RAS inhibitors

Abstract

This invention provides macrocyclic compounds capable of inhibiting the Ras protein, pharmaceutical compositions and protein conjugates thereof, and methods for using them in cancer treatment. [Solution] An example of a compound in this disclosure is a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof. JPEG2026108761000358.jpg93170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Patent No. 62 / 930,394, filed on 4 November 2019; No. 62 / 951,763, filed on 20 December 2019; No. 63 / 000,375, filed on 26 March 2020; and No. 63 / 043,601, filed on 24 June 2020, all of which are incorporated herein by reference. [Background technology]

[0002] The vast majority of small molecule drugs act by binding to functionally important pockets on target proteins, thereby regulating the activity of those proteins. For example, cholesterol-lowering drugs known as statins bind to the enzymatic active site of HMG-CoA reductase, thus preventing the enzyme from engaging with its substrate. The fact that many such drug / target interaction pairs are known can be misleading to some extent, leading people to believe that, given a reasonable amount of time, effort, and resources, small molecule modulators can be discovered for most, if not all, proteins. This is far from the truth. Current estimates suggest that only about 10% of all human proteins are targetable by small molecules. Bojadzic and Buchwald, Curr Top Med Chem 18:674-699 (2019). The other 90% are currently considered refractory or refractory to the small molecule drug discovery described above. Such targets are commonly referred to as "andruggable." These undruggable targets comprise a vast and extensive, underutilized reservoir of clinically important human proteins. Therefore, there is considerable interest in discovering novel molecular modalities capable of controlling the function of such undruggable targets.

[0003] The literature has well established that Ras proteins (K-Ras, H-Ras, and N-Ras) play essential roles in various human cancers and are therefore appropriate targets for anti-cancer therapies. In fact, mutations in the Ras protein account for approximately 30% of all human cancers in the United States, many of which are lethal. Dysregulation of the Ras protein due to mutation activation, overexpression, or upstream expression is common in human tumors, and mutation activation in Ras is frequently found in human cancers. For example, activation of a mutation at codon 12 in the Ras protein functions by inhibiting both the GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly distorting the population of Ras mutant proteins into an "on" (GTP-bound) state (Ras(ON)), leading to 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 (e.g., G13D) and codon 61 (e.g., Q61K) also contribute to oncogenic activity in some cancers.

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

[0005] RAS inhibitors are provided herein. The approach described herein requires the formation of a high-affinity triplicate complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein (e.g., Ras) and a cytosolic chaperone (presenter protein) that is widely expressed intracellularly (e.g., cyclophyllin A). More specifically, in some embodiments, the Ras inhibitors described herein include a novel binding pocket cytosol in Ras, which drives the formation of a high-affinity triplicate complex between the Ras protein and the widely expressed cytosolic chaperone cyclophyllin A (CYPA). While not theoretically bound, the inventors believe that one way in which the inhibitory effect on Ras is affected by the compounds and complexes of the present invention is the formation of steric occlusion of the interaction site between Ras and downstream effector molecules such as RAF and PI3K, which is necessary for the growth of oncogenic signals.

[0006] Therefore, in some embodiments, the present disclosure features a compound of structural formula I, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH3)C(O)-(CH2)-[wherein amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-10 member heteroarylenes, B does not exist, or -CH(R 9 )-or>C=CR 9 R 9’ [In the formula, carbon is -N(R 11a group bonded to the carbonyl carbon of C(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, G is an optionally substituted C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, an optionally substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[wherein the second C is bonded to -C(R 7 R 8 )-.], -C(O)NH-CH(R 6 )-[wherein the second C is bonded to -C(R 7 R 8 )-.], an optionally substituted C1-C4 heteroalkylene, or a 3- to 8-membered heteroarylene, L is absent or is a linker, W is hydrogen, cyano, S(O)2R', an optionally substituted amino, an optionally substituted amide, an optionally substituted C1-C4 alkoxy, an optionally substituted C1-C4 hydroxyalkyl, an optionally substituted C1-C4 aminoalkyl, an optionally substituted C1-C4 haloalkyl, an optionally substituted C1-C4 alkyl, an optionally substituted C1-C4 guanidinoalkyl, a 3- to 11-membered heterocycloalkyl optionally substituted with C0-C4 alkyl, an optionally substituted 3- to 8-membered cycloalkyl, or an optionally substituted 3- to 8-membered heteroaryl, X 1 is an optionally substituted C1-C2 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, an optionally substituted C1-C4 alkyl, an optionally substituted C2-C4 alkenyl, an optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2, Each R' is independently H or an optionally substituted C1-C4 alkyl group. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 Independently, C or N, Y 5 is CH, CH2, or N, Y 6 It is C(O), CH, CH2, or N, R 1 This is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 1 and R 2 These combine with the atoms to which they bond, forming optionally substituted 3-14 member heterocycloalkyl groups. R 2 It is either absent, or hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5 or 6-membered heteroaryl. R 3 It does not exist, or R 2 and R 3 These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R 4 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1 to 3 halogens. R 5These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens. R 6 R is hydrogen or methyl, 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 8 This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 These combine with the carbon atoms they bond to, forming C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8a These are independently hydrogen, halos, or optionally substituted C1-C3 alkyl groups, or they combine with the carbon they bond to to form a carbonyl group. R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, or R 9 And L combine with the atoms to which they are bonded to form optionally substituted 3-14 member heterocycloalkyl groups. R 9’ is a hydrogen- or optionally substituted C1-C6 alkyl group, R 10 These are hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl. R 10a is hydrogen or halo, R 11 is hydrogen or a C1-C3 alkyl group. Pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient are also provided. R 16 [This is hydrogen or a C1-C3 alkyl group (e.g., methyl).]

[0007] The present invention also provides a method for treating cancer in a subject requiring cancer treatment, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the present invention provides a method for treating a Ras protein-related disease in a subject requiring treatment for the Ras protein-related disease, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0009] A method for inhibiting the Ras protein in cells is provided, further comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0010] Any limitations discussed in relation to one embodiment of the present invention can be specifically conceived to apply to any other embodiment of the present invention. Furthermore, any compound or composition of the present invention can be used in any manner of the present invention, and any compound or composition of the present invention can be produced or utilized using any manner of the present invention. [Brief explanation of the drawing]

[0011] [Figure 1A] Compound A, a compound of the present invention, exhibits PK-dependent RAS pathway regulation in the Capan-2 CDX model (PDAC, KRAS G12V / WT). The second dose of compound A (indicated by the black arrow) was delivered 8 hours after the first dose. All dose levels are well tolerated. All dose levels are well tolerated. Tumor DUSP6 mRNA expression as a percentage of control, graphed as bars on the left y-axis. The dotted line indicates the return to control levels of DUSP6. Unbound plasma PK (nM), plotted as a line on the right y-axis on a Log10 scale. N=3 / time point. Error bars represent the standard error of the mean. [Figure 1B]Combinatorial antitumor activity and upstream SHP2 inhibition of compound A, a compound of the present invention, in a Capan-2 CDX model (PDAC, KRAS G12V / WT). Capan-2 cells were infused in 50% Matrigel. Animals were randomized and treatment was initiated with an average tumor volume of approximately 180 mm3. Animals were administered the SHP2 inhibitor RMC-4550 (20 mg / kg po q2d), compound A 100 mg po bid, a combination of RMC-4550 and compound A, or a control for 40 days. All dose levels were tolerated. n=10 / group (n=9 in the combination group). Ns=no significant difference; by one-way ANOVA, ***<0.001. [Modes for carrying out the invention]

[0012] Definitions and Chemical Terms In this application, unless otherwise clearly indicated by context, (i) the term “one (a)” means “one or more”; (ii) is used to mean “and / or” unless it is explicitly indicated that it means only alternative expressions or that such alternative expressions are mutually exclusive, however this disclosure supports the definitions that refer only to alternative expressions and to “and / or”; (iii) the terms “comprising” and “including” are understood to encompass itemized components or processes, whether presented by themselves or together with one or more additional components or processes; and (iv) where a scope is indicated, it includes endpoints.

[0013] As used herein, the term “approximately” is used to indicate that a value includes the standard deviation of the error of the device or method used to determine the value. In certain embodiments, unless otherwise stated or evident from the content (for example, if such a number may exceed 100% of the possible values), the term “approximately” refers to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, and 1% or less in either direction (above or below) the stated value.

[0014] As used herein, the term "adjacent" in the context of describing adjacent atoms means divalent atoms directly bonded by a covalent bond.

[0015] As used herein, “compounds of the present invention” and similar terms mean, whether expressly stated or not, the compounds of formula I and its subformulas, as well as the compounds of Tables 1 and 2, in addition to their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including atropisomers), and tautomers, as described herein, and the Ras inhibitors described herein.

[0016] The term "wild-type" refers to an entity possessing a structure or activity found in nature in a "normal" state or context (as opposed to variants, diseases, or changes). Those skilled in the art will understand that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles).

[0017] Those skilled in the art will understand that certain compounds described herein may exist in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic forms (e.g., hydrogen substituted with deuterium, in which one or more atoms are substituted with different isotopes of that atom). Unless otherwise specified or made clear from the context, the structures described may be understood to represent any such isomeric or isotopic forms, individually or in combination.

[0018] The compounds described herein may be asymmetric (for example, having one or more stereocenters). Any stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of this disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active forms or as racemates. Methods for preparing optically active forms from optically active starting materials, such as by resolving racemic mixtures or by stereoselective methods, are known in the art. Many geometric isomers, such as olefins and C=N double bonds, can also be present in the compounds described herein, and all such stable isomers are conceived in the present invention. The cis and trans geometric isomers of the compounds of this disclosure are described and can be isolated as mixtures of isomers or as separated isomers.

[0019] In some embodiments, one or more compounds described herein may exist in different tautomerized forms. Unless explicitly excluded, references to such compounds encompass all such tautomerized forms, as will be apparent from the context. In some embodiments, the tautomerized form arises from the exchange of a single bond with an adjacent double bond and the accompanying transfer of protons. In certain embodiments, the tautomerized form may be a prototropic tautomer, which is a protonated state of an isomer having the same empirical formula and total charge as the reference form. Examples of moieties having prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, amide-imoid acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. In some embodiments, the tautomers can be in equilibrium or sterically fixed to one form by appropriate substitution. In certain embodiments, the tautomers arise from acetal interconversion.

[0020] Unless otherwise specified, the structures shown herein also mean that they include compounds that differ only in the presence of one or more isotopic enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the present 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 Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as I. Isotope-labeled compounds (e.g.,3 H and 14 Compounds labeled with 1C can be useful in compound or substrate tissue partitioning assays. Tritium labeling (i.e., 3 H), and carbon 14 (i.e., 14 C) Isotopes can be useful due to their ease of preparation and detection. Furthermore, heavier isotopes, such as deuterium (i.e., 2 Substitution with H) etc. can lead to greater metabolic stability, which may result in certain therapeutic benefits (e.g., longer in vivo half-life or reduced dosage). In some embodiments, one or more hydrogen atoms are 2 H or 3 Replaced by H, or one or more carbon atoms 13 C or 14 It is replaced by carbon-rich carbon. 15 O, 13 N, 11 C and 18 Positron-emitting isotopes such as fluorine are useful in positron emission tomography (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 unlabeled reagents with isotopically labeled reagents, following a procedure similar to the procedure disclosed for the compounds of the present invention as described herein.

[0021] As is known from the prior art, many chemical components can be used in various different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be used in any such form, including any solid form. In some embodiments, the compounds described or explained herein can be provided or used in hydrate or solvate form.

[0022] In various parts of this specification, substituents of the compounds of this disclosure are disclosed in groups or ranges. This disclosure is specifically intended to include each individual partial combination of members of such groups and ranges. For example, the term “C1-C6 alkyl” is specifically intended to disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl individually. Furthermore, where a compound includes multiple positions in which substituents are disclosed in groups or ranges, this disclosure is intended to extend to individual compounds containing each and all individual element subcombinations at each position, as well as to groups of compounds (e.g., genera and sub-genera), unless otherwise specified.

