methyl-L-valinate with a protected (S)-pyrrolidine-3-carboxylic acid, followed by deprotection, coupling with a carboxylic acid containing an appropriately substituted Michael acceptor, and hydrolysis. A decomposition step can produce the appropriately substituted acetylpyrrolidine-3-carbonyl-N-methyl-L-valine (or alternative amino acid derivative (4)).

[0146] Methyl-amino-hexahydropyridazine-3-carboxylate-boronic ester (2) with aryl-3-(5-bromo-1-ethyl-1H-indol-3-yl)- in the presence of Pd catalyst Coupling of 2,2-dimethylpropan-1-ol (1), followed by hydrolysis and macrolactonization steps to produce the final macrocyclic ester and appropriately protected macrocyclic intermediate (5) can be done. Deprotection and coupling with an appropriately substituted intermediate 4 gives the macrocyclic product. Additional deprotection and / or functionalization steps may be required to produce the final compound.

[0147] Scheme 2. Alternative General Synthesis of Macrocyclic Esters [formation]

[0148] Alternatively, macrocyclic esters can be prepared as described in Scheme 2. A suitably protected bromo-indolyl (6) is coupled with a boronate ester (3) in the presence of a Pd catalyst, followed by iodination, deprotection and ester hydrolysis. Coupling with methyl (S)-hexahydropyridazine-3-carboxylate, followed by hydrolysis and macrolactonization can give iodo intermediates (7). Coupling with an appropriately substituted boronic ester and alkylation in the presence of a Pd catalyst can provide the fully protected macrocycle (5). Additional deprotection or functionalization steps are required to make the final compound.

[0149] Additionally, the compounds of the present disclosure can be synthesized using the methods described in the Examples below, along with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. . These methods include, but are not limited to, those described in the examples below. For example, one of ordinary skill in the art will be able to convert macrocyclic esters to the desired -B-L-W groups of compounds of formula (I) [where B, L, and W is as defined herein. ] could be introduced.

[0150] The compounds in Table 1 herein were prepared using the methods disclosed herein or, in combination with the knowledge of one of skill in the art, were prepared using the methods disclosed herein. The compounds in Table 2 can be prepared using the methods disclosed herein, or combined with the knowledge of one of skill in the art, can be prepared using the methods disclosed herein.

[0151] Scheme 3. General Synthesis of Macrocyclic Esters [formation]

[0152] An alternative general synthesis of macrocyclic esters is outlined in Scheme 3. An appropriately substituted indolyl boronic ester (8) is treated with protected 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropan-1-ol and an appropriate It can be prepared in four steps, starting from a boronic acid substituted with , including palladium-mediated coupling, alkylation, deprotection, and palladium-mediated borylation.

[0153] Coupling of (S)-2-amino-3-(4-bromothiazol-2-yl)propanoic acid (9) with methyl (S)-hexahydropyridazine-3-carboxylate gives methyl-amino- 3-(4-bromothiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (10) can be prepared.

[0154] Methyl-amino-3-(4-bromothiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (10) and appropriately substituted indolylboronic esters (8) in the presence of a Pd catalyst. ), followed by hydrolysis and macrolactonization steps to produce the final macrocyclic ester, affording the appropriately protected macrocyclic intermediate (11). Deprotection and coupling with an appropriately substituted intermediate 4 can afford the macrocyclic products. Additional deprotection or functionalization steps may be required to make final compounds 13 or 14.

[0155] Scheme 4. General Synthesis of Macrocyclic Esters [formation]

[0156] An alternative general synthesis of macrocyclic esters is described in Scheme 4. Appropriately substituted morpholines, or alternative herecyclic intermediates (15), can be coupled with appropriately protected intermediates 1 by palladium-mediated coupling. Subsequent ester hydrolysis and coupling with a piperazine ester provides intermediate 16.

[0157] Macrocyclic esters can be made by hydrolysis, deprotection, and macrocyclization sequences. Subsequent deprotection and coupling with intermediate 4 (or an analogue) affords the appropriately substituted final macrocyclic product. Additional deprotection or functionalization steps may be required to make the final compound 17.

[0158] Scheme 5. Common no macrocyclic esters [formation]

[0159] An alternative general synthesis of macrocyclic esters is described in Scheme 5. Starting from appropriately protected boronate ester 18 and bromoindolyl intermediate (19), including palladium-mediated coupling, hydrolysis, coupling with piperazine ester, hydrolysis, deprotection, and macrocyclization steps. can be used to prepare the appropriately substituted macrocycle (20). Subsequent coupling with an appropriately substituted protected amino acid, followed by palladium-mediated coupling provides intermediate 21. Additional deprotection and derivatization steps, including alkylation, may be required at this point.

[0160] The final macrocyclic ester can be made by coupling intermediate (22) with an appropriately substituted carboxylic acid intermediate (23). Additional deprotection or functionalization steps may be required to make the final compound (24).

[0161] Additionally, the compounds of the present disclosure can be synthesized using the methods described in the Examples below, along with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. . These methods include, but are not limited to, those described in the examples below. For example, one of ordinary skill in the art will be able to convert macrocyclic esters to the desired -B-L-W groups of compounds of formula (I) [where B, L, and W is as defined herein. ] could be introduced.

[0162] Pharmaceutical composition and method of use Pharmaceutical compositions and administration methods Compounds with which the present invention is concerned are RAS inhibitors and are useful in cancer therapy. Accordingly, one embodiment of the invention is a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, as well as a compound of the invention. Methods of preparing such compositions are provided.

[0163] As used herein, the term "pharmaceutical composition" means a compound, such as a compound of the invention, or a pharmaceutically acceptable salt thereof, formulated with pharmaceutically acceptable excipients. do.

[0164] In some embodiments, the compound is in a pharmaceutical composition in a unit dose suitable for administration in a therapeutic regimen that exhibits a statistically significant probability of achieving a given therapeutic effect when administered to a relevant population. exist. In some embodiments, the pharmaceutical compositions are: oral administration, e.g., oral medications (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and targeted for systemic absorption; Pills, powders, granules, pastes for application to the tongue; e.g. parenterally, e.g. by subcutaneous, intramuscular, intravenous or epidural injection as sterile solutions or suspensions or as sustained release formulations administration; topical application, e.g., as creams, ointments, or time-release patches, or sprays applied to the skin, lungs, or mouth; intravaginal or rectal e.g., as pessaries, creams, or foams; sublingual intraocular; transdermal; or nasal, pulmonary, and other mucosal surfaces.

[0165] As used herein, a "pharmaceutically acceptable excipient" is any inert ingredient that has the property of being toxic and non-inflammatory in a subject (e.g. suspending or dissolvable vehicle). Typical excipients include, for example, anti-adhesives, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents). , film formers or coating agents, flavors, fragrances, lubricants (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water of hydration. . Excipients include optionally substituted butylated hydroxyl toluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, Gelatin, optionally substituted hydroxylpropylcellulose, optionally substituted hydroxylpropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, alpha. Modified starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A. , vitamin E, vitamin C, and xylitol. Those of skill in the art are familiar with various agents and materials that are useful as excipients. 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. See Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. In some embodiments the composition comprises at least two different pharmaceutically acceptable excipients.

[0166] The compounds described herein are provided or utilized in salt form, e.g., pharmaceutically acceptable salt forms, whether expressly stated or not, unless expressly stated to the contrary. be able to. As used herein, the term “pharmaceutically acceptable salt” refers to a salt that is capable of producing human and Those salts of the compounds described herein are meant to be suitable for use in contact with other animal tissues, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G. Wermuth), Wiley -VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.

[0167] The compounds of the invention may have ionic groups so as to allow them to be prepared as pharmaceutically acceptable salts. These salts can be acid addition salts with inorganic or organic acids, or salts, in the case of the acid forms of the compounds of the invention, can be prepared from inorganic or organic bases. In some embodiments, compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid or tartaric acid to form acid addition salts and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine to form basic salts Suitable pharmaceutically acceptable acids and bases, such as , various amines, and the like, are well known in the art. Methods for preparing suitable salts are well established in the art.

[0168] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate. , camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexane acid, hydrobromide, hydrochloride, hydroiodide, 2-(optionally substituted) hydroxyl-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, apple acid, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, peroxide Sulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecane acid salts, valerates, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc., as well as nontoxic ammonium, quaternary ammonium, and amine cations (ammonium, tetramethylammonium, tetraethylammonium, methylamine , dimethylamine, trimethylamine, triethylamine, ethylamine, etc.).

[0169] As used herein, the term "subject" means any element in the animal kingdom. In some embodiments, "subject" refers to humans, at any stage of development. In some embodiments, "subject" refers to a human patient. In some embodiments, "subject" refers to non-human animals. In some embodiments, the non-human animal is a mammal (eg, rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, or pig). In some embodiments, subjects include, but are not limited to, mammals, birds, reptiles, amphibians, fish, or worms. In some embodiments, the subject can be a transgenic animal, transgenic animal, or clone.

[0170] As used herein, the term "dosage form" means a physically discrete unit of compound (eg, compound of the invention) for administration to a subject. Each unit contains a predetermined amount of compound. In some embodiments, such amounts are according to a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., a therapeutic dosing regimen used) is a unit dose (or a whole fraction thereof) suitable for administration. Those skilled in the art will appreciate that the total amount of therapeutic composition or compound administered to a particular subject will be determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0171] As used herein, the term "dosing regimen" refers to a collection of unit doses (usually two or more) administered individually to a subject, usually separated by periods of time. In some embodiments, a given therapeutic compound (eg, a compound of the invention) has a recommended dosing regimen, which may have one or more doses. In some embodiments, the dosing regimen comprises multiple doses, each of which is separated from each other by periods of time of equal length; Including at least two different time periods separating the doses. In some embodiments, all doses within a dosing regimen are the same unit dose. In some embodiments, different doses within a dosing regimen are different amounts. In some embodiments, the dosing regimen comprises a first dose at a first dose, followed by one or more additional doses at a second dose different from the first dose. In some embodiments, the dosing regimen comprises a first dose at a first dose, followed by one or more additional doses at a second dose that is the same as the first dose. In some embodiments, the dosing regimen correlates with desired or beneficial outcomes when administered across relevant populations (ie, is a therapeutic dosing regimen).

[0172] By "therapeutic regimen" is meant an administration regimen in which administration across a relevant population correlates with a desired or beneficial therapeutic outcome.

[0173] The term “treatment” (also “treating” or “treating”), in its broadest sense, means partially or completely relieving, alleviating, alleviating, inhibiting, partially or completely relieving, alleviating, alleviating, inhibiting, partially or completely delay the onset of any disease, disorder or condition, partially or completely reduce the severity of the specified disease, disorder or condition, or reduce one or more of the specified disease, disorder or condition Any administration of a substance (eg, a compound of the invention) that partially or completely reduces the occurrence of a symptom, characteristic, or cause is meant. In some embodiments, such treatment may be administered to subjects who show no signs of the relevant disease, disorder or condition, or who show only early signs of the disease, disorder or condition. Alternatively, or additionally, in some embodiments, such treatment can be administered to treat subjects exhibiting established symptoms of one or more of the relevant diseases, disorders, or conditions. . In some embodiments, treatment may be in subjects diagnosed as suffering from a related disease, disorder or condition. In some embodiments, treatment is in subjects known to have one or more susceptibility factors that are statistically correlated with an increased risk of progression of the relevant disease, disorder or condition. good.