[0023] The term “optionally substituted X” (e.g., optionally substituted alkyl) is intended to be equivalent to “X, where X is optionally substituted” (e.g., “alkyl, where the alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) itself is optional. Certain compounds of interest, as described herein, may contain one or more “optionally substituted” moieties. Typically, the term “substituted” means that one or more hydrogens of a specified moiety are substituted by a preferred substituent, e.g., one of the substituents or groups described herein, whether preceded by the term “optionally”. Unless otherwise specified, an “optionally substituted” group may have preferred substituents at each preferred position of the group. Furthermore, if two or more positions in any given structure can be substituted by two or more substituents selected from a particular group, the substituents may be identical or different at each position. For example, in the term “optionally substituted C1-C6 alkyl-C2-C9 heteroaryl”, the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. The substituent combinations conceivable in this disclosure are preferably obtained by forming stable or chemically suitable compounds. The term “stable,” as used in the present invention, means a compound that remains substantially unchanged when subjected to conditions anticipating its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0024] Suitable monovalent substituents on the replaceable carbon atoms of the "optionally substituted" group are, independently, deuterium, halogen, -(CH2)O-4R°, -(CH2)O-4OR°, and -O(CH2)O-4R°. °-O-(CH2)O-4C(O)OR°, -(CH2)O-4CH(OR°)2, -(CH2)O-4SR°, -(CH2)O-4Ph[may be substituted with R°], -(CH2)O-4O(CH2)O-1Ph[may be substituted with R°], -CH=CHPh[may be substituted with R°], -(CH2)O-4O(CH2)O-1-pyridyl[may be substituted with R°]. ], 4-8 member saturated or unsaturated heterocycloalkyl (e.g., pyridyl), 3-8 member saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), -NO2, -CN, -N3, -(CH2)O-4N(R°)2, -(CH2)O-4N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2)O-4N(R°)C(O)NR°2, -N(R°)C(S)NR°2, -(CH2)O-4N(R°) C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -C(S)R°, -(CH2)0-4C(O )OR°, -(CH2)0-4-C(O)-N(R°)2, -(CH2)0-4-C(O)-N(R°)-S(O)2-R°, -C(NCN)NR°2, -(CH2)0-4C(O)SR°, -(CH2)0-4C(O)OSi R°3, -(CH2)0-4OC(O)R°, -OC(O)(CH2)0-4SR°, -SC(S)SR°, -(CH2)0-4SC(O)R°, -(CH2)0-4C(O)NR°2, -C(S)NR°2, -C(S)SR °, -(CH2)0-4OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2)0-4SSR°, -(CH2)0-4S(O)2R °, -(CH2)0-4S(O)2OR°, -(CH2)0-4OS(O)2R°, -S(O)2NR°2, -(CH2)0-4S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(OR° )R°, -C(NOR°)NR°2, -C(NH)NR°2, -P(O)2R°, -P(O)R°2, -P(O)(OR°)2, -OP(O)R°2, -OP(O)(OR°)2, -OP(O)(OR°)R°, -SiR°3,-(C1-4 straight-chain or branched-chain alkylene)O-N(R°)2, or -(C1-4 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, -C1-6 aliphatic, -CH2Ph, -O(CH2)0-1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered, saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definition, two independently existing R°s together with the intervening atom(s) form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and these may be substituted as defined below.,

[0025] Suitable monovalent substituents on R° (or the ring formed using two independently existing R°s together with the intervening atom(s)) are independently halogen, -(CH2)0-2R ● , -(haloR ● ), -(CH2)0-2OH, -(CH2)0-2OR ● , -(CH2)0-2CH(OR ● )2, -O(haloR ● ), -CN, -N3, -(CH2)0-2C(O)R ● , -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR ● , -(CH2)0-2SR ● , -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR ● , -(CH2)0-2NR ● 2, -NO2, -SiR ● 3, -OSiR ● 3, -C(O)SR ● , -(C1-4 straight-chain or branched-chain alkylene)C(O)OR ● , or -SSR ● and may be, wherein each R ●The atoms are either unsubstituted or, where the prefix "halo" is located, substituted by only one or more halogens, and are independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents on the saturated carbon atom of R° include =O and =S.

[0026] Suitable divalent substituents on the saturated carbon atom of the "arbitrarily substituted" group are: =O, =S, =NNR * 2. =NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2))2-3O-, or -S(C(R * 2))2-3S- are listed, and in the formula, R exists independently in each case. * The group is selected from unsubstituted 5-6 membered, saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from hydrogen, C1-6 aliphatic which can be substituted as defined below, or nitrogen, oxygen, or sulfur. A preferred divalent substituent bonded to the vicinal substituteable carbon of the "optionally substituted" group is -O(CR * 2) 2-3O- are given, and in the formula, R exists independently of each other. * This is selected from hydrogen, C1-6 aliphatic atoms which can be substituted as defined below, or from unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0027] R * A suitable substituent on the aliphatic group is -R ● , (HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ●-NH2, -NHR ● , -NR ● 2, or -NO2, and in the formula, each R ● The ring is either unsubstituted, or, where it is preceded by "halo", substituted by only one or more halogens, and is independently a C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] A suitable substituent on the substituted nitrogen of the "arbitrarily substituted" group is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † These are listed, and in the formula, each R † R is independently a saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from hydrogen, C1-6 aliphatic which can be substituted as defined below, unsubstituted -OPh, or nitrogen, oxygen, or sulfur, or two independently existing R † These atoms, along with the atoms (or multiple atoms) interposed between them, form unsubstituted 3-12 member saturated, partially unsaturated, or aryl mono- or bicyclic rings containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] R † Suitable substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ●), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● R is either unsubstituted, or, where it is preceded by "halo", substituted by only one or more halogens, and is independently a C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, 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 atom include =O and =S.

[0030] As used herein, the term "acetyl" means the group -C(O)CH3.

[0031] As used herein, the term "alkoxy" means -O-C1-C 20 Alkyl grouping means that the alkoxy group is bonded to the rest of the compound via an oxygen atom.

[0032] As used herein, the term “alkyl” means a saturated, linear, or branched monovalent hydrocarbon group containing 1 to 20 (e.g., 1 to 10, or 1 to 6) carbon atoms. In some embodiments, the alkyl group is unbranched (i.e., linear), and in some embodiments, the alkyl group is branched. Alkyl groups are exemplified by, but are not limited to, methyl, ethyl, n- and isopropyl, n-, sec-, iso and tert-butyl, and neopentyl.

[0033] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group derived from a straight-chain or branched-chain saturated hydrocarbon by removing two hydrogen atoms, exemplified by methylene, ethylene, isopropylene, etc. x -C y"Alkylene" refers to an alkylene group having x to y carbon atoms. Exemplary values ​​for x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C 10 , C2-C 20 , C2-C6, C2-C 10 , or C2-C 20 Alkylene). In some embodiments, the alkylene may be further substituted with one, two, three, or four substituents as defined herein.

[0034] As used herein, the term “alkenyl” means, unless otherwise specified, a monovalent linear or branched group of 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms) containing one or more carbon-carbon double bonds, exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyls include both cis and trans isomers. As used herein, the term “alkenylene” means, unless otherwise specified, a divalent linear or branched group of 2 to 20 carbon atoms (e.g., 2 to 6 or 2 to 10 carbon atoms) containing one or more carbon-carbon double bonds.

[0035] As used herein, the term "alkynyl" refers to a monovalent linear or branched group consisting of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbon atoms) containing a carbon-carbon triple bond, as exemplified by ethynyl and 1-propynyl.

[0036] As used herein, the term "alkynyl sulfone" means structure [ka] [wherein R is any chemically suitable substituent as described herein.] represents a group containing ]

[0037] As used herein, the term "amino" means -N(R† )2, for example, represents -NH2 and -N(CH3)2.

[0038] As used herein, the term "aminoalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more amino moieties.

[0039] As used herein, the term “amino acid” means a molecule having a side chain, an amino group, and an acidic group (e.g., -CO2H or -SO3H), and an amino acid is bonded to a parent molecule by a side chain, an amino group, or an acidic group (e.g., a 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, for example, by the formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure H2N-C(H)(R)-COOH. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid, in some embodiments, an amino acid is a D-amino acid, and in some embodiments, an amino acid is an L-amino acid. “Standard amino acid” means any of the 20 standard L-amino acids commonly found in naturally occurring peptides. Examples of amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxylnorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolicine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0040] As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system formed by carbon atoms, wherein the ring bonded to the pendant group is aromatic. Examples of aryl groups include phenyl, naphthyl, phenantrenyl, and anthracenyl. The aryl ring may be bonded to its pendant group by any heteroatom or carbocyclic atom that results in a stable structure, and unless otherwise specified, any of the ring atoms may be substituted.

[0041] As used herein, the term "C0" represents a bond. For example, part of the term -N(C(O)-(C0-C5alkylene-H)- includes -N(C(O)-(C0alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0042] As used herein, the terms “carbocyclic” and “carbocyclyl” mean a monovalent, optionally substituted C3-C12 monocyclic, dicyclic, or tricyclic cyclic structure, which may optionally be bridged, condensed, or spirocyclic, where all rings are formed of carbon atoms and at least one ring is non-aromatic. Examples of carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups include cyclohexyl, cyclohexenyl, cyclooctinyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, and dekalinyl. The carbocyclic ring can be bonded to its pendant group at any ring atom that results in a stable structure, and any of the ring atoms may be optionally substituted unless otherwise specified.

[0043] As used herein, the term "carbonyl" refers to a C(O) group, which can also be represented as C=O.

[0044] As used herein, the term "carboxyl" means -CO2H, (C=O)(OH), COOH, or C(O)OH, or the corresponding aprotonated group.

[0045] As used herein, the term "cyano" refers to the -CN group.

[0046] As used herein, the term "cycloalkyl" means a monovalent saturated cyclic hydrocarbon group, which may be crosslinked, condensed, or a spirocyclic group having 3 to 8 carbon atoms, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.

[0047] As used herein, the term "cycloalkenyl" means a monovalent non-aromatic saturated cyclic hydrocarbon group, which, unless otherwise specified, may be crosslinked, condensed, or a spirocyclic group having 3 to 8 carbon atoms and containing one or more carbon-carbon double bonds.

[0048] As used herein, the term “diastereomer” means a stereoisomer that is not a mirror image of another and cannot be superimposed on another.

[0049] As used herein, “enantiomer” means each individual optically active form of the compound of the present invention having 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 at least 98% optical purity or enantiomer excess (measured by methods standard in the art).

[0050] The term "guanidyl" refers to the structure [ka] [wherein each R is independently any chemically suitable substituent as described herein.] This means a group having [a specific value].

[0051] As used herein, the term "guanidinoalkylalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted by one or more guanidyl moieties.

[0052] As used herein, the term "haloacetyl" means an acetyl group in which at least one hydrogen atom is substituted with a halogen.

[0053] As used herein, the term "haloalkyl" refers to an alkyl moiety in which one or more carbon atoms are replaced by one or more identical or different halogen moieties.

[0054] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0055] As used herein, the term “heteroalkyl” refers to an “alkyl” group (as defined herein) in which at least one carbon atom is replaced by a heteroatom (e.g., an O, N, or S atom). The heteroatom may appear in the middle or at the ends of the radical.

[0056] As used herein, the term “heteroaryl” refers to a monovalent monocyclic or polycyclic cyclic structure containing at least one complete aromatic ring. That is, these contain 4n+2 π electrons within the monocyclic or polycyclic ring system and contain at least one ring heteroatom selected from N, O, or S within the aromatic ring. Exemplary unsubstituted heteroaryl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbon atoms. The term “heteroaryl” also includes 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. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindylol. The heteroaryl ring can be bonded to its pendant group at any ring atom that results in a stable structure, and any of the ring atoms can be optionally substituted unless otherwise specified. In some embodiments, the heteroaryl is substituted with 1, 2, 3, or 4 substituents.

[0057] As used herein, the term "heterocycloalkyl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system, which may be bridged, condensed, or spirocyclic, in which at least one ring is non-aromatic, and the non-aromatic ring contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Five-membered rings have 0 to 2 double bonds, and six- and seven-membered rings have 0 to 3 double bonds. Exemplary unsubstituted heterocycloalkyl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbon atoms. The term "heterocycloalkyl" also refers to heterocyclic compounds having a bridged polycyclic structure in which one or more carbons or heteroatoms bridge two non-adjacent elements of a monocyclic ring, e.g., a quinuclidinyl group. The term "heterocycloalkyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, such as an aryl ring, cyclohexane ring, cyclohexene ring, cyclopentane ring, cyclopentene ring, pyridine ring, or pyrrolidine ring. Examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronaphthilidinyl. Heterocycloalkyl rings can be bonded to their pendant group at any ring atom that results in a stable structure, and any of the ring atoms can be substituted unless otherwise specified.

[0058] As used herein, the term "hydroxy" refers to the -OH group.

[0059] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety in which one or more carbon atoms are substituted with one or more -OH moieties.

[0060] As used herein, “isomer” means any tautomer, stereoisomer, atropisomer, enantiomer, or diastereomer of any compound of the present invention. The compounds of the present invention may have one or more chiral centers or double bonds and are therefore recognized to exist as stereoisomers, e.g., double bond isomers (i.e., geometric E / Z isomers), or diastereomers (e.g., enantiomers (i.e., (+) or (-), or cis / trans isomers)). According to the present invention, the chemical structures described herein, and therefore the compounds of the present invention, are recognized to exist as all corresponding stereoisomers, i.e., stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereally pure), as well as enantiomers. This includes both isomers and stereoisomeric mixtures (e.g., racemic compounds). Enantiomers and stereoisomeric mixtures of the compounds of the present invention can usually be broken down into their constituent enantiomers or stereoisomers by well-known methods, such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereoisomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthesis methods.

[0061] As used herein, the term "linker" means a divalent organic moiety in the compound of formula I that connects moiety B to moiety W, such that the resulting compound can achieve an IC50 of 2 μM or less in the following examples and the Ras-RAF disruption assay protocol provided herein.

[0062] The purpose of this biochemical assay is to measure the ability of the test compound to facilitate the formation of a ternary complex between the nucleotide load Ras isoform and cyclophyllin A, and the resulting ternary complex is BRAF. RBD It disrupts binding to constructs and inhibits Ras signaling via RAF effectors.

[0063] In an assay buffer containing 25 mM HEPES (pH 7.3), 0.002% Tween® 20, 0.1% BSA, 100 mM NaCl and 5 mM MgCl2, untagged cyclophyllin A, His6-K-RasGMPPNP (or other Ras variants), and GST-BRAF were added. RBD These compounds were combined in a 384-well assay plate at final concentrations of 25 μM, 12.5 nM, and 50 nM, respectively. The compounds were present in the plate wells as a 10-point 3-fold dilution series, starting at a final concentration of 30 μM. After incubation at 25°C for 3 hours, the mixture of anti-His Eu-W1024 and anti-GST allophycocyanin was added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reaction was incubated for a further 1.5 hours. The TR-FRET signal was read using a microplate reader (excitation 320 nm, fluorescence 665 / 615 nm). Compounds that promote the disruption of the Ras:RAF complex were identified as those that induced a decrease in the TR-FRET ratio compared to the DMSO control well.

[0064] 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 500 g / mol. In some embodiments, the linker has a molecular weight of less than 400 g / mol. In some embodiments, the linker has a molecular weight of less than 300 g / mol. In some embodiments, the linker has a molecular weight of less than 200 g / mol. In some embodiments, the linker has a molecular weight of less than 100 g / mol. In some embodiments, the linker has a molecular weight of less than 50 g / mol.

[0065] As used herein, the "monovalent organic moiety" is less than 500 kDa. In some embodiments, the "monovalent organic moiety" is less than 400 kDa. In some embodiments, the "monovalent organic moiety" is less than 300 kDa. In some embodiments, the "monovalent organic moiety" is less than 200 kDa. In some embodiments, the "monovalent organic moiety" is less than 100 kDa. In some embodiments, the "monovalent organic moiety" is less than 50 kDa. In some embodiments, the "monovalent organic moiety" is less than 25 kDa. In some embodiments, the "monovalent organic moiety" is less than 20 kDa. In some embodiments, the "monovalent organic moiety" is less than 15 kDa. In some embodiments, the "monovalent organic moiety" is less than 10 kDa. In some embodiments, the "monovalent organic moiety" is less than 1 kDa. In some embodiments, the "monovalent organic moiety" is less than 500 g / mol. In some embodiments, the "monovalent organic moiety" is in the range of 500 g / mol to 500 kDa.

[0066] As used herein, the term “stereoisomer” means all possible different isomeric and structural forms that a compound may have (for example, any compound of any formula described herein), in particular all possible stereochemical and structural isomeric forms of the basic molecular structure, including atropisomers, all diastereomers, enantiomers, or conformational isomers. Some of the compounds of the present invention may exist in different tautomers, all of which are included in the scope of the present invention.

[0067] As used herein, the term "sulfonyl" refers to the -S(O)2- group.

[0068] As used herein, the term "thiocarbonyl" means a -C(S)- group.

[0069] As used herein, the term "vinyl ketone" means a group containing a carbonyl group directly bonded to a carbon-carbon double bond.

[0070] As used herein, the term "vinyl sulfone" means a group containing a sulfonyl group directly bonded to a carbon-carbon double bond.

[0071] As used herein, the term "inon" means structure [ka] [wherein R is any chemically suitable substituent as described herein.] represents a group containing ]

[0072] Those skilled in the art reading this disclosure will understand that certain compounds described herein may be provided or available in any of the following forms, such as salt form, protected form, prodrug form, ester form, isomer form (e.g., optical or structural isomer), isotopic form, etc. In some embodiments, reference to a particular compound may relate to a particular form of that compound. In some embodiments, reference to a particular compound may relate to the compound in any form. In some embodiments, for example, a preparation of a single stereoisomer of a compound may be considered a different form of the compound from a racemic mixture of the compound; a particular salt of a compound may be considered a different form from another salt form of the compound; a preparation containing a structural isomer of a double bond ((Z) or (E)) may be considered a different form from one containing other structural isomers of the double bond ((E) or (Z)); and a preparation in which one or more atoms are isotopes different from those present in the reference preparation may be considered a different form.

[0073] (Detailed explanation) compound RAS inhibitors are provided herein. The approach described herein requires the formation of a high-affinity triplicate complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein (e.g., Ras) and a cytosolic chaperone (presenter protein) that is widely expressed intracellularly (e.g., cyclophyllin A). More specifically, in some embodiments, the Ras inhibitors described herein include a novel binding pocket cytosol in Ras, which drives the formation of a high-affinity triplicate complex between the Ras protein and the widely expressed cytosolic chaperone cyclophyllin A (CYPA). While not theoretically bound, the inventors believe that one way in which the inhibitory effect on Ras is affected by the compounds and complexes of the present invention is the formation of steric occlusion of the interaction site between Ras and downstream effector molecules such as RAFs, which is necessary for the growth of oncogenic signals.

[0074] While not bound by theory, the inventors hypothesize that non-covalent interactions of the compounds of the present invention with Ras and chaperone proteins (e.g., cyclophyllin A) may contribute to the inhibition of Ras activity. For example, van der Waals interactions, hydrophobic interactions, hydrophilic interactions, and hydrogen bonding interactions, as well as combinations thereof, may contribute to the ability of the compounds of the present invention to form complexes and act as RAS inhibitors. Thus, various Ras proteins can be inhibited by the compounds of the present invention (e.g., K-Ras, N-Ras, H-Ras at positions 12, 13, and 61, and their variants, e.g., G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, as well as others described herein).

[0075] Therefore, compounds having the structure of formula 00, or pharmaceutically acceptable salts thereof, are provided herein: [ka] [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH3)C(O)-(CH2)-[wherein amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-10 member heteroarylenes, G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[In the formula, the second C is -C(R 7 R 8 )- is bonded. ], -C(O)NH-CH(R 6 )-[In the formula, the second C is -C(R 7 R 8 )- is bonded to it. ], optionally substituted C1-C4 heteroalkylenes, or 3-8 member heteroarylenes, swIp (switch I / P-loop) refers to an organic moiety that non-covalently binds to both the switch I binding pocket and residues 12 or 13 of the P-loop of the Ras protein (see, for example, Johnson et al., 292:12981-12993 (2017), incorporated herein by reference). X 1 This is an optionally substituted C1-C2 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-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2. Each R' is independently H or an optionally substituted C1-C4 alkyl group. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 Independently, C or N, Y 5 is CH, CH2, or N, Y 6 It is C(O), CH, CH2, or N, R 1 This is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 1 and R 2 These combine with the atoms to which they bond, forming optionally substituted 3-14 member heterocycloalkyl groups. R 2 It is either absent, or hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5 or 6-membered heteroaryl. R 3 It does not exist, or R 2 and R 3 These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R 4 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1 to 3 halogens. R 5These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens. R 6 R is hydrogen or methyl, 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 8 This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 These combine with the carbon atoms they bond to, forming C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8a These are independently hydrogen, halos, or optionally substituted C1-C3 alkyl groups, or they combine with the carbon they bond to to form a carbonyl group. R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 10 These are hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl. R 10a is hydrogen or halo, and R 16 This is hydrogen or a C1-C3 alkyl group (e.g., methyl). In some embodiments, the resulting compounds can achieve an IC50 of 2 μM or less (e.g., 1.5 μM, 1 μM, 500 nM, or 100 nM or less) in the Ras-RAF disruption assay protocols described herein.

[0076] Therefore, compounds having the structure of formula I, or pharmaceutically acceptable salts thereof, are provided herein: [ka] [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH3)C(O)-(CH2)-[wherein amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-10 member heteroarylenes, B does not exist, or -CH(R9 )-or>C=CR 9 R 9’ [In the formula, carbon is -N(R 11 )[bonded to the carbonyl carbon of C(O)-], optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes, G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[In the formula, the second C is -C(R 7 R 8 )- is bonded. ], -C(O)NH-CH(R 6 )-[In the formula, the second C is -C(R 7 R 8 )- is bonded to it. ], optionally substituted C1-C4 heteroalkylenes, or 3-8 member heteroarylenes, L does not exist, or it is a linker. W is hydrogen, cyano, S(O)2R', optionally substituted amino, optionally substituted amide, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. X 1 This is an optionally substituted C1-C2 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-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2. Each R' is independently H or an optionally substituted C1-C4 alkyl group. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 Independently, C or N, Y 5 is CH, CH2, or N, Y 6 It is C(O), CH, CH2, or N, R 1 This is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 1 and R 2 These combine with the atoms to which they bond, forming optionally substituted 3-14 member heterocycloalkyl groups. R 2 It is either absent, or hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5 or 6-membered heteroaryl. R 3 It does not exist, or R 2 and R 3These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R 4 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1 to 3 halogens. R 5 These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens. R 6 R is hydrogen or methyl, 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 8 This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 These combine with the carbon atoms they bond to, forming C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8a These are independently hydrogen, halos, or optionally substituted C1-C3 alkyl groups, or they combine with the carbon they bond to to form a carbonyl group. R7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, or R 9 And L combine with the atoms to which they are bonded to form optionally substituted 3-14 member heterocycloalkyl groups. R 9’ is a hydrogen- or optionally substituted C1-C6 alkyl group, R 10 These are hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl. R 10a is hydrogen or halo, R 11 is hydrogen or C1-C3 alkyl, R 16 [This is hydrogen or a C1-C3 alkyl group (e.g., methyl).]

[0077] In some embodiments, the present disclosure features a compound of structural formula Ia, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH3)C(O)-(CH2)-[wherein amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-10 member heteroarylenes, B is -CH(R 9 )-or>C=CR 9 R 9’ [In the formula, carbon is -N(R 11 )[bonded to the carbonyl carbon of C(O)-], optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes, G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[In the formula, the second C is -C(R 7 R 8 )- is bonded. ], -C(O)NH-CH(R 6 )-[In the formula, the second C is -C(R 7 R 8 )- is bonded to it. ], optionally substituted C1-C4 heteroalkylenes, or 3-8 member heteroarylenes, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. X1 This is an optionally substituted C1-C2 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-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2. Each R' is independently H or an optionally substituted C1-C4 alkyl group. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 Independently, C or N, Y 5 is CH, CH2, or N, Y 6 It is C(O), CH, CH2, or N, R 1 This is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 1 and R 2 These combine with the atoms to which they bond, forming optionally substituted 3-14 member heterocycloalkyl groups. R 2It is either absent, or hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5 or 6-membered heteroaryl. R 3 It does not exist, or R 2 and R 3 These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R 4 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1 to 3 halogens. R 5 These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens. R 6 R is hydrogen or methyl, 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 8 This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 These combine with the carbon atoms they bond to, forming C=CR 7’ R8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8a These are independently hydrogen, halos, or optionally substituted C1-C3 alkyl groups, or they combine with the carbon they bond to to form a carbonyl group. R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 9 This is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, or R 9 And L combine with the atoms to which they are bonded to form optionally substituted 3-14 member heterocycloalkyl groups. R 9’ is a hydrogen- or optionally substituted C1-C6 alkyl group, R 10 These are hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl. R 10a is hydrogen or halo, and R 11[It is hydrogen or a C1-C3 alkyl group.]

[0078] In some embodiments, the present disclosure features a compound of structural formula Ib, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH3)C(O)-(CH2)-[wherein amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-6 member heteroarylenes, B is -CH(R 9 )-[In the formula, carbon is -N(R 11 )[bonded to the carbonyl carbon of C(O)-], optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes, G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[In the formula, the second C is -C(R 7 R 8 )- is bonded. ], -C(O)NH-CH(R 6 )-[In the formula, the second C is -C(R 7 R 8 )- is bonded to it. ], optionally substituted C1-C4 heteroalkylenes, or 3-8 member heteroarylenes, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. X 1 This is an optionally substituted C1-C2 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-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2. Each R' is independently H or an optionally substituted C1-C4 alkyl group. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 Independently, C or N, Y 5 and Y 6 They are independently CH or N, R 1 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2R is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, 3 It does not exist, or, R 2 and R 3 These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R 4 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1 to 3 halogens. R 5 These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens. R 6 R is hydrogen or methyl, 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 8 This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 These combine with the carbon atoms they bond to, forming C=CR 7’ R 8’, forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 9 This is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl. R 10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 [It is hydrogen or a C1-C3 alkyl group.]

[0079] In some embodiments of the compounds of the present invention, G is an optionally substituted C1-C4 heteroalkylene.

[0080] In some embodiments, the compounds of the present invention have the structure of formula Ic, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH3)C(O)-(CH2)-[wherein amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-6 member heteroarylenes, B is -CH(R 9 )-[In the formula, carbon is -N(R 11 )[bonded to the carbonyl carbon of C(O)-], optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. 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-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2. Each R' is independently H or an optionally substituted C1-C4 alkyl group. Y 1 is C, CH, or N, Y2 , Y 3 , Y 4 , and Y 7 Independently, C or N, Y 5 and Y 6 They are independently CH or N, R 1 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 These are hydrogen, optionally substituted C1-C6 alkyls, optionally substituted C2-C6 alkenyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-7 member heterocycloalkyls, optionally substituted 6 member aryls, and optionally substituted 5 or 6 member heteroaryls. R 3 It does not exist, or R 2 and R 3 These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R 4 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1 to 3 halogens. R 5 These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens. R 6 R is hydrogen or methyl, 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 8 This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 These combine with the carbon atoms they bond to, forming C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 9 This is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl. R 10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl, and R 11 [It is hydrogen or a C1-C3 alkyl group.]

[0081] In some embodiments of the present invention, X 2 is NH. In some embodiments, X 3 It is CH.

[0082] In some embodiments of the compounds of the present invention, R 11 is hydrogen. In some embodiments, R 11 is a C1-C3 alkyl group. In some embodiments, R 11 It is methyl.

[0083] In some embodiments, the compounds of the present invention have the structure of formula Id, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH3)C(O)-(CH2)-[wherein amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-6 member heteroarylenes, B is -CH(R 9 )-[wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. n is 0, 1, or 2. R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2. Each R' is independently H or an optionally substituted C1-C4 alkyl group. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 Independently, C or N, Y 5 and Y 6 They are independently CH or N, R 1 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 R is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, 3 It does not exist, or, R 2 and R 3 These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R 4 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1 to 3 halogens. R 5 These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens. R 6 R is hydrogen or methyl, 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 8 This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 These combine with the carbon atoms they bond to, forming C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl, and R 10 [These are hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.]