[0174] The term "therapeutically effective amount" means that, when administered to a population afflicted with or suspected of having a disease, disorder or condition, according to a therapeutic administration regimen, the disease, disorder or condition is treated. means an amount sufficient to In some embodiments, a therapeutically effective amount reduces the occurrence or severity of one or more symptoms of a disease, disorder or condition, or initiates one or more symptoms of a disease, disorder or condition. This is the amount to delay. Those skilled in the art will appreciate that the term "therapeutically effective amount" does not actually require that therapeutic success be achieved in a particular individual. Rather, a therapeutically effective amount can be an amount that, when administered to a subject in need of such treatment, produces a particular desired pharmacological response in a significant number of subjects. It is specifically understood that certain subjects may in fact be "refractory" to a "therapeutically effective amount." In some embodiments, references to a therapeutically effective amount refer to one or more specific tissues (e.g., tissues affected by a disease, disorder, or medical condition), or fluids (e.g., blood, saliva, serum, It can be a reference to a quantity measured in sweat, tears, urine). Those skilled in the art will appreciate that in some embodiments, a therapeutically effective amount can be formulated or administered in a single dose. In some embodiments, a therapeutically effective amount can be formulated or administered in multiple doses, eg, as part of an administration regimen.

[0175] For use as therapy in a subject, the compounds of the invention, or pharmaceutically acceptable salts thereof, can be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the method of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or therapy, the compound, or a pharmaceutically acceptable salt thereof, may be administered in a manner consistent with these parameters. It is formulated in A summary of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference. built in.

[0176] The compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical composition contains about 0.1% to about 99%, about 5% to about 90%, or about 1% It can contain up to about 20% (% by weight or volume) of a compound of the invention, or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, combined are present in an amount of 1-95% of the total weight of the composition, such as a pharmaceutical composition. can be done.

[0177] The compositions may be intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, intravaginal, intravesical, intraurethral, ​​intrathecal, It can be provided in a dosage form suitable for epidural, aural, or intraocular administration, injection, inhalation, or direct contact with nasal, urogenital, genital, or oral mucosa. Thus, pharmaceutical compositions include, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drinkables, osmotic delivery devices, suppositories, enemas. It can be in the form of a drug, an injectable solution, an implant, a spray, a preparation suitable for iontophoretic delivery, or an aerosol. The composition can be formulated according to conventional pharmaceutical practice.

[0178] As used herein, the term "administration" means administration of a composition (eg, a compound or preparation comprising a compound described herein) to a subject or system. Administration to animal subjects (eg, humans) may be by any suitable route. For example, in some embodiments, administration is bronchial (including bronchial instillation), buccal, enteral, interdermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal. Intrathecal, intravenous, intraventricular, mucosal, intranasal, oral, rectal, subcutaneous, sublingual, topical, intratracheal (including intratracheal instillation), transdermal, intravaginal, or intravitreal can be done.

[0179] Formulations may be prepared in a manner suitable for systemic administration or topical or local 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 generally include diluents and, optionally, adjuvants, buffers, preservatives, and the like. The compounds, or pharmaceutically acceptable salts thereof, can also be administered in liposomal compositions or as microemulsions.

[0180] For injection, formulations can be prepared in conventional forms, either as liquid solutions or suspensions, 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. Such compositions can also contain amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as sodium acetate, sorbitan monolaurate, and the like.

[0181] Various sustained release systems for drugs have also been devised. See, for example, US Pat. No. 5,624,677.

[0182] Systemic administration can also include relatively non-invasive methods such as the use of suppositories, transdermal patches, transmucosal delivery, and nasal administration. Oral administration is also preferred for the compounds of this invention, or pharmaceutically acceptable salts thereof. Suitable forms include syrups, capsules and tablets as is understood in the art.

[0183] 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 and second agents of a combination therapy can be formulated together or separately. Other modalities of combination therapy are described herein.

[0184] Individually or individually formulated agents can be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, and the like. Kits can include any component that aids in administering a unit dose to a subject, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, and the like. In addition, the unit dose kit can contain instructions for preparing or administering the composition. A kit may include a single-use unit dose for a given subject, a specific subject (at a constant concentration or in which the potency of an individual compound, or pharmaceutically acceptable salt thereof, varies as treatment progresses). It may be manufactured for multiple uses or a kit may contain multiple doses (bulk packaging) suitable for administration to multiple subjects. Kit components can be assembled into cartons, blister packs, bottles, tubes, and the like.

[0185] Formulations for oral use include tablets containing the active ingredient(s) in admixture with non-toxic pharmaceutically acceptable excipients. These excipients are, for example, inert diluents or fillers such as sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate , or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives, including microcrystalline cellulose, starches, including potato starch, croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose). , glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, optionally substituted hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone , or polyethylene glycol); and lubricating agents, lubricants, and anti-adhesive agents such as magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oils, or talc. Other pharmaceutically acceptable excipients can be coloring agents, flavoring agents, plasticizers, wetting agents, buffering agents, and the like.

[0186] Two or more compounds can be mixed or separated in a tablet, capsule, or other vehicle. In one example, a first compound is contained on the inside of the tablet, a second compound is present on the outside, and a substantial portion of the second compound is released prior to release of the first compound.

[0187] Formulations for oral use may be presented as chewable tablets or hard tablets 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. They are also presented as gelatin capsules or as soft gelatin capsules in which the active ingredient can be mixed with a water or oil broth, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets can be prepared using the above-described ingredients in tablets and capsules in a conventional manner, for example, using mixers, fluid bed equipment, or spray drying equipment.

[0188] Dissolution- or diffusion-controlled release can be achieved by appropriate coating of tablets, capsules, pellets, or granules of the compound, or by incorporating the compound, or a pharmaceutically acceptable salt thereof, into an appropriate matrix. . The sustained release coating can be a coating material as described above or, for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethyl cellulose, acrylic. Resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-(optionally substituted) hydroxyl methacrylate, methacrylate hydrogel, 1,3-butylene It can include one or more of glycol, ethylene glycol methacrylate, or polyethylene glycol. In sustained-release matrix preparations, matrix materials 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 may also be mentioned.

[0189] The liquid forms in which the compounds of this invention, or pharmaceutically acceptable salts thereof, and compositions can be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils, such as cottonseed, sesame, coconut, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0190] Generally, when administered to humans, oral dosages of the compounds of the invention, or any of their pharmaceutically acceptable salts, depend on the properties of the compound and can be readily determined by one skilled in the art. The dose is, for example, about 0.001 mg to about 2000 mg / day, about 1 mg to about 1000 mg / day, about 5 mg to about 500 mg / day, about 100 mg to about 1500 mg / day, about 500 mg to about 1500 mg / day, about 500 mg to about 2000 mg. / day, or any range variable of these.

[0191] In some embodiments, the pharmaceutical composition can further comprise additional compounds with antiproliferative activity. Depending on the method of administration, the compounds, or pharmaceutically acceptable salts thereof, are formulated into suitable compositions to enable easy delivery. Each compound of the combination therapy, or a pharmaceutically acceptable salt thereof, can be formulated in various ways known in the art. For example, the first and second agents of a combination therapy can be formulated together or separately. Desirably, the first and second agents are formulated together for simultaneous or near simultaneous administration of the agents.

[0192] The compounds and pharmaceutical compositions of the present invention can be formulated and utilized in combination therapy, i.e., the compounds and pharmaceutical compositions can be administered simultaneously with one or more other desired therapeutic agents or medical manipulations prior to these treatments. It will be appreciated that it can be formulated or administered at or after these. The particular combination of therapies (therapeutic agents or procedures) using a combination regimen takes into consideration the compatibility of the desired therapeutic agents or procedures and the desired therapeutic effect to be achieved. Further, it will be appreciated that the therapies used may achieve the desired effect for the same disease or may achieve different effects (eg control of any adverse effects).

[0193] As described herein, administration of each agent in combination therapy can independently be from 1 to 4 times daily for 1 day to 1 year, and also for the lifetime of the subject. There may be. Chronic long-term administration may be indicated.

[0194] how to use In some embodiments, the present invention discloses methods of treating diseases or disorders characterized by ectopic Ras activity caused by Ras mutants. In some embodiments, the disease or disorder is cancer.

[0195] Accordingly, a method of treating cancer in a subject in need of cancer treatment, said method comprising administering to said subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof , or administering a pharmaceutical composition comprising such a compound or salt. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer cancer, cancer of unknown primary origin, endometrial cancer, esophageal cancer, GI neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer. In some embodiments, the cancer is appendiceal cancer, endometrial cancer, or melanoma. A method of treating a Ras protein-related disease in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable compound thereof. Also provided are the above methods comprising administering a salt of the compound or salt, or a pharmaceutical composition comprising such a compound or salt.

[0196] In some embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods provided herein are used for the treatment of lung cancer, prostate cancer, e.g. It can be used to treat a wide variety of cancers, including tumors such as cancer, breast cancer, brain cancer, skin cancer, cervical cancer, and testicular cancer. More specifically, cancers treatable by the compounds or salts thereof, pharmaceutical compositions containing such compounds or salts, and the methods of the present invention include astrocyte, breast, cervical, colorectal, and uterine cancers. Tumor types include, but are not limited to, body, esophagus, stomach, head and neck, hepatocyte, laryngeal, lung, pharynx, ovary, prostate, and thyroid carcinoma and sarcoma. Other cancers include, for example: Cardiac, such as non-epithelial malignancies (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 (bronchial) carcinoma, bronchial adenoma, non-epithelial malignant tumor, lymphoma, cartilaginous hamartoma, mesothelioma; Gastrointestinal, e.g., esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (epithelial malignant tumor, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet cell tumor, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, VIP-producing tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma) , hamartoma, leiomyoma); Genitourinary organs such as kidney (adenocarcinoma, Wilms tumor, (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, non-epithelial malignant tumor), testicle (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, non-epithelial malignant tumor, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver, e.g. liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract, e.g. gallbladder cancer, ampullary cancer, cholangiocarcinoma; Bone, such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular sarcoma), multiple myeloma, malignant giant cell tumor chordoma, bone osteochronfroma (osteochondral exostosis), benign cartilage tumors, chondroblastoma, chondromyxofibroma, osteoid, and giant cell tumors; Nervous system, e.g. skull (osteoma, hemangioma, granuloma, xanthoma, osteitis osteoarthritis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytic tumor, medulloblastoma, glioma, ependymoma, germinoma (pineocytoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord neurofibroma, neurofibromatosis type I, meningioma, glioma, non-epithelial malignancy); Gynecology, e.g. uterus (endometrial cancer, uterine cancer, endometrial endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovary (ovarian cancer ( cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable carcinoma), granulosa-capsular cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, epithelial internal carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphylococcal sarcoma (embryonal rhabdomyosarcoma), fallopian tube (epithelial malignant tumor); Hematology, e.g. hematologic (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non Hodgkin's lymphoma (malignant lymphoma); Skin, such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, mole dysplasia nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; Adrenal, eg, neuroblastoma.

[0197] In some embodiments, the Ras protein is wild-type (Ras WT ). Thus, in some embodiments, the compounds of the invention are Ras WT (e.g. K-Ras WT , H-Ras WT , or N-Ras WT ) in methods of treatment of patients with cancer, including In some embodiments, the Ras protein is Ras amplification (e.g., K-Ras amp ). Thus, in some embodiments, the compounds of the invention are Ras amp (K-Ras amp , H-Ras amp , or N-Ras amp ) in methods of treatment of patients with cancer, including In some embodiments, the cancer comprises a Ras mutation, such as the Ras mutations described herein. In some embodiments, mutations are selected from: (a) the following K-Ras variants: 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 variants: 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 variants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K , E49K, T50I, A146V, or A59T, and combinations thereof; Or any combination of the above. 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 more than one Ras mutant. For example, a compound can inhibit both K-Ras G12C and K-Ras G13C. Compounds can inhibit both N-Ras G12C and K-Ras G12C. In some embodiments, compounds can inhibit both K-Ras G12C and K-Ras G12D. In some embodiments, compounds can inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, compounds can inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, the compounds of the present invention have Ras WT (e.g., K, H, or N-Ras WT and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G 12L , or G13V; K, H, or N-Ras WT and H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G 12N , or G12R; or K, H, or N-Ras WT 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, A1 46V , or A59T). In some embodiments, the compounds of the present invention have Ras amp (e.g., K, H, or N-Ras amp and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G 12L , or G13V; K, H, or N-Ras amp and H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G 12N , or G12R; or K, H, or N-Ras amp and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A1 46V , or A59T).