[0084] In some embodiments of the present invention, X 1 is an optionally substituted C1-C2 alkylene. In some embodiments, X 1 is methylene. In some embodiments, X 1 is a methylene group substituted with a C1-C6 alkyl group or halogen. In some embodiments, X 1 is -CH(Br)-. In some embodiments, X 1 It is -CH(CH3)-.

[0085] In some embodiments of the compounds of the present invention, R 3 It does not exist.

[0086] In some embodiments of the compounds of the present invention, R 4 It is hydrogen.

[0087] In some embodiments of the compounds of the present invention, R5 is hydrogen. In some embodiments, R 5 is a C1-C4 alkyl group optionally substituted with a halogen. In some embodiments, R 5 It is methyl.

[0088] In some embodiments of the compound of the present invention, Y 4 is C. In some embodiments, Y 5 is CH. 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 In some embodiments, Y 7 C is C.

[0089] In some embodiments, the compounds of the present invention have the structure of formula Ie, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, A is -N(H or CH3)C(O)-(CH2)-[In the formula, amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-6 member heteroarylenes, B is -CH(R 9 )-[wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. R 1 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 R is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, 3 It does not exist, or, R 2 and R 3 These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R 5 These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens. R 6 R is hydrogen or methyl, 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 8 This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 These combine with the carbon atoms they bond to, forming C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl, and R 10 [These are hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.]

[0090] In some embodiments of the compounds of the present invention, R 6 It is hydrogen.

[0091] In some embodiments of the compounds of the present invention, R 2 R is hydrogen, cyano, optionally substituted C1-C6 alkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-6 member heterocycloalkyl. In some embodiments, R 2 is an optionally substituted C1-C6 alkyl such as ethyl. In some embodiments, R 2 The fluoroC1-C6 alkyl group is, for example, -CH2CH2F, -CH2CHF2, or -CH2CF3.

[0092] In some embodiments of the compounds of the present invention, R 7 is an optionally substituted C1-C3 alkyl group. In some embodiments, R 7 It is a C1-C3 alkyl group.

[0093] In some embodiments of the compounds of the present invention, R 8 is an optionally substituted C1-C3 alkyl group. In some embodiments, R 8 These are C1-C3 alkyl groups such as methyl.

[0094] In some embodiments, the compounds of the present invention have the structure of formula If, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, 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 5- to 6-membered heteroarylene.] B is -CH(R9 )-[wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. R 1 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 These are C1-C6 alkyl or 3-6 member cycloalkyl groups. R 7 It is a C1-C3 alkyl group, R 8 It is a C1-C3 alkyl group, and R 9 This is an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group.

[0095] In some embodiments of the compounds of the present invention, R 1 R is a 5-10 member heteroaryl. In some embodiments, R 1is an arbitrarily substituted six-membered aryl or an arbitrarily substituted six-membered heteroaryl.

[0096] In some embodiments of the compounds of the present invention, R1 is [ka] or these stereoisomers. In some embodiments, R1 is [ka] or its stereoisomer. Depending on the embodiment, R1 is [ka] In some embodiments, R1 is [ka] or its stereoisomer. Depending on the embodiment, R1 is [ka] That is the case.

[0097] In some embodiments, the compounds of the present invention have the structure of formula Ig, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, 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 5- to 6-membered heteroarylene.] B is -CH(R 9)-[wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. R 2 These are C1-C6 alkyl or 3-6 member cycloalkyl groups. R 7 It is a C1-C3 alkyl group, R 8 It is a C1-C3 alkyl group, R 9 This is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl. X e is N, CH, or CR 17 And, X f is N or CH, R 12 is an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C6 heteroalkyl group, and R 17This is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl.

[0098] In some embodiments of the present invention, X e is N, and X f is CH. In some embodiments, X e CH is X f In some embodiments, X e CR 17 X f It is N.

[0099] In some embodiments of the compounds of the present invention, R 12 is an optionally substituted C1-C6 heteroalkyl. In some embodiments, R 12 teeth, [ka] That is the case.

[0100] In some embodiments, the compounds of the present invention have the structure of formula Ih, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, 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 5- to 6-membered heteroarylene.] B is -CH(R 9)-[wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. R 2 These are C1-C6 alkyl or 3-6 member cycloalkyl groups. R 7 It is a C1-C3 alkyl group, R 8 It is a C1-C3 alkyl group, R 9 This is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl. X e CH, or CR 17 And, R 17 This is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl.

[0101] In some embodiments, the compounds of the present invention have the structure of formula II, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, 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 5- to 6-membered heteroarylene.] B is -CH(R 9 )-[wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. R 2 These are C1-C6 alkyl or 3-6 member cycloalkyl groups. R 7 It is a C1-C3 alkyl group, R 8 It is a C1-C3 alkyl group, and R 9 This is an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group.

[0102] In some embodiments of the compounds of the present invention, A is an optionally substituted six-membered arylene. In some embodiments, A is structural [ka] [In the formula, R 13 is hydrogen, hydroxyl, amino, cyano, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. ] has. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 is hydroxyl. In some embodiments, A is an optionally substituted 5-10 membered heteroarylene. In some embodiments, A is [ka] In some embodiments, A is an optionally substituted 5-6 member heteroarylene. In some embodiments, A is [ka] In some embodiments, A is [ka] That is the case.

[0103] In some embodiments of the compound of the present invention, B is -CHR 9 - In some embodiments, R 9 is an optionally substituted C1-C6 alkyl or an optionally substituted 3-6 member cycloalkyl. In some embodiments, R 9 teeth, [ka] In some embodiments, R 9 teeth, [ka] In some embodiments, R 9This is an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group.

[0104] In some embodiments, B is an optionally substituted six-membered arylene.

[0105] In some embodiments, B is a 6-membered arylene. In some embodiments, B is [ka] In some embodiments, B does not exist.

[0106] In some embodiments of the compounds of the present invention, R 7 It is methyl.

[0107] In some embodiments of the compounds of the present invention, R 8 It is methyl.

[0108] In some embodiments of the compounds of the present invention, R 16 It is hydrogen.

[0109] In some embodiments of the compounds of the present invention, the linker has the structure of formula II: A 1 -( B 1 ) f -(C 1 ) g -( B 2 ) h -(D 1 )-(B 3 ) i -(C 2 ) j -( B 4 ) k -A 2 Formula II [In the formula, A 1 This is the bond between the linker and B; A 2This is the bond between W and the linker; B 1 B 2 B 3 , and B 4 These are, independently, an arbitrarily substituted C1-C2 alkylene, an arbitrarily substituted C1-C3 heteroalkylene, O, S, and NR. N Selected from; R N This includes hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C3 cycloalkyl, and optionally substituted C 2-C4 Alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted C1-C7 heteroalkyl; C 1 and C 2 Each is independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; D 1 This is an arbitrarily substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylene, optionally substituted 3-14 member heterocycloalkylene, optionally substituted 5-10 member heteroarylene, optionally substituted 3-8 member cycloalkylene, optionally substituted 6-10 member arylene, optionally substituted C2-C 10 Polyethylene glycolen, or optionally substituted C1-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 2It is a chemical bond that connects to [the other element]. In some embodiments, the linker is acyclic. In some embodiments, the linker has the structure of formula IIa: [ka] [In the formula, X a It does not exist, or it is N. R 14 is either absent, or a hydrogen- or optionally substituted C1-C6 alkyl or optionally substituted C1-C3 cycloalkyl, and L 2 It does not exist, or it is -C(O)-, -SO2-, an arbitrarily substituted C1-C4 alkylene, or an arbitrarily substituted C1-C4 heteroalkylene, X a , R 14 , or L 2 At least one of these exists. ] In some embodiments, the linker has the following structure: [ka] In some embodiments, L is [ka] In some embodiments, L is [ka] In some embodiments, the linker is a cyclic group or contains a cyclic group. In some embodiments, the linker has the structure of formula IIb: [ka] [In the formula, o is either 0 or 1, X b is C(O) or SO2, R 15 is a hydrogen- or optionally substituted C1-C6 alkyl group, 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 It is either absent, -C(O)-, -SO2-, optionally substituted C1-C4 alkylene, or optionally substituted C1-C4 heteroalkylene. In some embodiments, the linker has the following structure: [ka] [ka]

[0110] In some embodiments of the compounds of the present invention, W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or 3- to 8-membered heteroaryl.

[0111] In some embodiments of the compounds of the present invention, W is hydrogen. In some embodiments, W is an optionally substituted amino acid. In some embodiments, W is -NHCH3 or -N(CH3)2. In some embodiments, W is an optionally substituted C1-C4 alkoxy. In some embodiments, W is methoxy or isopropoxy. In some embodiments, W is an optionally substituted C1-C4 alkyl. In some embodiments, W is methyl, ethyl, isopropyl, tert-butyl, or benzyl. In some embodiments, W is an optionally substituted amide. In some embodiments, W is [ka] In some embodiments, W is an optionally substituted amide. In some embodiments, W is [ka] In some embodiments, W is an optionally substituted C1-C4 hydroxyalkyl. In some embodiments, W is [ka] In some embodiments, W is an optionally substituted C1-C4 aminoalkyl. In some embodiments, W is [ka] In some embodiments, W is an optionally substituted C1-C4 haloalkyl. In some embodiments, W is [ka] In some embodiments, W is an optionally substituted C1-C4 guanidinoalkyl. In some embodiments, W is [ka] In some embodiments, W is a 3- to 11-membered heterocycloalkyl group optionally substituted with a C0-C4 alkyl group. In some embodiments, W is [ka] [ka] [ka] [ka] [ka] In some embodiments, W is an optionally substituted 3- to 8-membered cycloalkyl group. In some embodiments, W is [ka] In some embodiments, W is an optionally substituted 3- to 8-membered heteroaryl. In some embodiments, W is [ka] In some embodiments, W is an optionally substituted 6- to 10-membered aryl (e.g., phenyl, 4-hydroxyphenyl, or 2,4-methoxyphenyl).

[0112] In some embodiments, the compounds of the present invention are selected from Table 1, or are pharmaceutically acceptable salts or stereoisomers thereof. In some embodiments, the compounds of the present invention are selected from Table 1, or are pharmaceutically acceptable salts or atropisomers thereof.

[0113] [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 1-97

Table 1-110

Table 1-120

Table 1-150

[0114] Note that some compounds exhibit flat or wedge-shaped bonds. In some cases, the relative stereochemistry of stereoisomers has been measured. In some cases, the absolute stereochemistry has been measured. In some cases, a single example number corresponds to a mixture of stereoisomers. All stereoisomers of the compounds in the table above are conceived by the present invention. In certain embodiments, atropisomers of the compounds in the table above are conceived. All compounds in parentheses indicate that the compound is a diastereomer and that the absolute stereochemistry of such a diastereomer cannot be shown.

[0115] In some embodiments, compounds from Table 2 or pharmaceutically acceptable salts thereof are provided. In some embodiments, the compounds of the present invention are selected from Table 2, or are pharmaceutically acceptable salts or atrop isomers thereof. [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]

[0116] Note that some compounds exhibit flat or wedge-shaped bonds. In some cases, the relative stereochemistry of stereoisomers has been measured. In some cases, the absolute stereochemistry has been measured. All stereoisomers of the compounds in the table above are conceived by this invention. In certain embodiments, atropisomers of the compounds in the table above are conceived.

[0117] In some embodiments, the compounds of the present invention are, or act as, prodrugs for administration to, for example, cells or other targets requiring administration.

[0118] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0119] A method for treating cancer in a subject requiring cancer treatment is provided, the method comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. The cancer may be, for example, pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid cancer, myelodysplastic syndrome, or small squamous cell carcinoma or follicular carcinoma. In some embodiments, the cancer includes Ras mutations such as K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, or K-Ras Q61L. Other Ras mutations are described herein.

[0120] A method for treating a Ras protein-related disorder in a subject requiring treatment for the disorder, further comprising administering to the subject a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0121] A method for inhibiting the Ras protein in cells is provided, further comprising contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. For example, the Ras protein is K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, or K-Ras Q61L. Other Ras proteins are described herein. The cells may be cancer cells such as pancreatic cancer cells, colorectal cancer cells, non-small cell lung cancer cells, acute myeloid leukemia cells, multiple myeloma cells, thyroid cancer cells, myelodysplastic syndrome cells, or small squamous cell carcinoma follicular carcinoma cells. Other types of cancer are described herein. The cells may be in vivo or in vitro.

[0122] With respect to the compounds of the present invention, one stereoisomer may exhibit better inhibition than another. For example, one atropisomer may exhibit inhibition, while other atropisomers may exhibit little to no inhibition.

[0123] In some embodiments, the methods or uses described herein further include administering an additional anticancer therapy. In some embodiments, the additional anticancer 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, 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, or a combination thereof. In some embodiments, the additional anticancer therapy is an SHP2 inhibitor. Other additional anticancer therapies are described herein.

[0124] Synthesis method The compounds described herein may be prepared from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic processes.

[0125] The compounds of the present invention can be prepared by several 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 shown in the following scheme, along with synthetic methods known in the field of organic synthesis chemistry, or variations thereof as understood by those skilled in the art. These methods include, but are not limited to, the methods described in the following scheme.

[0126] The compounds in Table 1 of this specification were prepared using the methods disclosed herein, or prepared using the methods disclosed herein in combination with the knowledge of those skilled in the art. The compounds in Table 2 can be prepared using the methods disclosed herein, or prepared using the methods disclosed herein in combination with the knowledge of those skilled in the art.

[0127] Scheme 1. General synthesis of macrocyclic esters [ka]

[0128] A general synthesis of macrocyclic esters is outlined in Scheme 1. A well-substituted arylindole intermediate (1) can be prepared in three steps, including palladium-mediated coupling, alkylation, and deprotection reactions, starting with protected 3-(5-bromo-2-iodo-1H-indole-3-yl)-2,2-dimethylpropan-1-ol and a well-substituted boronic acid.

[0129] Methyl-amino-hexahydropyridazine-3-carboxylate-boronic acid ester (2) can be prepared in three steps: protection, iridium catalyst-mediated borylation, and methyl(S)-hexahydropyridazine-3-carboxylate.

[0130] By coupling methyl-L-valine with a protected (S)-pyrrolidine-3-carboxylic acid, then deprotecting and coupling with a appropriately substituted carboxylic acid, and then hydrolysis, appropriately substituted acetylpyrrolidine-3-carbonyl-N-methyl-L-valine (4) can be produced.

[0131] In the presence of a Pd catalyst, the methyl-amino-hexahydropyridazine-3-carboxylate-boronic acid ester (2) and intermediate (1) are coupled, followed by hydrolysis and macrolactonization steps to produce the final macrocyclic ester and a well-protected macrocyclic intermediate (5). Deprotection and coupling with a well-substituted acetylpyrrolidine-3-carbonyl-N-methyl-L-valine (4) yield the macrocyclic product. Additional deprotection or functionalization steps are required to produce the final compound. For example, those skilled in the art can introduce a desired -BLW group [wherein B, L, and W are as defined herein] of the compound of formula (I) into the macrocyclic ester by using the methods illustrated in the Examples section of this specification.

[0132] Scheme 2. General synthesis of alternative macrocyclic esters [ka]

[0133] Alternatively, macrocyclic esters can be prepared as described in Scheme 2. A well-protected bromo-indolyl (6) can be coupled with a boronic acid ester (3) in the presence of a Pd catalyst, followed by iodination, deprotection, and ester hydrolysis. After coupling with methyl(S)-hexahydropyridazine-3-carboxylate, hydrolysis and macrolactonization can be followed to obtain an iodine intermediate (7). A fully protected macrocyclic compound (5) can be obtained by coupling with a well-substituted boronic acid ester in the presence of a Pd catalyst and alkylation. Additional deprotection or functionalization steps are required to produce the final compound. For example, those skilled in the art can introduce a desired -BLW group [wherein B, L, and W are as defined herein] of the compound of formula (I) into a macrocyclic ester by using the methods illustrated in the Examples section of this specification.

[0134] Scheme 3. General synthesis of macrocyclic esters. [ka]

[0135] Alternatively, a macrocyclic product can be obtained by deprotecting a fully protected macrocyclic compound (5) and then coupling it with a suitably substituted coupling partner and deprotecting it. Additional deprotection or functionalization steps are required to produce the final compound. For example, those skilled in the art can introduce a desired -BLW group [wherein B, L, and W are as defined herein] of the compound of formula (I) into a macrocyclic ester by using the methods illustrated in the Examples section of this specification.

[0136] Scheme 4. General synthesis of macrocyclic esters [ka]

[0137] A common alternative synthesis of macrocyclic esters is outlined in Scheme 4. Appropriately substituted indolylboronic acid esters (8) can be prepared in four steps, starting with protected 3-(5-bromo-2-iodo-1H-indole-3-yl)-2,2-dimethylpropan-1-ol and an appropriately substituted boronic acid, and involving palladium-mediated coupling, alkylation, deprotection, and palladium-mediated borylation reactions.

[0138] Methyl-amino-3-(4-bromothiazole-2-yl)propanoic acid (9) can be coupled with methyl(S)-hexahydropyridazine-3-carboxylate to prepare methyl-amino-3-(4-bromothiazole-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (10).

[0139] In the presence of a Pd catalyst, methyl-amino-3-(4-bromothiazole-2-yl)propanoyl)hexahydropyridazine-3-carboxylate (10) is coupled with a suitably substituted indolylboronic acid ester (8), followed by hydrolysis and macrolactonization steps to produce the final macrocyclic ester and a suitably protected macrocyclic intermediate (11). Deprotection and coupling with a suitably substituted carboxylic acid (or other coupling partner) or intermediate 4 can yield the macrocyclic product. Additional deprotection or functionalization steps may be required to produce the final compound 13 or 14.

[0140] Furthermore, the compounds of this disclosure can be synthesized using the methods described in the following examples, as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. These methods include, but are not limited to, the methods described in the following examples. For example, those skilled in the art can introduce a desired -BLW group [wherein B, L, and W are as defined herein] of the compound of formula (I) into a macrocyclic ester using the methods illustrated in the Examples section of this specification.

[0141] Pharmaceutical composition and method of use Pharmaceutical composition and administration method The compounds related to the present invention are RAS inhibitors and are useful in cancer treatment. Accordingly, one embodiment of the present invention provides a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, as well as a method for preparing such a composition using the compound of the present invention.

[0142] In the present invention, the term "pharmaceutical composition" means a compound such as the compound of the present invention, or a pharmaceutically acceptable salt thereof, formulated with a pharmaceutically acceptable excipient.

[0143] In some embodiments, the compound is present in the pharmaceutical composition in a unit dose appropriate for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to the relevant population. In some embodiments, the pharmaceutical composition can be specifically formulated for administration in solid or liquid form, including: oral administration, e.g., oral tablets (aqueous or non-aqueous or suspension), tablets, e.g., cheek, sublingual, and those targeted for intracellular absorption, pills, powders, granules, and pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection as a sterile solution or suspension, or as a sustained-release formulation; topical application, e.g., as a cream, ointment, or sustained-release patch, or as a spray applied to the skin, lungs, or oral cavity; e.g., as a pessary, cream, or foam suitable for vaginal or rectal, sublingual, intraocular, transdermal, or transnasal, lung, and other mucosal surfaces.

[0144] As used herein, “pharmaceutically acceptable excipient” means any inert component having properties that are toxic and non-inflammatory within the subject matter (e.g., a vehicle capable of suspending or dissolving an active compound). Typical excipients include, for example, anti-adhesives, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavorings, fragrances, lubricants (flow enhancers), preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydration water. Examples of excipients include, but are not limited to, optionally substituted butylated hydroxytoluene (BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropylcellulose, optionally substituted hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those skilled in the art are familiar with a wide variety of agents and materials useful as excipients. For example, for example, Ansel, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical See Press, 2005. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients.

[0145] The compounds described herein may be provided or used in salt form, e.g., pharmaceutically acceptable salt form, whether or not expressly stated otherwise. As used herein, the term “pharmaceutically acceptable salt” means these salts of the compounds described herein that are suitable for use in contact with human and other animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., within the normal range of reasonable medical judgment, and that are balanced by 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. PHStahl). The 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.

[0146] The compounds of the present invention may have ionic groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts with inorganic or organic acids, or, in the case of the acidic form of the compounds of the present invention, the salts may be prepared from inorganic or organic bases. In some embodiments, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art for forming acid addition salts, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, or tartaric acid, and for forming basic salts, such as potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, and various amines. Methods for preparing suitable salts are well established in the art.

[0147] Typical acid addition salts include acetate, adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, and 2-(optionally substituted)hydroxylethane. Examples include sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates, undecanoates, and valersates. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations (including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine).

[0148] As used herein, the term “subject” means any element in the animal kingdom. In some embodiments, “subject” means a human at any stage of development. In some embodiments, “subject” means a human patient. In some embodiments, “subject” means a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cattle, primates, or pigs). In some embodiments, subjects may be mammals, birds, reptiles, amphibians, fish, or insects, but are not limited to these. In some embodiments, subjects may be transgenic animals, genetically modified animals, or clones.

[0149] As used herein, the term “dosage form” means a physically distinct unit of a compound (e.g., the compound of the present invention) for administration to a subject. Each unit contains a predetermined amount of the compound. In some embodiments, such an amount is a unit dose (or its entire fraction) appropriate for administration according to an administration regimen (i.e., using a therapeutic administration regimen) that has been measured to correlate with a desired or beneficial outcome when administered to the relevant population. Those skilled in the art will understand that the total amount of a therapeutic composition or compound administered to a particular subject may be determined by one or more attending physicians and may involve administration of multiple dosage forms.

[0150] As used herein, the term “dosage regimen” means a set of unit doses (usually two or more) administered individually to a subject, usually separated by a period of time. In some embodiments, a given therapeutic compound (e.g., a compound of the present invention) has a recommended dosage regimen, which may have one or more doses. In some embodiments, the dosage regimen comprises multiple doses, each separated from the others by a period of time equal in length, and in some embodiments, the dosage regimen comprises multiple doses and at least two different period of time separating the individual doses. In some embodiments, all doses in the dosage regimen are identical unit doses. In some embodiments, different doses in the dosage regimen are different amounts. In some embodiments, the dosage regimen comprises one or more further doses, a first dose at a first dose, followed by a second dose different from the first dose. In some embodiments, the dosage regimen comprises one or more further doses, a first dose at a first dose, followed by a second dose that is the same as the first dose. In some embodiments, the administration regimen correlates with a desired or beneficial outcome when administered across relevant populations (i.e., it is a therapeutic administration regimen).

[0151] A "treatment regimen" refers to a dosing regimen across relevant populations that correlates with a desired or beneficial therapeutic outcome.

[0152] The term “treatment” (and additionally, “to treat” or “to treat”) means, in its broadest sense, any administration of a substance (e.g., a compound of the present invention) that partially or completely remits, alleviates, reduces or inhibits a particular disease, disorder or condition; partially or completely delays the onset of a particular disease, disorder or condition; partially or completely reduces the severity of a particular disease, disorder or condition; or partially or completely reduces the occurrence of one or more symptoms, features, or causes of a particular disease, disorder or condition. In some embodiments, such treatment may be administered to subjects who show no signs of the related disease, disorder or condition, or to subjects who show only the initial signs of the disease, disorder or condition. Alternatively, or in addition, in some embodiments, such treatment may be administered to subjects showing established signs of one or more of the related diseases, disorders or conditions. In some embodiments, treatment may be administered to subjects diagnosed with suffering from the related disease, disorder or condition. In some embodiments, the treatment may be administered to subjects known to have one or more susceptibility factors that are statistically correlated with an increased risk of progression of the associated disease, disorder, or condition.

[0153] The term “therapeutic dose” means a quantity sufficient to treat a disease, disorder, or condition when administered to a population suffering from or suspected of having a disease, disorder, or condition, according to a therapeutic administration regimen. In some embodiments, a therapeutic dose is a quantity that reduces the onset or severity of one or more symptoms of the disease, disorder, or condition, or delays the onset of one or more symptoms of the disease, disorder, or condition. Those skilled in the art will understand that the term “therapeutic dose” does not actually require that successful treatment be achieved in a particular individual. Rather, a therapeutic dose can be a quantity that, when administered to subjects requiring such treatment, produces a specific desired pharmacological response in a significant number of subjects. It is specifically understood that a particular subject may actually be “refractory” to the “therapeutic dose.” In some embodiments, a reference to a therapeutic dose may refer to a quantity measured in one or more specific tissues (e.g., tissues affected by the disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those skilled in the art will understand that in some embodiments, a therapeutically effective amount can be formulated or administered as a single dose. In some embodiments, a therapeutically effective amount can be formulated or administered in multiple doses, for example, as part of an administration regimen.

[0154] The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be formulated as pharmaceutical or veterinary compositions for use as a treatment for a target. Depending on the target to be treated, the method of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or treatment, the compounds, or pharmaceutically acceptable salts thereof, are formulated in a manner that matches these parameters. A summary of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21 stThis can be found in Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988–1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0155] Each composition can be prepared according to conventional mixing, granulation, or coating methods, and the pharmaceutical composition may contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% (by weight or by volume) of the compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds described herein or a pharmaceutically acceptable salt thereof may be present in total in an amount of 1 to 95% of the total weight of the composition, such as the pharmaceutical composition.

[0156] The composition can be provided in dosage forms suitable for intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, transnasal, intravaginal, intrabladderal, intraurethral, ​​intrathecal, epidural, transaural, or intraocular administration, or for injection, inhalation, or direct contact with the nasal, genitourinary, reproductive, or oral mucosa. Accordingly, the pharmaceutical composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, oral medications, infiltration delivery devices, suppositories, enemas, injections, implants, sprays, preparations suitable for iontophoresis delivery, or aerosols. The composition can be formulated according to conventional pharmaceutical regulations.

[0157] As used herein, the term “administration” means the administration of a composition (e.g., a compound, or a preparation containing a compound as described herein) to a subject or system. Administration to an animal subject (e.g., a human) may be by any suitable route. For example, in some embodiments, administration may be bronchial (including bronchial infusion), cheek, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, transnasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, intratracheal (including intratracheal infusion), transdermal, vaginal, or intravitreous.

[0158] Formulations can be prepared in a manner suitable for systemic administration or local or local administration. Systemic formulations may be designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection), or they may be prepared for transdermal, transmucosal, or oral administration. Formulations generally contain diluents, and optionally adjuvants, buffers, and preservatives. The compound, or a pharmaceutically acceptable salt thereof, may also be administered in a liposome composition or as a microemulsion.