[0198] Methods for detecting Ras mutations are known in the art. Such means include direct sequencing and TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; include but are not limited to: See also WO2020 / 106640 for example.

[0199] 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-Ras amp is. The compound is similarly Ras WT (e.g., K-, H-, or N-Ras WT ), or Ras amp (e.g., K-, H-, or N-Ras amp ).

[0200] In some embodiments, the cancer is Ras mutation and STK11 LOF , contains KEAP1, EPHA5, or NF1 mutations. 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 K-Ras G12C mutation and STK11 LOF Contains mutations. In some embodiments, the cancer is non-small cell lung cancer and K-Ras G12C mutation and STK11 LOF Contains mutations. In some embodiments, the cancer is a K-Ras G13C Ras mutation and STK11 LOF , contains KEAP1, EPHA5, or NF1 mutations. 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 G12C or 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, ovarian cancer, cholangiocarcinoma, or myxappendicular 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, the compound may also be Ras WT (e.g., K-, H-, or N-Ras WT ), or Ras amp (e.g., K-, H-, or N-Ras amp ).

[0201] Also provided is a method of inhibiting Ras protein in a cell, said method comprising contacting said cell with an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. do. A method of inhibiting RAF-Ras binding is provided, said method comprising contacting said cell with an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. A cell can be a cancer cell. Cancer cells may be of any type of cancer described herein. Cells may be in vivo or in vitro.

[0202] Combination therapy Methods of the invention can include compounds of the invention used alone or in combination with one or more additional therapies (eg, non-drug treatments or therapeutic agents). The dosage of one or more additional therapies (eg, non-drug therapies or therapeutic agents) can be reduced from the standard dosage when administered alone. For example, doses can be determined empirically from drug combinations and permutations or estimated by isobolographic analysis (eg, Black et al., Neurology 65:S3-S6 (2005)).

[0203] A compound of the invention may be administered before, after, or concurrently with one or more such additional therapies. When combined, the dosage of a compound of the invention and the dosage of one or more additional therapies (e.g., non-drug therapeutics or therapeutic agents) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect) do. A compound of the present invention and an additional therapy, such as an anticancer agent, can be administered together in a single pharmaceutical composition or separately, and when administered separately, can be administered simultaneously or sequentially. Such sequential administration may be at short or long intervals between administrations.

[0204] In some embodiments, the additional therapy is administration of side effect limiting agents (eg, agents intended to reduce the incidence or severity of side effects of treatment). For example, in some embodiments, compounds of the present invention can also be used in combination with therapeutic agents to treat nausea. Examples of drugs that can be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0205] In some embodiments, the one or more additional therapies include non-drug therapy (eg, surgery or radiation therapy). In some embodiments, the one or more additional therapies are therapeutic agents (e.g., compounds that are antiangiogenic agents, signal transduction inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors or biologics). In some embodiments, the one or more additional therapies include non-drug treatments (e.g., surgery or radiation therapy) and therapeutic agents (e.g., anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolytic agents). inhibitors, or compounds or biologics that are inhibitors of autophagy). In other embodiments, the one or more additional therapies comprises two therapeutic agents. In still other embodiments, the one or more additional therapies comprises three therapeutic agents. In some embodiments, the one or more additional therapies comprise four or more therapeutic agents.

[0206] In this combination therapy section, all references to listed agents are incorporated by reference, whether or not explicitly stated.

[0207] non-drug therapy Examples of non-drug therapies include, but are not limited to, radiation therapy, cryotherapy, hyperthermia therapy, surgery (eg, surgical resection of tumor tissue), and T cell adoptive transfer (ACT) therapy.

[0208] In some embodiments, the compounds of the invention may be used as adjuvant therapy after surgery. In some embodiments, the compounds of the invention can be used as neoadjuvant therapy prior to surgery.

[0209] Radiation therapy can be used to inhibit abnormal cell proliferation or to treat hyperproliferative disorders such as cancer in a subject, such as 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 external beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, total body radiation therapy, Radiation therapy and permanent or temporary interstitial brachytherapy include, but are not limited to. As used herein, the term "brachytherapy" is delivered by spatially confined radioactive material inserted into the body at or near the site of a tumor or other proliferative tissue disease. Refers to radiation therapy. The term includes, but is not limited to, radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi- 212, P-32, and radioactive isotopes of Lu). Radiation sources suitable for use as cell conditioning agents of the present invention include both solids and liquids. As non-limiting examples, the radiation source can be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or photons, beta particles, It can be gamma rays, or other radionuclides that emit a therapeutic beam. The radioactive substance can also be a fluid made from any solution of radionuclide(s), such as a solution of I-125 or I-131, or a radioactive fluid such as Au-198 or Y-90. can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides of . Additionally, the radionuclide(s) can be embodied in gels or radioactive microspheres.

[0210] In some embodiments, the compounds of the present invention can render abnormal cells more sensitive to radiation therapy intended to kill such cells or inhibit their proliferation. Accordingly, the present invention further relates to a method of sensitizing abnormal cells in a mammal to radiotherapy, comprising administering an effective amount of a compound of the present invention to sensitize the abnormal cells to radiotherapy. to the mammal. The amount of compound in this method can be determined according to the means for ascertaining effective amounts of such compound described herein. In some embodiments, the compounds of the invention may be used as adjuvant therapy after radiation therapy or as neoadjuvant therapy before radiation therapy.

[0211] In some embodiments, the non-drug therapy is T cell adoptive transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. T cells can be engineered 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 the subject prior to expansion and genetic modification of the T cells. T cells can be obtained from several sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymic tissue, tissue from sites of infection, ascites, pleural effusion, splenic tissue, and tumors. Any number of T cell lines available in the art may be used in certain embodiments of the invention. In some embodiments, the T cells are autologous T cells. Whether before or after genetic modification of the T cell to express a desired protein (e.g., CAR), the T cell is generally treated with, for example, U.S. Pat. No. 5,858,358, No. 6,887,466, No. 6,905,681, No. 7,144,575, No. 7,067,318, No. 7,172,869, No. 7,232,566, No. 7,175,843, No. 7,572,631, No. 5,883,223 Nos. 6,905,874, 6,797,514, and 6,867,041 can be used to activate and propagate.

[0212] therapeutic agent A therapeutic agent can be a compound used to treat cancer or a condition associated therewith.

[0213] For example, the therapeutic agent can be a steroid. Accordingly, in some embodiments the one or more additional therapies comprise steroids. Suitable steroids include 21-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortibazole, deflazacort, desonide, desoxymethasone, dexamethasone, diflorazone, diflucortolone, difprednate, enoxolone, fluazacort, fluchloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, flucortin butyl, flucortolone, fluorometholone, fluperorone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide , fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halomethasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, predonicarbate, prednisolone, prednisolone 25-diethylamino May include, but are not limited to, acetate, prednisolone sodium phosphate, prednisone, prednibal, prednylidene, rimexolone, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexaacetonide, and salts or derivatives thereof. .

[0214] Further examples of therapeutic agents that can be used in combination therapy with the compounds of the present invention include compounds described in the following patents: U.S. Pat. 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885; 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.

[0215] A therapeutic agent can be a biologic (eg, a cytokine (eg, an interleukin such as interferon or IL-2)) used to treat cancer or a condition associated therewith. In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof). , which inflict pain on targets to stimulate anticancer responses or antagonize antigens important to cancer. Also included are antibody-drug conjugates.

[0216] A 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). Antibodies can be, for example, humanized or fully human antibodies. In some embodiments, the checkpoint inhibitor is a fusion protein, eg, an Fc receptor fusion protein. In some embodiments, a 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 checkpoint protein ligand. In some embodiments, the checkpoint inhibitor is an inhibitor (eg, an inhibitory antibody or small molecule inhibitor) of CTLA-4 (eg, an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PD-1 (eg, an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PDL-1 (eg, an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (eg, inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL-2 (eg, 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 -7 family ligands, or combinations thereof, inhibitors or antagonists (eg, inhibitory antibodies or small molecule inhibitors). In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibodies such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ) , BGB-A317 (BeiGene & Celgene), or the checkpoint inhibitors disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol. , BMS936559, MEDl4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lililumab, IPH2101, 1-7F9, and KW-6002.

[0217] The therapeutic agent may be an anti-TIGIT antibody such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0218] A therapeutic agent is an agent that treats cancer or a condition associated therewith (e.g., a cytotoxic agent, a non-peptide small molecule, or other compound useful in the treatment of cancer or a condition associated therewith, collectively "anti-cancer"). drug”). Anti-cancer agents can be, for example, chemotherapeutic agents or targeted therapeutic agents.

[0219] Anticancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folate-like pyrimidine analogues, purine analogues and related inhibitors, vinca alkaloids, epipodopyrotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives , adrenocorticolytic agents, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogues. Additional anticancer agents include leucovorin (LV), ilenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, the one or more additional therapies comprise two or more anticancer agents. Two or more anticancer agents can be used in cocktails that are administered in combination or separately. Suitable dosing regimens for combination anticancer agents are known in the art, see, for example, Saltz et al., Proc.Am.Soc.Clin.Oncol.18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0220] Other non-limiting examples of anticancer agents include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); ® (gefitinib); alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocone, metledopa, and uredopa; imines and methylamelamines, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamines; acetogenins (particularly bratacin and bratacinone); camptothecins (eg, the synthetic analogue topotecan) bryostatin; callistatin; CC-1065 (e.g. its adzelesin, carzelesin, and baizelesin synthetic analogues); cryptophycins (specifically cryptophycin 1 and cryptophycin 8); dolastatin; analogues KW-2189 and CB1-TM1); eruterobin; pancratistatin; sarcodictin A; spongistatin; tamine oxide hydrochloride, melphalan, novenbitine, phenesterine, prednimustine, trophosfamide, and uracil mustard; nitrosoureas, such as camulustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, such as enzyne antibiotics ( For example, calicheamicins, such as calicheamicin gamma ll and calicheamicin omega ll (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicins such as dynemicin A; clodronate; bisphosphonates such as; esperamicin; neocardinostatin chromophore and related chromoprotein enediyne antibiotic chromophore, aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, Caminomycin, carminomycin, cardinophylline, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino - mitomycins such as doxorubicin, deoxydoxorubicin, epirubicin, ethorubicin, idarubicin, marcellomycin, mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potofilomycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, pteropterin, trimetrexate; purines such as fludarabine, 6-mercaptopurine, thiamipurine, thioguanine analogues; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; aminoglutethimi anti-adrenal agents such as de, mitotane, trilostane; folic acid replacement fluids such as floric acid; acegratone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; epothilones such as epothilone B; etogluside; gallium nitrate; hydroxyurea; lentinan; maytansinoids such as lonidaine, maytansine and ansamitocin; Fenameth; Pirarubicin; Losoxantrone; Podophyllic Acid; 2-Ethylhydrazide; Procarbazine; 2′,2″-trichlorotriethylamine; trichothecenes such as T-2 toxin, veraculin A, roridin A, and anguidine; urethane; vindesine; dacarbazine; -C"); cyclophosphamide; thiotepa; taxoids such as Taxol® (paclitaxel), Abraxane® (chromophore-free, albumin-engineered nanoparticulate formulation of paclitaxel), and Taxotere® ) (doxetaxel); chlorambucil; tamoxifen (Nolvadex™); raloxifene; aromatase inhibitor 4(5)-imidazole; )); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar® gemcitabine; 6-thioguanine; 16); Ifosfamide; Mitoxantrone; Vincristine; Navelbine® (vinorelbine); Novantrone; Teniposide; retinoids such as retinoic acid; esperamicin; capecitabine (eg, Xeloda®); and pharmaceutically acceptable salts of any of the above.