[0159] For injection, formulations can be prepared in conventional forms, such as a solution or suspension, or as a solid suitable for solution or suspension in liquid before injection, or as an emulsion. Suitable excipients include, for example, water, saline, dextrose, and glycerol. Such compositions may also contain certain amounts of non-toxic auxiliary substances (e.g., wetting agents or emulsifiers), pH buffers, such as sodium acetate and sorbitan monolaurate.

[0160] Various sustained-release systems for pharmaceuticals have also been devised. See, for example, U.S. Patent No. 5,624,677.

[0161] Systemic administration can also be achieved through relatively non-invasive methods such as suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds of the present invention or pharmaceutically acceptable salts thereof. Preferred forms, as understood in the art, include syrups, capsules, and tablets.

[0162] Each compound described herein, 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 individually. Other modalities of combination therapy are described herein.

[0163] Individually formulated or separately manufactured drugs can be packaged together as a kit. Non-limiting examples include, but are not limited to, kits containing two pills, pills and powder, suppositories and liquid in a vial, or two topical creams. A kit may include any components that assist in administering a unit dose to a subject, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, or inhalers. In addition, a unit dose kit may include instructions for preparing or administering the composition. A kit may be manufactured as a single-use unit dose for a particular subject, or as a multi-use unit dose for a specific subject (where the efficacy of individual compounds or their pharmaceutically acceptable salts changes at a constant concentration or as treatment progresses), or a kit may contain multi-use doses (bulk packaging) suitable for administration to multiple subjects. The components of a kit can be assembled into cartons, blister packs, bottles, tubes, etc.

[0164] Formulations for oral use include tablets containing the active ingredient(s) in a mixture with pharmaceutically acceptable, non-toxic excipients. These excipients may include, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starch containing potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulators and disintegrants (e.g., cellulose derivatives containing microcrystalline cellulose, starch containing potato starch, croscarmellose sodium, alginate, or arginine); binders (e.g., sucrose, glucose, sorbitol, acacia, arginine, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, aluminum magnesium silicate, sodium carboxymethylcellulose, methylcellulose, optionally substituted hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); as well as smoothers, lubricants, and anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may include colorants, flavorings, plasticizers, wetting agents, and buffering agents.

[0165] Two or more compounds can be mixed or fractionated in a tablet, capsule, or other vehicle. In one example, the first compound is contained inside the tablet, the second compound is on the outside, and a substantial portion of the second compound is released before the first compound.

[0166] Formulations for oral use may be provided as chewable tablets, or as rigid gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or as flexible gelatin capsules in which the active ingredient can be mixed with water or an oil culture medium, e.g., peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets can be prepared using the above-mentioned components below tablets and capsules by conventional methods, for example, using a mixer, fluidized bed apparatus, or spray dryer.

[0167] Dissolution or diffusion-controlled release can be achieved by appropriate coatings for tablet, capsule, pellet, or granule formation of the compound, or by incorporating the compound, or a pharmaceutically acceptable salt thereof, into a suitable matrix. Sustained-release coatings may include the coating materials described above, or one or more of the following: shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, 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 glycol, ethylene glycol methacrylate, or polyethylene glycol. In sustained-release matrix formulations, examples of matrix materials include hydrated methylcellulose, carnauba wax and stearyl alcohol, Carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0168] Liquid forms in which the compounds of the present invention, or pharmaceutically acceptable salts thereof, and compositions may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0169] In general, when administered to humans, the oral dose of any of the compounds of the present invention, or any of its pharmaceutically acceptable salts, depends on the properties of the compound and can be quickly determined by those skilled in the art. The dose may be, 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 of these range variables.

[0170] In some embodiments, the pharmaceutical composition may further contain additional compounds having antiproliferative activity. Depending on the method of administration, the compounds, or pharmaceutically acceptable salts thereof, are formulated into a suitable composition that allows for easy delivery. Each compound, or pharmaceutically acceptable salt thereof, of the combination therapy can be formulated in various ways known in the art. For example, the first and second agents of the combination therapy can be formulated together or individually. Preferably, the first and second agents are formulated together for simultaneous or near-simultaneous administration.

[0171] It will be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and used in combination therapy, that is, the compounds and pharmaceutical compositions can be formulated or administered simultaneously with, before, or after one or more other desired therapeutic agents or medical procedures. In specific combinations of treatments (therapeutic agents or procedures) using combination regimens, the suitability of the desired therapeutic agent or procedure and the desired therapeutic effect to be achieved will be taken into consideration. Furthermore, it will be understood that the treatments used may achieve the desired effect for the same disease, or different effects (e.g., control of any adverse effects).

[0172] As described herein, each drug in combination therapy may be administered independently once to four times a day for a period of one to one year, and may also be administered throughout the patient's lifetime. Chronic long-term administration may be indicated.

[0173] How to use In some embodiments, the present invention discloses methods for treating diseases or disorders characterized by ectopic Ras activity caused by Ras variants. In some embodiments, the disease or disorder is cancer.

[0174] Accordingly, the present invention also provides a method for treating cancer in a subject requiring treatment for cancer, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such 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 intestine cancer, ampulla cancer, germ cell carcinoma, cervical 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. The present invention also provides a method for treating Ras protein-related disorders in a subject requiring treatment for Ras protein-related disorders, wherein the method comprises administering to the subject a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing such compound or salt.

[0175] In some embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds or salts, and the methods provided herein can be used to treat a wide variety of cancers, including, for example, lung cancer, prostate 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, but are not limited to, astrocyte, breast, cervix, colorectal, uterine, esophageal, gastric, head and neck, hepatocyte, larynx, lung, pharyngeal, ovarian, prostate, and thyroid cancer and sarcoma. Other cancers include, for example: Cardiac malignancies, for example, non-epithelial malignancies (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; Lung cancers, for example, bronchogenic carcinomas (squamous cell carcinomas, anaplastic small cell carcinomas, anaplastic large cell carcinomas, adenocarcinomas), alveolar (bronchial) carcinomas, bronchial adenomas, non-epithelial malignancies, lymphomas, chondrotoxic hamartomas, mesotheliomas; The gastrointestinal tract, for example, the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), the stomach (epithelial malignant tumor, lymphoma, leiomyosarcoma), the pancreas (ductal adenocarcinoma, islet cell tumor, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, VIP-producing tumor), the small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), and the large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); The urogenital organs, for example, the kidneys (adenocarcinoma, Wilms' tumor, (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, non-epithelial malignant tumor), testicles (seminal carcinoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, non-epithelial malignant tumor, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); Liver, for example, liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer, for example, gallbladder cancer, ampulla cancer, bile duct cancer; Bone, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system, for example, skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meninges (meningioma, meningiosarcoma, gliomas), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, non-epithelial malignant tumors); Gynecology, for example, the uterus (endometrial cancer, uterine cancer, endometrial cancer of the uterine body), the cervix (cervical cancer, pre-tumor cervical dysplasia), the ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), the vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), the vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), the fallopian tubes (epithelial malignant tumors); Hematological conditions, such as blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); Skin conditions such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic moles, lipomas, hemangiomas, dermatofibromas, keloids, and psoriasis; Adrenal glands, for example, neuroblastoma.

[0176] In some embodiments, the Ras protein is wild-type (Ras WT Therefore, in some embodiments, the compounds of the present invention are Ras WT (For example, K-Ras WT H-Ras WT , or N-Ras WT It is used in treatment methods for patients with cancer including ). In some embodiments, the Ras protein is used for Ras amplification (e.g., K-Ras amp Therefore, in some embodiments, the compounds of the present invention are Ras amp (K-Ras amp H-Ras amp , or N-Ras amp It is used in methods for treating patients with cancer including ). In some embodiments, the cancer includes Ras mutations such as the Ras mutations described herein. In some embodiments, the mutations are selected from the following: (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; and (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 includes 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 includes an N-Ras mutation selected from the group consisting of G12C, Q61H, Q61K, Q61L, Q61P, and Q61R. In some embodiments, the cancer includes an H-Ras mutation selected from the group consisting of Q61H and Q61L. In some embodiments, the cancer includes a Ras mutation selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the cancer contains at least two Ras mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V, and G13V. In some embodiments, the compounds of the present invention inhibit two or more Ras mutations. For example, the compound may inhibit both K-Ras G12C and K-Ras G13C. The compound may inhibit both N-Ras G12C and K-Ras G12C. In some embodiments, the compound may inhibit both K-Ras G12C and K-Ras G12D. In some embodiments, the compound may inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, the compound may inhibit both K-Ras G12V and K-Ras G12S. In some embodiments, the compounds of the present invention inhibit one or more additional Ras mutations in addition to Ras WT Inhibits (for example, K, H, or N-Ras) WT And, K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V;K, H, or N-Ras WTH-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H, or N-Ras 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, A146V, or A59T). In some embodiments, the compounds of the present invention are Ras in addition to one or more additional Ras mutations. amp Inhibits (for example, K, H, or N-Ras) amp And, K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V;K, H, or N-Ras amp H-Ras Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R; or K, H, or N-Ras amp (and N-Ras Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T).

[0177] Methods for detecting Ras mutations are known in the art. Such methods include, but are not limited to, direct sequencing and the use of highly sensitive diagnostic assays (using the CE-IVD mark) including TheraScreen PCR; AmoyDx; PNAClamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro, which are incorporated herein by reference, for example. See also, for example, WO2020 / 106640.

[0178] In some embodiments, the cancer is non-small cell lung cancer, and the Ras mutation includes K-Ras mutations such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is colorectal cancer, and the Ras mutation includes K-Ras mutations such as K-Ras G12C, K-Ras G12V, or K-Ras G12D. In some embodiments, the cancer is pancreatic cancer, and the Ras mutation includes K-Ras mutations such as K-Ras G12D or K-Ras G12V. In some embodiments, the cancer is pancreatic cancer, and the Ras mutation includes N-Ras mutations such as N-Ras G12D. In some embodiments, the cancer is melanoma, and the Ras mutation includes N-Ras mutations 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 That is. Unless already specified, in any of the above, the compound is similarly Ras WT (For example, K-, H-, or N-Ras) WT ), or Ras amp (For example, K-, H-, or N-Ras) amp ) may be inhibited.

[0179] In some embodiments, cancer is caused by Ras mutations and STK11LOF , including KEAP1, EPHA5, or NF1 mutations. In some embodiments, the cancer is non-small cell lung cancer and includes the K-Ras G12C mutation. In some embodiments, the cancer is non-small cell lung cancer and includes the K-Ras G12C mutation and STK11 LOF The mutation is included. In some embodiments, the cancer is non-small cell lung cancer, and the K-Ras G12C mutation and STK11 LOF Includes mutations. In some embodiments, the cancer is a K-Ras G13C Ras mutation and STK11 LOF , comprising KEAP1, EPHA5, or NF1 mutations. In some embodiments, the cancer is non-small cell lung cancer and comprises the K-Ras G12D mutation. In some embodiments, the cancer is non-small cell lung cancer and comprises the K-Ras G12V mutation. In some embodiments, the cancer is colorectal cancer and comprises the K-Ras G12C mutation. In some embodiments, the cancer is pancreatic cancer and comprises the K-Ras G12D mutation. In some embodiments, the cancer is pancreatic cancer and comprises the K-Ras G12V mutation. In some embodiments, the cancer is endometrial cancer and comprises the K-Ras G12C mutation. In some embodiments, the cancer is gastric cancer and comprises the K-Ras G12C mutation. In any of the above, the compound is similarly Ras WT (For example, K-, H-, or N-Ras) WT ), or Ras amp (For example, K-, H-, or N-Ras) amp ) may be inhibited.

[0180] The present invention also provides a method for inhibiting the Ras protein within cells, wherein the method comprises contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. The present invention also provides a method for inhibiting RAF-Ras binding, wherein the method comprises contacting the cells with an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof. The cells may be cancer cells. The cancer cells may be of any type of cancer described herein. The cells may be in vivo or in vitro.

[0181] Combination therapy The methods of the present invention may include compounds of the present invention used alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). The dosage of one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) may be reduced from the standard dosage when administered alone. For example, the dosage may be determined empirically from the combination and permutation of drugs or estimated by isoborographic analysis (e.g., Black et al.). al., Neurology 65:S3-S6(2005)).

[0182] The compounds of the present invention may be administered before, after, or concurrently with one or more additional therapies. When combined, the dosage of the compounds of the present invention and the dosage of one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) provide a therapeutic effect (e.g., a synergistic or additive therapeutic effect). The compounds of the present invention and additional therapies, such as anticancer agents, may be administered together or separately in a single pharmaceutical composition, and if administered separately, they may be administered simultaneously or sequentially. Such sequential administration may have short or long intervals between doses.

[0183] In some embodiments, additional therapy involves the administration of side effect limiting agents (e.g., agents intended to reduce the occurrence or severity of side effects of the treatment). For example, in some embodiments, the compounds of the present invention may also be used in combination with therapeutic agents for treating nausea. Examples of agents that can be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0184] In some embodiments, one or more additional therapies include non-pharmacological treatment (e.g., surgery or radiotherapy). In some embodiments, one or more additional therapies include therapeutic agents (e.g., compounds or biological agents that are anti-angiogenic agents, signaling inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors). In some embodiments, one or more additional therapies include non-pharmacological treatment (e.g., surgery or radiotherapy) and therapeutic agents (e.g., compounds or biological agents that are anti-angiogenic agents, signaling inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors). In other embodiments, one or more additional therapies include two therapeutic agents. In yet another embodiment, one or more additional therapies include three therapeutic agents. In some embodiments, one or more additional therapies include four or more therapeutic agents.

[0185] In this section on combination therapies, all references for the listed medications are incorporated by reference, whether explicitly stated or not.

[0186] Non-pharmacological therapy Examples of non-pharmacological treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and T-cell adoptive transfer (ACT) therapy.

[0187] In some embodiments, the compounds of the present invention can be used as adjuvant therapy after surgery. In some embodiments, the compounds of the present invention can be used as preoperative adjuvant therapy before surgery.

[0188] Radiotherapy may be used in subjects (e.g., mammals (e.g., humans)) to inhibit abnormal cell proliferation or to treat hyperproliferative disorders such as cancer. Techniques for administering radiotherapy are known in the art. Radiotherapy can be administered by one or a combination of several methods, including, but not limited to, external beam therapy, internal radiotherapy, implantable radiation, stereotactic radiosurgery, total body radiotherapy, radiotherapy, and permanent or transient interstitial near-brightening therapy. As used herein, the term “near-brightening therapy” refers to radiotherapy delivered by spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term is intended to include, but is not limited to, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu). Suitable radiation sources for use as cell modifiers in the present invention include both solids and liquids. In non-limiting examples, the radiation source may be radionuclides such as I-125, I-131, Yb-169, Ir-192 as solid sources, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic rays. The radioactive material may also be a fluid prepared from any solution of the radionuclide(s), e.g., a solution of I-125 or I-131, or the radioactive fluid may be produced using a suitable fluid slurry containing small particles of a solid radionuclide such as Au-198 or Y-90. Furthermore, the radionuclide(s) may be embodied in gels or radioactive microspheres.

[0189] In some embodiments, the compounds of the present invention can make abnormal cells more sensitive to radiotherapy aimed at killing or inhibiting the proliferation of such cells. Therefore, the present invention further relates to a method for sensitizing abnormal cells in mammals to radiotherapy, the method comprising administering to a mammal an amount of the compound of the present invention effective in sensitizing the abnormal cells to radiotherapy. The amount of the compound in this method can be determined according to the means for determining an effective amount of such compound described herein. In some embodiments, the compounds of the present invention may be used as adjuvant therapy after radiotherapy or as neoadjuvant therapy before radiotherapy.

[0190] In some embodiments, the non-pharmacological treatment is T cell adoptive transfer (ACT) therapy. In some embodiments, the T cells are activated T cells. The T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into T cells. The T cell source is obtained from a subject before proliferation 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, umbilical cord blood, thymic tissue, tissue from infection sites, ascites, pleural fluid, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art may be used. In some embodiments, the T cells are autologous T cells. Regardless of whether the T cells are genetically modified to express a desired protein (e.g., CAR), T cells are generally, for example, U.S. Patent Nos. 6,352,694, 6,534,055, 6,905,680, 6,692,964, 5,858,358, 6,887,466, 6,905,681, and It can be activated and propagated using the methods described in Nos. 7,144,575, 7,067,318, 7,172,869, 7,232,566, 7,175,843, 7,572,631, 5,883,223, 6,905,874, 6,797,514, and 6,867,041.

[0191] Therapeutic drugs The therapeutic agent may be a compound used to treat cancer or related conditions.

[0192] For example, the therapeutic agent may be a steroid. Therefore, in some embodiments, one or more additional therapies include a steroid. Preferred steroids include 21-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, crocortol, cloprednol, corticosterone, cortisone, cortibazole, deflazacort, desonide, dexoxymethasone, dexamethasone, diflorasone, diflucortol, difprednate, enoxolone, fluazacort, fluchloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, flucortin butyl, flucortolone, fluorometholone, fluperolone acetate, flupredniden acetate, fluprednisolone, and flulandrenolide. Examples include, but are not limited to, fluticasone propionate, formocortal, halcinonide, halobetazole propionate, halomethasone, hydrocortisone, loteprednol etavonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, sodium prednisolone phosphate, prednisone, prednival, prednylidene, rimexolone, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexaacetonide, and their salts or derivatives.

[0193] Further examples of therapeutic agents that may be used in combination therapy with the compounds of the present invention include the compounds described in the following patents: U.S. Patent Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, as well as International Publication No. WO01 Nos. / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089, and WO00 / 02871.

[0194] The therapeutic agent may be a biological agent used to treat cancer or related conditions (e.g., cytokines (e.g., interferons or interleukins such as IL-2)). In some embodiments, the biological agent is a biological agent of the immunoglobulin system, e.g., monoclonal antibodies (e.g., humanized antibodies, fully human antibodies, Fc fusion proteins, or functional fragments thereof) that inflict pain on a target to stimulate an anti-cancer response or antagonize antigens important to cancer. Antibody-drug conjugates are also included.

[0195] The therapeutic agent may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody). The antibody may be, for example, a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is a drug such as an antibody that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is a drug such as an antibody that interacts with a ligand for a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL-2 (e.g., PDL-2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof.In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), PD-L1 antibody, e.g., avelumab, durvalumab, atezolizumab, pizilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or Preusser, M. et al. Checkpoint inhibitors disclosed in al. (2015) Nat. Rev. Neurol. include, but are not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDl4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirirumab, IPH2101, 1-7F9, and KW-6002.

[0196] The therapeutic agent may be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (ethigirimab).

[0197] Therapeutic agents may be drugs that treat cancer or related conditions (e.g., cytotoxic agents, non-peptide small molecules, or other compounds useful in treating cancer or related conditions, collectively referred to as “anticancer agents”). Anticancer agents may be, for example, chemotherapeutic agents or targeted therapy agents.

[0198] Anticancer agents include mitotic inhibitors, insertive antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyrotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum-coordinated complexes, anthracendione-substituted ureas, methylhydrazine derivatives, corticosteroids, progestins, estrogens, antiestrogens, androgens, and gonadotropin-releasing hormone analogs. Further anticancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, one or more additional therapies comprise two or more anticancer agents. Two or more anticancer drugs can be used in a cocktail, either administered in combination or individually. Preferred administration regimens for combination anticancer drugs are known in the art and are described, for example, in Saltz et al., Proc.Am.Soc.Clin.Oncol.18:233a(1999) and Douillard et al., Lancet 355(9209):1041-1047(2000).

[0199] Other non-exclusive examples of anticancer drugs include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents, e.g., thiotepa and cyclophosphamide; alkyl sulfonates, e.g., busulfan, improsulfan, and pigosulfan; aziridines, e.g., be Nzodopa, carbocone, metsuredopa, and uredopa; ethyleneimines and methylamelamines, e.g., altoretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bratacin and bratacinone); camptothecin (e.g., synthetic analog topotecan); briostatin; callistatin; CC-1065 (e.g., its adzeresin, karzeresin, and Beizelesin synthetic analogs); cryptophycin (specifically, cryptophycin 1 and cryptophycin 8); dorastatin; duocalmycin (e.g., synthetic analogs KW-2189 and CB1-TM1); eryuterobin; pancratistatin; sarcodictiin A; spongistatin; nitrogen mustard, e.g., chlorambucil, chlornafadin, colophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine Minoxide hydrochloride, melphalan, nobenbitin, fenestrine, prednimustine, trophosphamide, and uracil mustard; nitrosoureas, e.g., camulstine, chlorozotosine, fotemustine, lomustine, nimustine, and ranimustine; antibiotics, e.g., engine antibiotics (e.g., calicheamicin, e.g., calicheamicin gamma II and calicheamicin omega II (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); dynemicins such as dynemicin A; bisphosphonates such as clodronate; esperamicin;Neocardinostatin chromophore and related pigment protein enediin antibiotic chromophore, acrasinomycin, actinomycin, autoramycin, azaserin, bleomycin, kactinomycin, calicheamicin, carabicin, kaminomycin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detrubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino - Doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin C and other mitomycins, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potophyllomycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, pteropterin, and trimethrexate; f Purine analogs such as rudarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid infusions such as fluphosphate; acegraton; aldofamide glycoside; aminolevulinic acid Acids; Enyluracil; Amsacrine; Bestrabusil; Bisanthren; Edatrexate; Defofamine; Demecolsin; Diadiquan; Elfomithine; Erliptinium acetate; Epotilon B and other Epotilons; Etoglucid; Gallium nitrate; Hydroxyurea; Lentinan; Mytansinoids such as Ronidynin, Mytansin and Ansamitosin; Mitoguazone; Mitoxantrone; Mopidamole; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid;2-Ethylhydrazide; Procarbazine; PSK® Polysaccharide Complex (JHS Natural Products, Eugene, OR); Lazoxane; Rhizoxin; Schizophyllan; Spirogermanium; Tenuazonic Acid; Triadicone; 2,2',2''-Trichlorotriethylamine; Trichothecenes such as T-2 toxin, Veraculine A, Loridine A, and Anguidine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Taxoids, e.g., Taxol® (paclitaxel), Abraxane® (chromophore-free, albumin-modified nanoparticle formulation of paclitaxel), and Taxotere® (doxetaxel); Chlorambucil; Tamoxifen (Nolvadex®); Raloxifene; Aromatase inhibitory 4(5)-imidazole; 4-hydroxytamoxifen; Trioxyfen; Keoxyfen; LY 117018; Onapristone; Toremifene (Fareston®); Flutamide, Niltamide, Bicalutamide, Leuprolide, Goserelin; Chlorambucil; Gemzar® Gemcitabine; 6-Thiogunine; Mercaptopurine; Platinum analogs such as cisplatin, oxaliplatin, and carboplatin; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine; Navelbine® (Vinorelbine); Novantrone; Teniposide; Edatrexate; Daunomycin; Aminopterin; Ibandronate; Irinotecan (e.g., CPT-11); Topoisomerase inhibitors RFS Examples include difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperamicin; capecitabine (e.g., Xeloda®); and any pharmaceutically acceptable salt of any of the above.

[0200] Non-exclusive examples of additional anticancer drugs include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, Avisin, avagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfarazine, arbocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracendione, anti-CD22 immunotoxin, antitumor drugs (e.g., cell cycle nonspecific antitumor drugs, and other antitumor drugs described herein), antitumor herbs, apadiquon, atiprimod, azathioprine, berotecan, bendamustine, and BIBW. 2992, Bilicodal, Brostarisin, Briostatin, Butionine sulfoximine, CBV (chemotherapy), Calyculine, Dichloroacetate, Discordamorid, Elsamitolu, Enocitabine, Eribulin, Exatecan, Exislind, Ferginol, Forodesine, Phosfestrol, ICE chemotherapy regimen, IT-101, Imexone, Imiquimod, Indocarbazole, Ilofluben, Lanikidal, Lalotaxel, Lenalidomide, Lucanton, Lulutotecan, Maphosfamide, Mitozolomide, Examples include napoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, reximod, rubitecan, SN-38, salinosporamide A, sapacitabine, stanford V, swainsonin, talaporfin, talikidal, tegafur-uracil, temodal, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, bajimezan, vinflunin, ZD6126, and zoskidal.

[0201] Further non-exclusive examples of anticancer drugs include vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophilotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mitramycin), mitomycin, and enzymes (e.g., enzymes that systemically metabolize L-asparagine and combine it with its own asparagine). L-asparaginase, which eliminates cells that lack the ability to function, antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustard (e.g., mechloretamine, cyclophosphamide and its analogs, melphalan, and chlorambucil), ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors such as abemaciclib, ribociclib, and palbociclib), sericiclib, UCN-01, P1446A-05 Antiproliferative / antimitotic metabolites and related inhibitors (e.g., PD-0332991, Dynacyclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and its analogues, as well as streptozocin), trazeneth-dacarbadinine (DTIC), folic acid analogues, pyrimidine analogues (e.g., fluorouracil, floxuridine, and cytarabine), purine analogues, etc.) For example, mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum-coordinate complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apisidan, suberoylanilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., vistocertib, temsirolimus, everolimus, ridafololimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array520), DNA binding agents (e.g., Zalypsis®), PI3K inhibitors such as PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g., CAL-130), copanlisib, alpelisib, and idelalisib; multikinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen), and hormone agonists such as leutinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38)), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Za Examples include natural products such as rnestra (trademark), 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), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists.

[0202] In some embodiments, the anticancer agent is selected from mechloretamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analogue or derivative variant of the foregoing.

[0203] In some embodiments, the anticancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies, e.g., trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors, e.g., gefitinib (Iressa®), erlotinib (Tarceva®), pyritinib, 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.

[0204] In some embodiments, the anticancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib, brigatinib, entrectinib, ensartinib (X-396), lorlatinib, ASP3026, CEP-37440, 4SC-203, TL-398, PLB1003, TSR-011, CT-707, TPX-0005, and AP26113. Additional examples of ALK kinase inhibitors are described in Examples 3-39 of WO05 / 016894.