[0221] Additional non-limiting examples of anticancer agents include Trastuzumab (Herceptin®), Bevacizumab (Avastin®), Cetuximab (Erbitux®), Rituximab (Rituxan®) , Taxol®, Arimidex®, ABVD, avidin, avagovomab, acridinecarboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alalazine, albocidib, 3-aminopyridine-2- carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agents (e.g., cell cycle non-specific antineoplastic agents, and other antineoplastic agents described herein), antineoplastic Herbs, apaziquone, atiprimod, azathioprine, berotecan, bendamustine, BIBW 2992, viricodar, brostalicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, dichloroacetic acid, discodamolide, elsamitl, enocitabine, eribulin, exatecan, exis lind, feruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexone, imiquimod, indolocarbazole, irofulvene, ranikidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel , PAC-1, pawpaw, pixantrone, proteasome inhibitor, rebecamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, sweinsonine, talaporfin, talikidar, tegafur-uracil, temodar, tesetaxel, tetranitrate triplatin, tris(2-chloroethyl)amine, troxacitabine, uramustine, bajimezan, vinflunine, ZD6126, and zosuquidar.

[0222] Further non-limiting examples of anticancer agents include vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin ( actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mitramycin), mitomycin, enzymes (e.g., the ability to systemically metabolize L-asparagine and synthesize its own asparagine) L-asparaginase), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustard (e.g., mechlorethamine, cyclophosphamide and analogues, melphalan, and chlorambucil ), ethyleneimine and methylmelamine (e.g. hexamethylmelamine and thiotepa), CDK inhibitors (e.g. CDK4 / 6 inhibitors such as abemaciclib, ribociclib, palbociclib), seliciclib, UCN-01, P1446A-05, PD- 0332991, Dynaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogues, and streptozocin), trazenes-dacarbazinin (DTIC) , folic acid analogues, pyrimidine analogues (e.g., fluorouracil, floxuridine, and cytarabine), antiproliferative / antimitotic metabolites and related inhibitors such as purine analogues (e.g., mercaptopurine, thioguanine, pento statins, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglucose. techimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoylanilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., , vistosertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array 520), DNA binders (e.g., Zalypsis®), 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 (e.g. TG02 and sorafenib), hormones (e.g. estrogen) ), and hormone agonists such as leutinating hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38 MAPK inhibitors, anti-IL-6 ( CNT0328), telomerase inhibitors (e.g. GRN 163L), Aurora kinase inhibitors (e.g. MLN8237), cell surface monoclonal antibodies (e.g. anti-CD38 (HUMAX-CD38)), anti-CS1 (e.g. elotuzumab), HSP90 inhibitors (e.g. 17AAG and KOS953), 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 targeting agents (e.g. MKC-3946), cFMS inhibitors (e.g. ARRY-382), Natural products such as JAK1 / 2 inhibitors (eg, CYT387), PARP inhibitors (eg, olaparib and veliparib (ABT-888)), and BCL-2 antagonists.

[0223] In some embodiments, the anti-cancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or analogs or derivative variants of any of the foregoing.

[0224] In some embodiments, the anti-cancer 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®), Piritinib, CP-654577, CP-724714, Canertinib (CI 1033), HKI-272, Lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626 , HKI-357, BIBW 2992, ARRY-334543, and JNJ-26483327.

[0225] In some embodiments, the anti-cancer 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.

[0226] In some embodiments, the anticancer agent is an inhibitor of downstream members of receptor tyrosine kinase (RTK) / growth factor receptors (e.g., SHP2 inhibitors (e.g., SHP099, TNO155, RMC-4550, RMC -4630, JAB-3068, RLY-1971), SOS1 inhibitors (e.g., BI-1701963, BI-3406), Raf inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, PTEN inhibitors, AKT inhibitors , or an mTOR inhibitor (e.g., an mTORC1 inhibitor or an mTORC2 inhibitor) In some embodiments, the anti-cancer agent is JAB-3312 In some embodiments, the anti-cancer agent is , AMG 510, MRTX1257, MRTX849, JNJ-74699157 (ARS-3248), LY3499446, ARS-853, or ARS-1620), or a Ras vaccine, or to directly or indirectly reduce the oncogenic activity of Ras Another treatment designed. Other examples of RAS inhibitors that can be combined with the Ras inhibitors of the present invention are shown below, which are hereby incorporated by reference in their entireties: WO2020050890, WO2020047192, WO2020035031, WO2020028706, WO2019241157, WO2019232419, WO2019217691, WO2019217307, WO2019215203, WO2019213526, WO2019213516, WO2019155399, WO2019150305, WO2019110751, WO2019099524, WO 2019051291, WO2018218070, WO2018217651, WO2018218071, WO2018218069, WO2018206539, WO2018143315, WO2018140600, WO2018140599, WO2018140598, WO201 8140514, WO2018140513, WO2018140512, WO2018119183, WO2018112420, WO2018068017, WO2018064510, WO2017201161, WO2017172979, WO2017100546, WO2017087528, WO2017058807, WO2017058805, WO2017058728, WO2017058902, WO 2017058792, WO2017058768, WO2017058915, WO2017015562, WO2016168540, WO2016164675, WO2016049568, WO2016049524, WO2015054572, WO2014152588, WO201 4143659, and WO2013155223.

[0227] In some embodiments, therapeutic agents that may be combined with compounds of the present invention are inhibitors of the MAP kinase (MAPK) pathway (or "MAPK inhibitors"). MAPK inhibitors include, but are not limited to, one or more of the MAPK inhibitors described in Cancers (Basel) 2015 Sep;7(3):1758-1784. For example, MAPK inhibitors include trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132, vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655), CI-1040, PD-0325901, CH5126766, MAP855, AZD6244, refametinib ( RDEA 119 / BAY 86-9766), GDC-0973 / XL581, AZD8330 (ARRY-424704 / ARRY-704), RO5126766 (described in Roche, PLoS One.2014 Nov 25;9(11)), and GSK1120212 (or JTP -74057, described in Clin Cancer Res. 2011 Mar 1;17(5):989-1000). MAPK inhibitors can be PLX8394, LXH254, GDC-5573, LY3009120.

[0228] In some embodiments, the anti-cancer agent is a disruptor or inhibitor of RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathways. PI3K / AKT inhibitors include, but are not limited to, one or more of the PI3K / AKT inhibitors described in Cancers (Basel) 2015 Sep;7(3):1758-1784. For example, the PI3K / AKT inhibitor may be selected from one or more of NVP-BEZ235, BGT226, XL765 / SAR245409, SF1126, GDC-0980, PI-103, PF-04691502, PKI-587, GSK2126458.

[0229] In some embodiments, the anti-cancer agent is a PD-1 or PD-L1 antagonist.

[0230] 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 can be a pan-RTK inhibitor, such as afatinib.

[0231] IGF-1R inhibitors include lincitinib, or a pharmaceutically acceptable salt thereof.

[0232] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Additional antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment capable of partially or completely blocking EGFR activation by its natural ligand. 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 Yang et al., Cancer Res. 1999, 59:1236-1243. include those described in The EGFR inhibitor can 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 with binding specificity thereof.

[0233] Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (TykerB®). For example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8, and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). Further limited examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, and any pharmaceutically acceptable salts of such EGFR inhibitors: EP0520722; EP0566226; WO96 / 33980; U.S. Patent No. 5,747,498; WO96 / 30347; / 38983;WO95 / 19774; WO95 / 19970; WO97 / 13771; WO98 / 02437; WO98 / 02438; WO97 / 32881; DE19629652; WO98 / 33798; WO97 / 32880; WO97 / 32880; / 07726;WO97 / WO98 / 14449; WO98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; 5146; WO99 / 35132; WO99 / 07701; and 092 / 20642. Additional 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. mentioned. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0234] MEK inhibitors include, but are not limited to, pimasertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation that is a Class I MEK1 mutation selected from 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.

[0235] PI3K inhibitors include wortmannin, 17-hydroxywortmannin analogues described in WO06 / 044453, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazine-1 -yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as Pictilisib or GDC-0941 and described in WO09 / 036082 and WO09 / 055730), 2-methyl- 2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (BEZ 235 or NVP-BEZ 235 and described in WO06 / 122806), (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl- 4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740), LY294002 (2-(4-morpholinyl )-8-phenyl-4H-1-benzopyran-4-one (available from Axon Medchem), PI 103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4 ,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride (available from Axon Medchem), PIK 75(2-methyl-5-nitro-2-[(6-bromoimidazo[1, 2-a]pyridin-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem), PIK 90 (N-(7,8-dimethoxy-2,3- Dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl) -furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione (available from Axon Medchem), TGX-221 (7-methyl-2-(4-morpholinyl)-9- [1-(Phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrinidin-4-one (available from Axon Medchem), XL-765, and XL-147, but are not limited to No. Other PI3K inhibitors include demethoxyviridine, 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.

[0236] AKT inhibitors include Akt-1-1 (inhibits Akt1) (Barnett et al., Biochem. J. 2005, 385(Pt.2):399-408); Akt-1-1,2 (Ak1 and 2) (Barnett et al., Biochem. J. 2005, 385(Pt.2):399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91:1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g. WO05 / 011700); indole-3-carbinol and its derivatives (e.g. U.S. 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 (e.g. Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al. , Cancer Res. 2004, 64:4394-9).

[0237] mTOR inhibitors include ATP-competitive mTORC1 / mTORC2 inhibitors such as PI-103, PP242, PP30; Torin 1; FKBP12 potentiators; 4H-1-benzopyran-4-one derivatives; ) and derivatives thereof such as temsirolimus (Torisel®); everolimus (Afinitor®, WO94 / 09010); ridaforolimus (also known as deforolimus or AP23573); rapalogs such as WO98 / 02441 and WO01 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779) 40-epi-(tetrazolite)-rapamycin (also called ABT578); 32-deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapanicin; derivatives disclosed in WO05 / 005434; 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 / 111130, WO9 4 / 02136, WO94 / 02485 , WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018 / 204416, and phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252), but these is not limited to In some embodiments, the mTOR inhibitor is a disteric inhibitor (see, eg, WO2018 / 204416, WO2019 / 212990, and WO2019 / 212991), eg, RMC-5552.

[0238] BRAF inhibitors that may be used in combination with the compounds of the invention include, for example, vemurafenib, dabrafenib, and encorafenib. BRAF may contain class 3 BRAF mutations. In some embodiments, the Class 3 BRAF mutation is the following amino acid substitutions in human BRAF: D287H;P367R;V459L;G466V;G466E;G466A;S467L;G469E; G596D; G596R; and one or more of A762E.

[0239] 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 major anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance to targeted therapeutic agents, including BCL-2 inhibitors such as ABT-263, as well as to conventional chemotherapy.

[0240] In some embodiments, the additional therapeutic agent is a SHP2 inhibitor. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene and contributes to multiple cellular functions such as 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. Two SH2 domains control the subcellular localization and functional regulation of SHP2. The molecule exists in an inactive, autoinhibitory conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. For example, stimulation by cytokines or growth factors acting through receptor tyrosine kinases (RTKs) leads to exposure of the catalytic site, resulting in enzymatic activation of SHP2.

[0241] SHP2 is involved in signaling through the RAS mitogen-activated protein kinase (MAPK), JAK-STAT, or phosphoinositol 3-kinase-AKT pathways. Mutations in the PTPN11 gene and subsequent mutations in SHP2 have been associated with several human developmental disorders such as Noonan syndrome and Leopard syndrome, as well as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast cancer. It has been identified in human cancers such as , lung cancer, and colon cancer. Some of these mutations destabilize the autoinhibitory conformation of SHP2 and promote SHP2 autoactivation or enhanced growth factor-driven activation. SHP2 is therefore a very attractive target for the development of novel therapeutics for the treatment of various diseases, including cancer. SHP2 inhibitors (e.g., RMC-4550 or SHP099) in combination with RAS pathway inhibitors (e.g., MEK inhibitors) inhibit multiple cancer cell lines (e.g., pancreatic, lung, ovarian, and breast) in vitro. It has been shown to inhibit the growth of Therefore, combination therapy with SHP2 inhibitors and RAS pathway inhibitors could be a general strategy to prevent tumor resistance in a wide range of malignancies.

[0242] Non-limiting examples of such SHP2 inhibitors are known in the art and can be found in Chen et al. Mol Pharmacol.2006,70,562; Sarver et al., J.Med.Chem.2017,62,1793; 2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734; and PCT applications WO2015107493; WO2015107494; WO201507495; 03406;WO2011022440;WO2017156397;WO2017079723 WO2017211303; WO2012041524; WO2017211303; WO2019051084; WO2017211303; US20160030594; US20110281942; WO2010011666; WO2017100279; WO2019051469; US8637684; WO2007117699; WO2015003094; WO2005094314; WO2008124815; WO2009049098; WO2017078499; WO2017210134; WO2018013597; WO2018129402 WO2018130928; WO20181309928; WO2018136264; WO2018136265; WO2018160731; WO2018172984;

[0243] 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 moiety, 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) 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.

[0244] 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. be done. In some embodiments, the additional therapeutic agent is selected from the group consisting of MEK inhibitors, SHP2 inhibitors, and PD-L1 inhibitors. See, for example, Hallin et al., Cancer Discovery, DOI:10.1158 / 2159-8290 (October 28, 2019), and Canon et al., Nature, 575:217 (2019). In some embodiments, Ras inhibitors of the invention are used in combination with MEK inhibitors and SOS1 inhibitors. In some embodiments, Ras inhibitors of the invention are used in combination with PDL-1 inhibitors and SOS1 inhibitors. In some embodiments, Ras inhibitors of the invention are used in combination with PDL-1 inhibitors and SHP2 inhibitors. In some embodiments, Ras inhibitors of the invention are used in combination with MEK inhibitors and SHP2 inhibitors. In some embodiments, the cancer is colorectal cancer and treatment comprises administering a Ras inhibitor of the invention in combination with a second or third therapeutic agent.

[0245] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0246] Immunotherapy includes monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T cells (e.g. CAR-T cells), bispecific antibodies (e.g. BiTE), as well as anti-PD-1, Anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents include, but are not limited to.

[0247] Immunomodulatory drugs (IMiDs) are a class of immunomodulatory drugs (drugs that modulate the immune response) that contain an imide group. The IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).

[0248] Exemplary anti-PD-1 antibodies, and methods of their use, are found 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), as well as elsewhere herein.

[0249] GITR agonists include GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), e.g., GITR fusion proteins described in U.S. Pat. Or, for example, U.S. Pat. Nos. 7,025,962, EP1947183, U.S. Pat. 7190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0250] Another example of therapeutic agents that may be used in combination with compounds of the present invention are anti-angiogenic agents. Anti-angiogenic agents include, but are not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof. Antiangiogenic agents can be agonists, antagonists, allosteric modulators, toxins, or more generally act to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition). and thereby promote cell death or arrest cell proliferation. In some embodiments, the one or more additional therapies comprise anti-angiogenic agents.

[0251] Antiangiogenic agents can be MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910 , WO99 / 52889, WO99 / 29667, WO99 / 007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US2009 / 0012085, and US Pat. 861,510. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity to inhibit MMP-1. More preferred are other matrix metalloproteinases (i.e. MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP -12, and MMP-13), it selectively inhibits MMP-2 or AMP-9. Some specific examples of MMP inhibitors are AG-3340, RO 32-3555, and RS13-0830.

[0252] Further exemplary anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen binding regions that specifically bind kinase domain receptors), anti-VEGF agents (e.g., VEGF (e.g., bevacizumab), or antibodies or antigen binding regions that specifically bind to soluble VEGF receptors or ligand binding regions thereof), e.g., VEGF-TRAP™, and anti-VEGF receptor agents (e.g., that specifically bind to EGFR inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto), such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Ang1 and Anti-Ang2 agents (e.g., antibodies or antigen binding regions that specifically bind to them or their receptors, e.g., Tie2 / Tek), as well as anti-Tie2 kinase inhibitors (e.g., antibodies that specifically bind to them or antigen binding area). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712, US6,413,932), anti-TWEAK agents (e.g., antibodies or antigen binding regions that specifically bind, or soluble TWEAK receptor antagonists, see US 6,727,225), ADAM disto integrin domains that antagonize the binding of integrins to their ligands (US 2002 / 0042368), specific binding anti-eph receptor or anti-ephrin antibodies or antigen binding regions (see US 6,727,225). U.S. Pat. Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124, and patent family members thereof), and anti-PDGF-BB antagonists (e.g., specific (antibodies or antigen binding regions that bind to PDGF-BB ligands), as well as antibodies or antigen binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind to .Additional anti-angiogenic agents include SD-7784 (Pfizer, USA), cilengitide (Merck KGaA, Germany, EPO0770622), pegaptanib octasodium (Gilead Sciences, USA), alphastatin (BioActa, UK), M- PGA (Celgene, USA, US5712291), Ilomastat (Arriva, USA, US5892112), Emaxanib (Pfizer, USA, US5792783), Vatalanib (Novartis, Switzerland), 2-Methoxyestradiol (EntreMed, USA), TLC ELL-12 (Elan , Ireland), anecortave acetate (Alcon, USA), alpha-D148 Mab (Amgen, USA), CEP-7055 (Cephalon, USA), anti-Vn Mab (Crucell, Netherlands), DAC antiangiogenic agent (ConjuChem, Canada) , Angiosidine (InKine Pharmaceutical, USA), KM-2550 (Kyowa Hakko, Japan), SU-0879 (Pfizer, USA), CGP-79787 (Novartis, Switzerland, EP0970070), ARGENT Technology (Ariad, USA), YIGSR- Stealth (Johnson & Johnson, USA), fibrinogen-E fragment (BioActa, UK), angiogenesis inhibitor (Trigen, UK), TBC-1635 (Encysive Pharmaceuticals, USA), SC-236 (Pfizer, USA), ABT-567 ( Abbott, USA), Metastatin (EntreMed, USA), Maspin (Sosei, Japan), 2-Methoxyestradiol (Oncology Sciences Corporation, USA), ER-68203-00 (IV AX, USA), BeneFin (Lane Labs, USA) , Tz-93 (Tsumura, Japan), TAN-1120 (Takeda, Japan), FR-111142 (Fujisawa, Japan, JP02233610), Platelet factor 4 (RepliGen, USA, EP407122), Vascular endothelial growth factor antagonist (Borean, Denmark), bevacizumab (pINN) (Genentech, USA), angiogenesis inhibitor (SUGEN, USA), XL 784 (Exelixis, USA), XL 647 (Exelixis, USA), MAb, alpha5beta3 integrin, 2nd generation (Applied Molecular Evolution, USA and MedImmune, 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 antiangiogenic agents (XOMA, USA), PI 88 (Progen, Australia), cilengitide (Merck KGaA, Germany, Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA), AVE 8062 (Ajinomoto, Japan) , AS 1404 (Cancer Research Laboratory, New Zealand), SG 292 (Telios, USA), Endostatin (Boston 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), pegaptanib (Pinn) (Gilead Sciences, USA), xanthorizole (Yonsei University, South Korea), vaccine, gene-based VEGF-2 (Scripps Clinic and Research Foundation, USA), SPV5.2 (Supratek, Canada), SDX 103 (University of California at San Diego, USA), PX 478 (ProlX, USA), Metastatin (EntreMed, USA), Troponin I (Harvard University, USA) ), SU 6668 (SUGEN, USA), OXI 4503 (OXiGENE, USA), o-guanidine (Dimensional Pharmaceuticals, USA), motupolamine 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), vaccines, angiogenesis agents (EntreMed, USA), urokinase plasminogen activation Factor inhibitor (Dendreon, USA), Oglufanide (pINN) (Melmotte, USA), HIF-lalfa inhibitor (Xenova, UK), CEP 5214 (Cephalon, USA), BAY RES 2622 (Bayer, Germany), Angiosidine ( InKine, USA), A6 (Angstrom, USA), KR 31372 (Korea Research Institute of Chemical Technology, South Korea), GW 2286 (GlaxoSmithKline, UK), EHT 0101 (ExonHit, France), CP 868596 (Pfizer, USA), CP 564959 (OSI, USA), CP 547632 (Pfizer, USA), 786034 (GlaxoSmithKline, UK), KRN 633 (Kirin Brewery, Japan), drug delivery system, intraocular, 2-methoxyestradiol, anguinex (Maastricht University, Netherlands and Minnesota University, USA), ABT 510 (Abbott, USA), AAL 993 (Novartis, Switzerland), VEGI (ProteomTech, USA), tumor necrosis factor-alpha inhibitor, SU 11248 (Pfizer, USA and SUGEN, USA) , ABT 518 (Abbott, USA), YH16 (Yantai Rongchang, China), S-3APG (Boston Children's Hospital, USA and EntreMed, USA), MAb, KDR (ImClone Systems, USA), MAb, Alpha 5 Beta (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), Ilsogladine (Nippon Shinyaku, Japan) , RG 13577 (Aventis, France), WX 360 (Wilex, Germany), Squalamine (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), VE-cadherin-2 antagonist (ImClone Systems, USA), Vasostatin (National Institutes of Health, USA), Flk-1 (ImClone Systems, USA), TZ 93 (Tsumura, Japan), Tumstatin (Beth Israel) Hospital, USA), truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA), Tie-2 ligand (Regeneron, USA), and thrombo. Spongin 1 inhibitors (Allegheny Health, Education and Research Foundation, USA).

[0253] Additional examples of therapeutic agents that may be used in combination with the compounds of the present invention include agents that specifically bind and inhibit the activity of growth factors such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor) (e.g. , antibodies, antigen-binding regions, or soluble receptors), as well as antibodies or antigen-binding regions that specifically bind to its receptor, c-Met.

[0254] Another example of therapeutic agents that may be used in combination with the compounds of the present invention are autophagy inhibitors. Autophagy inhibitors include chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, type 2A or type 1 autophagy-inhibiting algae toxins that inhibit the protein phosphatase of algae, analogs of cAMP, and drugs that elevate cAMP levels such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, antisense or siRNAs that inhibit expression of proteins including, but not limited to, ATG5 (related to autophagy) may also be used. In some embodiments, the one or more additional therapies comprise autophagy inhibitors.

[0255] Another example of therapeutic agents that may be used in combination with the compounds of the present invention are antineoplastic agents. In some embodiments, the one or more additional therapies comprise antineoplastic agents. Non-limiting examples of antineoplastic agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglavine, Arsenic Oxide, BAM-002 (Novelos), Bexarotene, Bicalutamide, Bromodeoxyuridine, Capecitabine, Thermoleukin, Cetrorelix, Cladribine, Clotrimazole, Cytarabine Octophosphate, DA 3030 (Dong-A), Daclizumab, Denileukin Diftitox , deslorelin, dexrazoxane, dirazep, docetaxel, docosanol, doxercalciferol, doxfluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab eflornithine, emiteflu , epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur Combination, Glycopene, Goserelin, Heptaplatin, Human Chorionic Gonadotropin, Human Fetal Alpha Fetoprotein, Ibandronic Acid, Idarubicin (imiquimod, interferon alpha, interferon alpha, native, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-NI, interferon alpha-n3, interferon alfacon-1, interferon alpha, native, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, native interferon gamma-la, interferon gamma-lb, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lovaplatin, lonidamine, lovastatin, masoprocol , melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mispaired double-stranded RNA, mitoguazone, mitractol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, naltograstim, nedaplatin, nilutamide, noscapine, Novel erythropoietic protein, NSC631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon alpha-2b, pentosan, sodium polysulfate, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal Antibodies, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium etidronate Re186, RII retinamide, rituximab, romurtide, samarium (153Sm) lexidronam, sargramostim, schizophyllan, sobuzoxan, sonermine , strontium-89 chloride, suramin, tasonermine, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasine, thyroid-stimulating hormone alpha, topotecan, toremifene, tositumomab-iodine-131, trastuzumab, treosulfan, tretinoin , trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, native form, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, viruridine, dinostatin stimaramer or zoledronic acid abarelix; AE941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC8015 (Dendreon), decitabine, dexaminoglutethimide, diazicon, EL532 (Elan), EM800 (Endorecherche), eniluracil, Ethanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, gallocitabine, gastrin-17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat , IM862 (Cytran), Interleukin-2, Iproxifen, LDI200 (Milkhaus), Religistim, Lintuzumab, CA125MAb (Biomira), Cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), Idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine 131MAb (Techniclone), polymorphic epithelial mucin-yttrium 90MAb (Antisoma), marimastat, menogalil, mitumomab, motexafin, gadolinium, MX6 ( Galderma), nerarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porphyromycin, prinomastat, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, saliblastin, thrombopoietin, tinethylethiopurpurine, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysis product vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital), or valspodar.

[0256] Additional examples of therapeutic agents that may be used in combination with the compounds of the present invention include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; dacetuzumab; muromonab-CD3; ipirumumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP 224; ad-trastuzumab emtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®) basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (Adcetris®); canakinumab (Ilaris®); daclizumab (Zenapax®); daratumumab (Darzalex®); denosumab (Prolia®); eculizumab (Soliris®); tuzumab ozogamicin (Mylotarg®); golimumab (Simponi®); ibritumomab tiuxetan (Zevalin®); infliximab (Remicade®); Natalizumab (Tysabri®); Obinutuzumab (Gazyva®); Ofatumumab (Arzerra®); Omalizumab (Xolair®); Palivizumab (Synagis®); (Perjeta®); Pertuzumab (Perjeta®); Ranibizumab (Lucentis®); Laxibacumab (Abthrax®); Tocilizumab (Actemra®); 131; tositumomab and tositumomab-i-131 (Bexxar®); ustekinumab (Stelara®); AMG 102; AMG 386; AMG 479; .

[0257] The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the disclosure are co-administered with other therapies as described herein. When used in combination therapy, the compounds described herein can be administered concurrently or separately with the second agent. This combined administration can include simultaneous administration of the two 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, a compound of the invention and any therapy described herein can be administered simultaneously, with both agents present in separate formulations. In another alternative, a compound of the disclosure can be administered followed by any therapy described herein, or vice versa. In some embodiments of separate administration protocols, a compound of the present invention and any therapy described herein are administered minutes apart, or hours apart, or days apart.

[0258] In some embodiments of any of the methods described herein, the first therapy (e.g., compound of the invention) and one or more additional therapies are administered simultaneously or sequentially in any order. administered. The first therapeutic agent may be administered immediately before or after one or more additional therapies, or 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, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours , up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7, 1-14, 1-21, or 1-30 days before or after.

[0259] The invention also provides (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the invention); and a package with instructions inserted therein. In some embodiments, the kit comprises (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the invention) and (b) one or more additional therapies (e.g., non-drug (c) a package interspersed with instructions for practicing any of the methods described herein.

[0260] Since one aspect of the present invention contemplates the treatment of diseases or symptoms associated therewith using a combination of pharmaceutically active compounds that can be administered separately, the present invention provides separate pharmaceutical compositions in kit form. Further relates to combining. A kit may comprise two separate pharmaceutical compositions, a compound of the invention and one or more additional therapies. The kit may include containers for housing separate compositions, such as divided bottles or divided foil packets. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit may include instructions for using the separate components. The form of the kit is such that when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), when they are administered at different dosing intervals, or when titrations of the individual components of the combination are administered by a prescribing healthcare professional. It is particularly advantageous when desired by

[0261] numbered embodiment [1] A compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof: [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-10 It binds to the carbon atom of the member heteroarylene. ] and B does not exist or -CH(R 9 )-, >C=CR 9 R. 9’ , or >CR 9 R. 9’ [Wherein, carbon is -N(R 11 )C(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 It is attached to the carbonyl carbon of the heteroarylene. ] and G is any permuted C 1 -C 4 Alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, -C(O)O-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], -C(O)NH-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], arbitrarily permuted C 1 -C 4 heteroalkylene or 3- to 8-membered heteroarylene, L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH and X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 is CH, CH 2 , or N, and Y 6 is C(O), CH, CH 2 , or N, and R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; or R. 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl, R. 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl or in combination with the carbon to which they are attached to form a carbonyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is H, F, optionally permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or R. 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R. 9’ is hydrogen or optionally substituted C 1 -C 6 is alkyl, or R. 9 and R 9’ are combined with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, R. 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, R. 10a is hydrogen or halo, R. 11 is hydrogen or C 1 -C 3 is an alkyl, and R. 21 is H or C 1 -C 3 is alkyl. ]. [2] C with G arbitrarily permuted 1 -C 4 The compound of paragraph [1], or a pharmaceutically acceptable salt thereof, which is heteroalkylene.

[0262] [3] The compound of paragraph [1] or [2], or a pharmaceutically acceptable salt thereof, wherein said compound has the structure of Formula Ic: [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )-[where carbon is -N(R 11 )C(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 It is attached to the carbonyl carbon of the heteroarylene. ] and L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; X 2 is O or NH and X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 and Y 6 is independently CH or N, R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R. 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, and R. 11 is hydrogen or C 1 -C 3 is alkyl. ].

[0263] [4]X 2 is NH, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to [3].

[0264] [5]X 3 is CH, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to [4].

[0265] [6]R 11 is hydrogen, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to [5].

[0266] [7]R 11 is C 1 -C 3 The compound according to any one of paragraphs [1] to [5], or a pharmaceutically acceptable salt thereof, which is alkyl.

[0267] [8]R 11 The compound of paragraph [7], or a pharmaceutically acceptable salt thereof, wherein is methyl.

[0268] [9] The compound of any one of paragraphs [1]-[6], wherein the compound has the structure of Formula Id, or a pharmaceutically acceptable salt thereof: [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 and Y 6 is independently CH or N, R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R. 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, and R. 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is alkyl. ].

[0269]

[10] X 1 is arbitrarily permuted C 1 -C 2 The compound according to any one of paragraphs [1] to [9], or a pharmaceutically acceptable salt thereof, which is alkylene.

[0270]

[11] X 1 is methylene, or a pharmaceutically acceptable salt thereof, according to paragraph

[10] .

[0271]

[12] R 5 is hydrogen, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to

[11] .

[0272]

[13] R 5 is C optionally substituted with halogen 1 -C 4 The compound according to any one of paragraphs [1] to

[11] , or a pharmaceutically acceptable salt thereof, which is alkyl.

[0273]

[14] R 5 The compound of paragraph

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

[0274]

[15] Y 4 is C, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to

[14] .

[0275]

[16] R 4 is hydrogen, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to

[15] .

[0276]

[17] Y 5 is CH, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to

[16] .

[0277]

[18] Y 6 is CH, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to

[17] .

[0278]

[19] Y 1 is C, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to

[18] .

[0279]

[20] Y 2 is C, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to

[19] .

[0280]

[21] Y 3 is N, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to

[20] .

[0281]

[22] R 3 The compound according to any one of paragraphs [1] to

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

[0282]

[23] Y 7 is C, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to

[22] .

[0283]

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

[23] , wherein the compound has the structure of Formula Ic, or a pharmaceutically acceptable salt thereof: [formation] [In the formula, A is -N (H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R. 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl, and R. 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is alkyl. ].

[0284]

[25] R 6 is hydrogen, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [3] to

[24] .

[0285]

[26] R 2 is hydrogen, cyano, optionally substituted C 1 -C 6 The compound according to any one of paragraphs [1] to

[25] , which is alkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 6-membered heterocycloalkyl , or a pharmaceutically acceptable salt thereof.

[0286]

[27] R 2 C with arbitrarily permuted 1 -C 6 The compound of paragraph

[26] , or a pharmaceutically acceptable salt thereof, which is alkyl.

[0287]

[28] R 2 The compound of paragraph

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

[0288]

[29] R 7 is arbitrarily permuted C 1 -C 3 The compound according to any one of paragraphs [1] to

[28] , or a pharmaceutically acceptable salt thereof, which is alkyl.

[0289]

[30] R 7 is C 1 -C 3 The compound of paragraph 29, or a pharmaceutically acceptable salt thereof, which is alkyl.

[0290]

[31] R 8 is arbitrarily permuted C 1 -C 3 The compound according to any one of paragraphs [1] to 30, or a pharmaceutically acceptable salt thereof, which is alkyl.

[0291]

[32] R 8 is C 1 -C 3 The compound of paragraph

[31] , or a pharmaceutically acceptable salt thereof, which is alkyl.

[0292]

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

[32] , wherein the compound has the structure of formula If, or a pharmaceutically acceptable salt thereof: [formation] [In the formula, A is -N (H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; R. 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl or optionally substituted 5- to 10-membered heteroaryl; R. 2 is C 1 -C 6 alkyl or 3- to 6-membered cycloalkyl, R. 7 is C 1 -C 3 is an alkyl, R. 8 is C 1 -C 3 is an alkyl, and R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl. ].

[0293]

[34] R 1 is optionally substituted 6- to 10-membered aryl, optionally substituted 3- to 6-membered cycloalkenyl, or optionally substituted 5- to 10-membered heteroaryl, paragraphs [1] to [33 ] or a pharmaceutically acceptable salt thereof.

[0294]

[35] R 1 is optionally substituted 6-membered aryl, optionally substituted 6-membered cycloalkenyl, or optionally substituted 6-membered heteroaryl, or the compound according to paragraph

[34] , or a pharmaceutical compound thereof permissible salt.

[0295]

[36] R 1 but, [formation] or a pharmaceutically acceptable salt thereof according to paragraph

[35] .

[0296]

[37] R 1 but, [formation] or a pharmaceutically acceptable salt thereof according to paragraph

[36] .

[0297]

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

[37] , wherein the compound has the structure of Formula Ig, or a pharmaceutically acceptable salt thereof: [formation] [In the formula, A is -N (H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-6 is attached to the carbon atom of the member heteroarylene. ] and B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; R. 2 is C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl or 3- to 6-membered cycloalkyl, R. 7 is C 1 -C 3 is an alkyl, R. 8 is C 1 -C 3 is an alkyl, and R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, X e and X f is independently N or CH, and R. 12 is an arbitrarily permuted C 1 -C 6 alkyl or optionally substituted C 1 -C 6 Heteroalkyl, optionally substituted 3- to 7-membered heterocycloalkyl. ].

[0298]

[39] X e is N and X f The compound of paragraph

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

[0299]

[40] X e is CH and X f is N, or a pharmaceutically acceptable salt thereof, according to paragraph

[38] .

[0300]

[41] R 12 is arbitrarily permuted C 1 -C 6 The compound according to any one of paragraphs

[38] to

[40] , or a pharmaceutically acceptable salt thereof, which is heteroalkyl.

[0301]

[42] R 12 but, [formation] The compound according to any one of paragraphs

[38] to

[41] , or a pharmaceutically acceptable salt thereof.

[0302]

[43] The compound of paragraph [1] or [2], or a pharmaceutically acceptable salt thereof, wherein said compound has the structure of Formula VI: [formation] [Where the dashed lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds, A is -N(H or CH 3 )C(O)-(CH 2 )-[wherein the amino nitrogen is -CH(R 10 )-, optionally substituted 3-6 membered cycloalkylene, optionally substituted 3-6 membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-10 It binds to the carbon atom of the member heteroarylene. ] and B does not exist or -CH(R 9 )-, >C=CR 9 R. 9’ , or >CR 9 R. 9’ [Wherein, carbon is -N(R 11 )C(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 It is attached to the carbonyl carbon of the heteroarylene. ] and G is any permuted C 1 -C 4 Alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, -C(O)O-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], -C(O)NH-CH(R 6 )-[ where C is -C(R 7 R. 8 )-. ], arbitrarily permuted C 1 -C 4 heteroalkylene or 3- to 8-membered heteroarylene, L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, haloacetal, or alkynyl sulfone; X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH and X 3 is N or CH, n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, Y 1 is C, CH, or N, and Y 2 , Y 3 , Y 4 , and Y 7 is independently C or N, and Y 5 is CH, CH 2 , or N, and Y 6 is C(O), CH, CH 2 , or N, and R. 2 is absent, hydrogen, optionally substituted C 1 -C6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 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 hetero is aryl and R 3 does not exist, or R. 2 and R 3 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, R. 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1-3 halogens, R. 5 is C optionally substituted with hydrogen, halogen 1 -C 4 alkyl, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl, R. 6 is hydrogen or methyl and R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl; or R. 6 and R 7 are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7 and R 8 are combined with the carbon atom to which they are attached, C=CR 7 'R 8 ’;C=N(OH), C=N(O-C 1 -C 3 alkyl), C=O, C=S, C=NH, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, R. 7a and R 8a are independently hydrogen, halo, optionally substituted C 1 -C 3 alkyl or in combination with the carbon to which they are attached to form a carbonyl, R. 7’ is hydrogen, halogen, or optionally substituted C 1 -C 3 is alkyl and R 8’ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 5-10 membered heteroaryl, or optionally substituted 6 ~10-membered aryl; or R. 7’ and R 8’ are combined with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl, R. 9 is H, F, optionally permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or R. 9 and L, combined with the atoms to which they are attached, form an optionally substituted 3- to 14-membered heterocycloalkyl; R. 9’ is hydrogen or optionally substituted C 1 -C 6 is alkyl, or R. 9 and R 9’ are combined with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, R. 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 is an alkyl, R. 10a is hydrogen or halo, R. 11 is hydrogen or C 1 -C 3 is an alkyl, R. 21 is hydrogen or C 1 -C 3 is alkyl (e.g., methyl), and X e and X f is independently N or CH. ].

[0303]

[44] The compound of paragraph

[43] , or a pharmaceutically acceptable salt thereof, wherein said compound has the structure of Formula VIa: [formation] [wherein A is an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or an optionally substituted is a 5- to 6-membered heteroarylene, B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and L is absent or is a linker, W is a bridging group comprising a vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone; X 1 is an arbitrarily permuted C 1 -C 2 Alkylene, NR, O, or S(O) n and X 2 is O or NH and n is 0, 1, or 2; R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 Alkynyl, C(O)R', C(O)OR', C(O)N(R') 2 , S(O)R', S(O) 2 R', or S(O) 2 N(R') 2 and each R' is independently H or an optionally substituted C 1 -C 4 is an alkyl, R. 2 is C 1 -C 6 Alkyl, C 1 -C 6 fluoroalkyl or 3- to 6-membered cycloalkyl, R. 7 is C 1 -C 3 is an alkyl, R. 8 is C 1 -C 3 is an alkyl, and R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, X e and X f is independently N or CH, R. 11 is hydrogen or C 1 -C 3 is an alkyl, and R. 21 is hydrogen or C 1 -C 3 is alkyl. ].

[0304]

[45] The compound of paragraph

[43] or

[44] , or a pharmaceutically acceptable salt thereof, wherein said compound has the structure of Formula VIb: [formation] [Wherein, A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted is a 5- to 6-membered heteroarylene, B is -CH(R 9 )-[wherein carbon is -NHC(O)-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or the carbonyl carbon of a 5- to 6-membered heteroarylene. ] and R. 9 is an arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or L is absent or is a linker, W is a cross-linking group including vinyl ketone, vinyl sulfone, inone, or alkynyl sulfone. ].

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

[45] , or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 6-membered arylene.

[0305]

[47] The compound of paragraph

[46] , or a pharmaceutically acceptable salt thereof, wherein A has the following structure: [formation] [In the formula, R 13 is hydrogen, halo, hydroxy, amino, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 is heteroalkyl, and R. 13a is hydrogen or halo. ].

[48] R 13 and R 13a is each hydrogen, or a pharmaceutically acceptable salt thereof, according to paragraph

[47] .

[0306]

[49] R 13 is hydroxy, methyl, fluoro, or difluoromethyl, or a pharmaceutically acceptable salt thereof, according to paragraph

[47] .

[0307]

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

[45] , or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 5- to 6-membered heteroarylene.

[0308]

[51] A [formation] or a pharmaceutically acceptable salt thereof according to paragraph

[50] .

[0309]

[52] A optionally permuted C 1 -C 4 The compound according to any one of paragraphs [1] to

[45] , or a pharmaceutically acceptable salt thereof, which is heteroalkylene.

[0310]

[53] B [formation] or a pharmaceutically acceptable salt thereof according to paragraph

[52] .

[0311]

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

[45] , or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene.

[0312]

[55] A [formation] or a pharmaceutically acceptable salt thereof according to paragraph

[54] .

[0313]

[56] W [formation] or a pharmaceutically acceptable salt thereof according to paragraph

[55] .

[0314]

[57] B-CHR 9 The compound according to any one of paragraphs [1] to

[56] , or a pharmaceutically acceptable salt thereof, which is -.

[0315]

[58] R 9 , F, arbitrarily permuted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 The compound according to paragraph

[57] , which is heteroalkyl, optionally substituted 3-6 membered cycloalkyl, or optionally substituted 3-7 membered heterocycloalkyl, or a pharmaceutically acceptable salt.

[0316]

[59] R 9 but, [formation] or a pharmaceutically acceptable salt thereof according to paragraph

[58] .

[0317]

[60] R 9 but, [formation] or a pharmaceutically acceptable salt thereof according to paragraph

[59] .

[0318]

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

[56] , or a pharmaceutically acceptable salt thereof, wherein B is an optionally substituted 6-membered arylene.

[0319]

[62] The compound of paragraph

[61] , or a pharmaceutically acceptable salt thereof, wherein B is a 6-membered arylene.

[0320]

[63] B [formation] or a pharmaceutically acceptable salt thereof according to paragraph

[61] .

[0321]

[64] R 7 is a methyl group, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to

[63] .

[0322]

[65] R 8 is a methyl group, or a pharmaceutically acceptable salt thereof according to any one of paragraphs [1] to

[64] .

[0323]

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

[65] , wherein said linker has the structure of formula II, or a pharmaceutically acceptable salt thereof: A. 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 Formula II [In the formula, A 1 is the bond between the linker and B; A 2 is the bond between W and the linker; B 1 , B 2 , B 3 , and B 4 are each independently an arbitrarily permuted C 1 -C 2 Alkylene, optionally substituted C 1 -C 3 heteroalkylene, O, S, and NR N is selected from;R N is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted C 1 -C 7 is heteroalkyl; C 1 and C 2are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; D 1 is an arbitrarily permuted C 1 -C 10 Alkylene, optionally substituted C 2 -C 10 alkenylene, optionally substituted C 2 -C 10 alkynylene, optionally substituted 3-14 membered heterocycloalkylene, optionally substituted 5-10 membered heteroarylene, optionally substituted 3-8 membered cycloalkylene, optionally substituted 6-10 member arylene, optionally substituted C 2 -C 10 polyethylene glycolene or optionally substituted C 1 -C 10 heteroalkylene, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h -to-(B 3 ) i -(C 2 ) j -(B 4 ) k -A 2 is a chemical bond that binds to ].

[0324]

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

[66] , or a pharmaceutically acceptable salt thereof, wherein the linker is acyclic.

[0325]

[68] The compound of paragraph

[67] , or a pharmaceutically acceptable salt thereof, wherein said linker has the structure of Formula IIa: [formation] [In the formula, X a does not exist or is N, and R. 14 is absent, hydrogen, or optionally substituted C 1 -C 6 is an alkyl, and L. 2 does not exist or -SO 2 -, arbitrarily permuted C 1 -C 4 Alkylene, or optionally substituted C 1 -C 4 is a heteroalkylene, X a , R 14 , or L 2 There is at least one of ].

[0326]

[69] The compound of paragraph

[68] , or a pharmaceutically acceptable salt thereof, wherein said linker has the following structure: [formation]

[0327]

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

[66] , or a pharmaceutically acceptable salt thereof, wherein the linker is a cyclic group or contains a cyclic moiety.

[0328]

[71] The compound of paragraph

[70] , or a pharmaceutically acceptable salt thereof, wherein said linker has the structure of Formula IIb: [formation] [Where o is 0 or 1, R. 15 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted 3-8 membered cycloalkylene, or optionally substituted 3-8 membered heterocycloalkylene, X 4 is absent or arbitrarily permuted C 1 -C 4 Alkylene, O, NCH 3 , or any permuted C 1 -C 4 is a heteroalkylene, Cy is optionally substituted 3- to 8-membered cycloalkylene, optionally substituted 3- to 8-membered heterocycloalkylene, optionally substituted 6- to 10-membered arylene, or optionally substituted 5- to is a 10-membered heteroarylene, and L. 3 does not exist or -SO 2 -, arbitrarily permuted C 1 -C 4 Alkylene, or optionally substituted C 1 -C 4 It is heteroalkylene. ].

[0329]

[72] The compound of paragraph

[71] , or a pharmaceutically acceptable salt thereof, wherein said linker has the following structure: [formation] [In the formula, R 15 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene, and R. 15a , R 15b , R 15c , R 15d , R 15e , R 15f , and R 15g is independently hydrogen, halo, hydroxy, cyano, amino, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 is alkoxy; or, R 15b and R 15d are combined with the carbon to which they are attached to form an optionally substituted 3- to 8-membered cycloalkylene or an optionally substituted 3- to 8-membered heterocycloalkylene. ]

[73] The compound of paragraph

[72] , or a pharmaceutically acceptable salt thereof, wherein said linker has the following structure: [formation] [formation]

[0330]

[74] The compound of paragraph

[71] , or a pharmaceutically acceptable salt thereof, wherein said linker has the following structure: [formation] [formation] [formation] [formation]

[0331]

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

[74] , or a pharmaceutically acceptable salt thereof, wherein W is a cross-linking group containing a vinyl ketone.

[0332]

[76] The compound of paragraph

[75] , wherein W has the structure of Formula IIIa, or a pharmaceutically acceptable salt thereof: [formation] [In the formula, R 16a , R 16b , and R 16c is independently hydrogen, -CN, halogen, or -OH, -O-C 1 -C 3 Alkyl, -NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , or -C optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl 1 -C 3 is alkyl. ].

[0333]

[77] W [formation] or a pharmaceutically acceptable salt thereof according to paragraph

[76] .

[0334]

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

[74] , or a pharmaceutically acceptable salt thereof, wherein W is an inone-containing bridging group.

[0335]

[79] The compound of paragraph

[78] , wherein W has the structure of Formula IIIb, or a pharmaceutically acceptable salt thereof: [formation] [In the formula, R 17is hydrogen; -OH, -O-C 1 -C 3 Alkyl, -NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 or -C optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl 1 -C 3 alkyl; or 4- to 7-membered saturated heterocycloalkyl. ].

[80] W

[0336] [formation] [formation] or a pharmaceutically acceptable salt thereof, according to paragraph

[79] .

[0337]

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

[74] , or a pharmaceutically acceptable salt thereof, wherein W is a cross-linking group containing vinylsulfone.

[0338]

[82] The compound of paragraph

[81] , wherein W has the structure of Formula IIIc, or a pharmaceutically acceptable salt thereof: [formation] [In the formula, R 18a , R 18b , and R 18c is independently hydrogen, -CN, or -OH, -O-C 1 -C 3 Alkyl, -NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 , or -C optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl 1 -C 3 is alkyl. ].

[0339]

[83] W [formation] or a pharmaceutically acceptable salt thereof according to paragraph

[82] .

[0340]

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

[74] , or a pharmaceutically acceptable salt thereof, wherein W is a cross-linking group containing alkynylsulfone.

[0341]

[85] The compound of paragraph

[84] , wherein W has the structure of Formula IIId, or a pharmaceutically acceptable salt thereof: [formation] [In the formula, R 19 is hydrogen; -OH, -O-C 1 -C 3 Alkyl, -NH 2 , -NH(C 1 -C 3 alkyl), -N(C 1 -C 3 alkyl) 2 or -C optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl 1 -C 3 alkyl; or 4- ...

Claims

1. The structure of formula Ig: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, In the formula, A is -N(H or CH ３ )C(O)-(CH ２ )—[wherein the amino nitrogen is —CH(R １０ )-, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene; B is -CH(R ９ )-, where the carbon is bonded to the carbonyl carbon of -NHC(O)-, an optionally substituted 3- to 6-membered cycloalkylene, an optionally substituted 3- to 6-membered heterocycloalkylene, an optionally substituted 6-membered arylene, or a 5- to 6-membered heteroarylene; L is absent or has the structure of formula II: A 1 - (B 1 ) f - (C 1 ) g - (B 2 ) h - (D 1 ) - (B 3 ) i - (C 2 ) j - (B 4 ) k - A 2 Formula II wherein A 1 is the bond between the linker and B; A 2 is the bond between W and the linker; B 1 , B 2 , B 3 , and B 4 are each independently selected from optionally substituted C 1 -C 2 alkylene, optionally substituted C 1 -C 3 heteroalkylene, O, S, and NR N ; R N is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted 3-14 membered heterocycloalkyl, optionally substituted 6-10 membered aryl, or optionally substituted C 1 -C 7 heteroalkyl; are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; D 1 is an optionally substituted C 1 -C 10 alkylene, an optionally substituted C 2 -C 10 alkenylene, an optionally substituted C 2 -C 10 alkynylene, an optionally substituted 3- to 14-membered heterocycloalkylene, an optionally substituted 5- to 10-membered heteroarylene, an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 6- to 10-membered arylene, an optionally substituted C 2 -C 10 polyethyleneglycolene, or an optionally substituted C 1 -C 10 heteroalkylene, or A 1 -(B 1 ) f -(C 1 ) g -(B 2 ) h - is -(B 3) i -(C 2 ) j -(B 4 ) k -A 2 , W is a bridging group comprising a vinyl ketone, vinyl sulfone, ynone, or alkynyl sulfone; R ２ is C １ -C ６ Alkyl, C １ -C ６ fluoroalkyl, or 3- to 6-membered cycloalkyl; R ７ is C １ -C ３ is alkyl, R ８ is C １ -C ３ is alkyl, and R ９ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; X ｅ and X ｆ is independently N or CH, and R １２ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; The compound, or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein A is an optionally substituted 6-membered arylene.

3. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein A is an optionally substituted 5- to 6-membered heteroarylene.

4. A is an optionally substituted C １ -C ４ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is heteroalkylene.

5. 2. The compound of claim 1, wherein A is an optionally substituted 3- to 6-membered heterocycloalkylene, or a pharma- ceutically acceptable salt thereof.

6. A is 【Chemistry 2】 6. The compound of claim 5, which is: or a pharma- ceutically acceptable salt thereof.

7. B is -CHR ９ The compound according to any one of claims 1 to 6, wherein R is -, or a pharma- ceutically acceptable salt thereof.

8. R ９ is optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ 8. The compound of claim 7, which is heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl, or a pharma- ceutically acceptable salt thereof.

9. The compound of claim 8, or a pharma- ceutically acceptable salt thereof, wherein R9 is isopropyl.

10. The compound of any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein B is an optionally substituted 6-membered arylene.

11. 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof, wherein B is 6-membered arylene.

12. 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein the linker is acyclic.

13. The linker has the structure of Formula IIa: 【Chemistry 3】 [In the formula, X ａ is absent or is N, R １４ is absent, hydrogen, or optionally substituted C １ -C ６ is alkyl, and L ２ does not exist or -SO ２ -, optionally substituted C １ -C ４ Alkylene, or optionally substituted C １ -C ４ is heteroalkylene, X ａ , R １４ , or L ２ At least one of the following is present.

13. The compound of claim 12, having the formula: or a pharma- ceutically acceptable salt thereof.

14. 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein the linker is or comprises a cyclic moiety.

15. The linker has the structure of formula IIb: 【Chemistry 4】 [In the formula, o is 0 or 1, R １５ is hydrogen, optionally substituted C １ -C ６ alkyl, optionally substituted 3- to 8-membered cycloalkylene, or optionally substituted 3- to 8-membered heterocycloalkylene; X ４ is absent or optionally substituted C １ -C ４ Alkylene, O, NCH ３ or optionally substituted C １ -C ４ is heteroalkylene, Cy is an optionally substituted 3- to 8-membered cycloalkylene, an optionally substituted 3- to 8-membered heterocycloalkylene, an optionally substituted 6- to 10-membered arylene, or an optionally substituted 5- to 10-membered heteroarylene; and L ３ does not exist or -SO ２ -, optionally substituted C １ -C ４ Alkylene, or optionally substituted C １ -C ４ is heteroalkylene.

15. The compound of claim 14, having the formula: or a pharma- ceutically acceptable salt thereof.

16. The linker, 【Chemistry 5】 16. The compound of claim 15, which is: or a pharma- ceutically acceptable salt thereof.

17. 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein W is a bridging group comprising a vinyl ketone.

18. W has the structure of formula IIIa: 【Chemistry 6】 [In the formula, R １６ａ , R １６ｂ , and R １６ｃ are independently hydrogen, -CN, halogen, or -OH, -O-C １ -C ３ Alkyl, -NH ２ , -NH(C １ -C ３ alkyl), -N(C １ -C ３ Alkyl) ２ or 4- to 7-membered saturated heterocycloalkyl, １ -C ３ is alkyl.

18. The compound of claim 17, having the formula: or a pharma- ceutically acceptable salt thereof.

19. 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein W is an ynone-containing bridging group.

20. W has the structure of formula IIIb: 【Chemistry 7】 [In the formula, R １７ is hydrogen; １ -C ３ Alkyl, -NH ２ , -NH(C １ -C ３ alkyl), -N(C １ -C ３ Alkyl) ２ , 4- to 7-membered saturated cycloalkyl, or 4- to 7-membered saturated heterocycloalkyl, １ -C ３ is alkyl.

20. The compound of claim 19, having the formula: or a pharma- ceutically acceptable salt thereof.

21. W is 【Chemistry 8】 21. The compound of claim 20, which is: or a pharma- ceutically acceptable salt thereof.

22. 22. The compound of any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, wherein W is a bridging group comprising a vinyl sulfone.

23. W has the structure of formula IIIc: 【Chemistry 9】 [In the formula, R １８ａ , R １８ｂ , and R １８ｃ are independently hydrogen, —CN, or —OH, —O—C １ -C ３ Alkyl, -NH ２ , -NH(C １ -C ３ alkyl), -N(C １ -C ３ Alkyl) ２ or -C1-C3 alkyl optionally substituted with one or more substituents independently selected from 4- to 7-membered saturated heterocycloalkyl.

23. The compound of claim 22, having the formula: or a pharma- ceutically acceptable salt thereof.

24. 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein W is a bridging group comprising an alkynylsulfone.

25. W has the structure of formula IIId: 【Chemistry 10】 [In the formula, R １９ is hydrogen; １ -C ３ Alkyl, -NH ２ , -NH(C １ -C ３ alkyl), -N(C １ -C ３ Alkyl) ２ or 4- to 7-membered saturated heterocycloalkyl, optionally substituted with one or more substituents independently selected from １ -C ３ alkyl; or 4- to 7-membered saturated heterocycloalkyl.

25. The compound of claim 24, having the formula: or a pharma- ceutically acceptable salt thereof.

26. The compound of claim 1, wherein: 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 【Chemistry 11-4】 【Chemistry 11-5】 【Chemistry 11-6】 【Chemistry 11-7】 【Chemistry 11-8】 【Chemistry 11-9】 【Chemistry 11-10】 【Chemistry 11-11】 【Chemistry 11-12】 【Chemistry 11-13】 【Chemistry 11-14】 【Chemistry 11-15】 【Chemistry 11-16】 【Chemistry 11-17】 【Chemistry 11-18】 【Chemistry 11-19】 【Chemistry 11-20】 【Chemistry 11-21】 【Chemistry 11-22】 【Chemistry 11-23】 【Chemistry 11-24】 【Chemistry 11-25】 【Chemistry 11-26】 【Chemistry 11-27】 【Chemistry 11-28】 【Chemistry 11-29】 【Chemistry 11-30】 【Chemistry 11-31】 【Chemistry 11-32】 【Chemistry 11-33】 【Chemistry 11-34】 【Chemistry 11-35】 【Chemistry 11-36】 【Chemistry 11-37】 【Chemistry 11-38】 【Chemistry 11-39】 【Chemistry 11-40】 【Chemistry 11-41】 【Chemistry 11-42】 【Chemistry 11-43】 【Chemistry 11-44】 【Chemistry 11-45】 【Chemistry 11-46】 【Chemistry 11-47】 【Chemistry 11-48】 【Chemistry 11-49】 【Chemistry 11-50】 【Chemistry 11-51】 【Chemistry 11-52】 【Chemistry 11-53】 【Chemistry 11-54】 【Chemistry 11-55】 【Chemistry 11-56】 【Chemistry 11-57】 【Chemistry 11-58】 【Chemistry 11-59】 【Chemistry 11-60】 【Chemistry 11-61】 【Chemistry 11-62】 【Chemistry 11-63】 【Chemistry 11-64】 【Chemistry 11-65】 【Chemistry 11-66】 【Chemistry 11-67】 【Chemistry 11-68】 【Chemistry 11-69】 【Chemistry 11-70】 【Chemistry 11-71】 【Chemistry 11-72】 【Chemistry 11-73】 【Chemistry 11-74】 【Chemistry 11-75】 【Chemistry 11-76】 【Chemistry 11-77】 【Chemistry 11-78】 2. The compound of claim 1, selected from the group consisting of:

27. A compound having the following structure: 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof.

28. 28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

29. A compound having the following structure: 【Chemistry 13】 Compound.

30. A pharmaceutical composition comprising the compound of claim 29 and a pharma- ceutically acceptable excipient.

31. 31. A pharmaceutical composition according to claim 28 or 30 for use in the treatment of cancer.

32. 32. The pharmaceutical composition of claim 31, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, or endometrial cancer.

33. 33. The pharmaceutical composition of claim 31 or 32, wherein the cancer comprises a Ras mutation.

34. 34. The pharmaceutical composition of claim 33, wherein the Ras mutation is K-Ras G12C, K-Ras G13C, H-Ras G12C, H-Ras G12C, N-Ras G12C, or N-Ras G13C.

35. 31. A pharmaceutical composition according to claim 28 or 30 for use in the treatment of a Ras protein-associated disease.

36. A pharmaceutical composition described in any one of claims 31 to 35, further comprising an additional anti-cancer therapy.

37. 37. The pharmaceutical composition of claim 36, wherein the additional anti-cancer 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, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

38. 38. The pharmaceutical composition of claim 36 or 37, wherein the additional anti-cancer therapy is an SHP2 inhibitor.

39. A pharmaceutical composition for use in combination with pembrolizumab in the treatment of lung cancer, comprising the following structure: 【Chemistry 14】 or a pharma- ceutically acceptable salt thereof, The pharmaceutical composition, wherein the lung cancer comprises a Ras G12C mutation.

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