[0205] In some embodiments, the anticancer agent is an inhibitor of a downstream member of the receptor tyrosine kinase (RTK) / growth factor receptor (e.g., SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, RLY-1971), SOS1 inhibitor (e.g., BI-1701963, BI-3406), Raf inhibitor, MEK inhibitor, ERK inhibitor, PI3K inhibitor, PTEN inhibitor, AKT inhibitor, or mTOR inhibitor (e.g., mTORC1 inhibitor or mTORC2 inhibitor). In some embodiments, the anticancer agent is JAB-3312. In some embodiments, the anticancer agent is AMG 510, MRTX1257, MRTX849, JNJ-74699157 (ARS-3248), LY3499446, ARS-853, or ARS-1620), or a Ras vaccine, or another treatment designed to directly or indirectly reduce the oncogenic activity of Ras.Other examples of RAS inhibitors that can be combined with the Ras inhibitor of the present invention are listed below, which are incorporated herein by reference in their entirety: WO2020050890, WO2020047192, WO2020035031, WO2020028706, WO2019241157, WO2019232419, WO2019217691, WO2019217307, WO2019215203, WO2019213526, WO2019213516, WO2019155399, WO2019150305, WO2019110751, WO2019099524, WO2019051291, WO 2018218070, WO2018217651, WO2018218071, WO2018218069, WO2018206539, WO2018143315, WO2018140600, WO201 8140599, WO2018140598, WO2018140514, WO2018140513, WO2018140512, WO2018119183, WO2018112420, WO20180 68017, WO2018064510, WO2017201161, WO2017172979, WO2017100546, WO2017087528, WO2017058807, WO20170588 05, WO2017058728, WO2017058902, WO2017058792, WO2017058768, WO2017058915, WO2017015562, WO2016168540, WO2016164675, WO2016049568, WO2016049524, WO2015054572, WO2014152588, WO2014143659, and WO2013155223.

[0206] In some embodiments, therapeutic agents that can be combined with the compounds of the present invention are inhibitors of the MAP kinase (MAPK) pathway (or "MAPK inhibitors"). Examples of MAPK inhibitors include, but are not limited to, one or more 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, pimacertib, TAK733, RO4987655 (CH4987655), CI-1040, PD-0325901, CH5126766, MAP855, AZD6244, refametinib (RDEA 119 / BAY 86-9766), GDC-0973 / XL581, AZD8330 (ARRY-424704 / ARRY-704), RO5126766 (Roche, PLoS One. 2014 Nov). One or more of the following may be selected (as described in 25;9(11)) and GSK1120212 (or JTP-74057, as described in Clin Cancer Res. 2011 Mar 1;17(5):989-1000). MAPK inhibitors may be PLX8394, LXH254, GDC-5573, or LY3009120.

[0207] In some embodiments, the anticancer agent is a disruptor or inhibitor of the RAS-RAF-ERK, PI3K-AKT-TOR, or PI3K-AKT signaling pathway. Examples of PI3K / AKT inhibitors include, but are not limited to, one or more PI3K / AKT inhibitors listed 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, and GSK2126458.

[0208] In some embodiments, the anticancer agent is a PD-1 or PD-L1 antagonist.

[0209] 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 immunotherapies. In some embodiments, the therapeutic agent may be a pan-RTK inhibitor, such as afatinib.

[0210] IGF-1R inhibitors include lincitinib or its pharmaceutically acceptable salts.

[0211] 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®), zaltumumab, nimotuzumab, and matuzumab. Further antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its native ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br.J. Cancer 1993, 67:247-253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res. 1995, 1:1311-1318; Huang et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang et al., Cancer Res. 1999, 59:1236-1243. The EGFR inhibitor may be a monoclonal antibody Mab E7.6.3 (Yang, 1999 above), or Mab C225 (ATCC accession number HB-8508), or an antibody or antibody fragment having binding specificity thereto.

[0212] Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (TykerB®). See, for example, Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8, and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). Further examples of the limited scope 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;EP0787772;WO97 / 30034;WO97 / 30044;WO97 / 38994;WO97 / 49688;EP837063;WO98 / 02434;WO97 / 38983;WO95 / 19774;WO95 / 19970;WO97 / 13771;WO98 / 02437;WO9 8 / 02438;WO97 / 32881;DE19629652;WO98 / 33798;WO97 / 32880;WO97 / 32880;EP68202 7;WO97 / 02266;WO97 / 27199;WO98 / 07726;WO97 / 34895;WO96 / 31510;WO98 / 14449;WO 98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; U.S. Patent No. 5,789,427; U.S. Patent No. 5,650,415; U.S. Patent No. 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and O92 / 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. In some embodiments, EGFR inhibitors are ERBB inhibitors. In humans, the ERBB family includes HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0213] MEK inhibitors include, but are not limited to, pimacertib, 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.

[0214] PI3K inhibitors include wartmannin, 17-hydroxywartmannin analog described in WO06 / 044453, 4-[2-(1H-indazole-4-yl)-6-[[4-(methylsulfonyl)piperazine-1-yl]methyl]thieno[3,2-d]pyrimidine-4-yl]morpholine (also known as pictilisib or GDC-0941, described in WO09 / 036082 and WO09 / 055730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo[4,5-c]quinoline-1-yl]phenyl]propionitrile (BEZ 235 or NVP-BEZ) Also known as 235 and described in WO06 / 122806), (S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (available from Axon Medchem), PI 103 hydrochloride (3-[4-(4-morpholinylpyrido[3',2':4,5]fl[3,2-d]pyrimidine-2-yl]phenol hydrochloride (available from Axon Medchem), PIK 75(2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridine-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem), PIK 90(N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem), AS-252424(5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidined-2,4-dione (Axon Examples include, but are not limited to, TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrinidine-4-one (available from Axon Medchem), XL-765, and XL-147.Other PI3K inhibitors include demethoxypyridine, 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.

[0215] Examples of AKT inhibitors include Akt-1-1 (inhibits Akt1) (Barnett et al., Biochem.J.2005,385(Pt.2):399-408); Akt-1-1,2 (inhibits 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. Patent No. 6,656,963; Sarkar and Li J Nutr.2004,134(12)). Examples include, but are not limited to, Suppl):3493S-3498S); Perifosine (e.g., interfering with Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res. 2004, 10(15):5242-52); Phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and trisirivine (TCN or API-2 or NCI discriminant: NSC 154020; Yang et al., Cancer Res. 2004, 64:4394-9).

[0216] mTOR inhibitors include ATP-competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, e.g., temsirolimus (Torisel®); everolimus (Afinitor®, WO94 / 09010); ridafololimus (also known as deforolimus or AP23573); rapalogs, e.g., those disclosed in WO98 / 02441 and WO01 / 14387, e.g., AP23464 and AP23841; 40-(2-hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazolite)-rapamycin (also referred to as ABT578); 32-deoxo Rapamycin; 16-pentinyloxy-32(S)-dihydrolapanisin; derivatives disclosed in WO05 / 005434; U.S. Patents 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, as well as WO94 / 090101, WO92 / 051 Examples include, but are not limited to, derivatives disclosed in 79, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and WO2018 / 204416, as well as phosphorus-containing rapamycin derivatives (e.g., WO05 / 016252). In some embodiments, the mTOR inhibitor is a disteric inhibitor (see, for example, WO2018 / 204416, WO2019 / 212990, and WO2019 / 212991), e.g., RMC-5552.

[0217] Examples of BRAF inhibitors that can be used in combination with the compounds of the present invention include vemurafenib, dabrafenib, and encorafenib. BRAF may include class 3 BRAF mutations. In some embodiments, class 3 BRAF mutations are selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R; and A762E.

[0218] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. The 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, as well as resistance to targeted therapies, including BCL-2 inhibitors such as ABT-263, as well as to conventional chemotherapy.

[0219] In some embodiments, additional therapeutic agents are SHP2 inhibitors. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, which contributes to multiple cellular functions, including proliferation, differentiation, maintenance of the cell cycle, and migration. SHP2 has two N-terminal Src homology domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains regulate the intracellular localization and functional regulation of SHP2. The molecule exists in an inactive, self-inhibitory 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 via receptor tyrosine kinases (RTKs) leads to exposure of the catalytic site, resulting in enzymatic activation of SHP2.

[0220] SHP2 is involved in signaling via the RAS mitogen-activated protein kinase (MAPK), JAK-STAT, or phosphoinositol 3-kinase-AKT pathways. Mutations in the PTPN11 gene and subsequent SHP2 mutations have been identified in several human developmental disorders, including Noonan syndrome and Leopard syndrome, as well as in human cancers such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, lung cancer, and colon cancer. Some of these mutations destabilize the autoinhibitory conformation of SHP2, promoting SHP2 autoactivation or enhanced growth factor-driven activation. Therefore, SHP2 is a very attractive target for the development of novel therapies for the treatment of various diseases, including cancer. SHP2 inhibitors (e.g., RMC-4550 or SHP099) combined with RAS pathway inhibitors (e.g., MEK inhibitors) have been shown to inhibit the growth of several cancer cell lines (e.g., pancreatic cancer, lung cancer, ovarian cancer, and breast cancer) in vitro. Therefore, combination therapy using SHP2 inhibitors and RAS pathway inhibitors can be a common strategy for preventing tumor resistance in a wide range of malignancies.

[0221] Such non-limiting examples of SHP2 inhibitors are known in the art, including Chen et al., Mol Pharmacol. 2006, 70, 562; Sarver et al., J. Med. Chem. 2017, 62, 1793; Xie et al., J. Med. Chem. 2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734; as well as PCT applications WO2015107493; WO2015107494; WO201507495; WO2016203404; WO2016203405; WO2016203406; WO2011022440; WO2017156397; WO2017079 723;WO2017211303;WO2012041524;WO2017211303;WO2019051084;WO2017211303;US20160 030594;US20110281942;WO2010011666;WO2014113584;WO2014176488;WO2017100279;WO2 019051469;US8637684;WO2007117699;WO2015003094;WO2005094314;WO2008124815;WO2 009049098;WO2009135000;WO2016191328;WO2016196591;WO2017078499;WO2017210134;W Examples include O2018013597;WO2018129402;WO2018130928;WO20181309928;WO2018136264;WO2018136265;WO2018160731;WO2018172984; and WO2010121212, each of which is incorporated herein by reference.

[0222] In some embodiments, the SHP2 inhibitor binds to the active site. In some embodiments, the SHP2 inhibitor is a mixed-type irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, for example, 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.

[0223] In some embodiments, additional therapeutic agents are selected from the group consisting of MEK inhibitors, HER2 inhibitors, SHP2 inhibitors, CDK4 / 6 inhibitors, mTOR inhibitors, SOS1 inhibitors, and PD-L1 inhibitors. See, for example, Hallin et al., Cancer Discovery, DOI:10.1158 / 2159-8290 (October 28, 2019) and Canon et al., Nature, 575:217 (2019). In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PDL-1 inhibitor and an SOS1 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a PDL-1 inhibitor and an SHP2 inhibitor. In some embodiments, the Ras inhibitor of the present invention is used in combination with a MEK inhibitor and an SHP2 inhibitor. In some embodiments, the cancer is colorectal cancer, and the treatment comprises administering the Ras inhibitor of the present invention in combination with a second or third therapeutic agent.

[0224] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0225] Immunotherapy includes, but is not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically modified T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTE), and anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents.

[0226] Immunomodulators (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).

[0227] Exemplary anti-PD-1 antibodies and their uses are described in Goldberg et al., Blood 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168 A1), and further described elsewhere in this specification.

[0228] GITR agonists include GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Patent No. 6,111,090, No. 8,586,023, WO2010 / 003118, and WO2011 / 090754, or, for example, U.S. Patent No. 7,025,962, EP1947183, U.S. Patent No. 7,812,135, No. 8,388,967, No. 8,591, Examples of anti-GITR antibodies include, but are not limited to, those described in No. 886, No. 7,618,632, EP1866339, and WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726.

[0229] Another example of a therapeutic agent that may be used in combination with the compounds of the present invention is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemical compositions, antibodies, antigen-binding domains, radionuclides, and combinations and conjugates thereof, which are synthetically prepared in vitro. Anti-angiogenic agents may be agonists, antagonists, allosteric modulators, toxins, or, more generally, may act to inhibit or stimulate their targets (e.g., by activating or inhibiting receptors or enzymes), thereby promoting cell death or halting cell proliferation. In some embodiments, one or more additional therapies include an anti-angiogenic agent.

[0230] Anti-angiogenic agents may include MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limited examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include arecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors include WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, and WO99 / 5288. As described in 9, WO99 / 29667, WO99 / 007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US2009 / 0012085, and U.S. Patents 5,863,949 and 5,861,510. Preferred MMP-2 and MMP-9 inhibitors are those with little or no activity to inhibit MMP-1. More preferred are those that selectively inhibit MMP-2 or AMP-9 compared to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors are AG-3340, RO 32-3555, and RS13-0830.

[0231] Further exemplary anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., VEGF (e.g., bevacizumab), or antibodies or antigen-binding regions that specifically bind to their soluble VEGF receptors or ligand-binding regions), e.g., VEGF-TRAP®, and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind to them), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them), e.g., 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), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them). Other anti-angiogenic agents include Canas, IL-8, B-FGF, Tek antagonists (US2003 / 0162712, US6,413,932), anti-Tweak agents (e.g., antibodies or antigen-binding domains that specifically bind, or soluble Tweak receptor antagonists, see US6,727,225), ADAM distointegrin domains that antagonize the binding of integrins to their ligands (US2002 / 0042368), and anti-eph receptors or anti-ephrin antibodies or antigen-binding domains that specifically bind. Examples include (U.S. Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124, and their respective patent family members), and anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind to them), 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 them). Additional anti-angiogenic agents include SD-7784 (Pfizer, USA) and silentide (Merck). KGaA (Germany, EPO0770622), pegaptanib octa sodium (Gilead Sciences, USA), alpha-statin (BioActa, UK), M-PGA (Celgene, USA, US5712291), ilostat (Arriva, USA, US5892112), emaxanib (Pfizer, USA, US5792783), batalanib (Novartis, Switzerland), 2-methoxyestradiol (EntreMed, USA), TLC ELL-12 (Elan, Ireland), anecoltab acetate (Alcon, USA), alpha-D148 Mab (Amgen, USA), CEP-7055 (Cephalon, USA), antiviral Mab (Crucell, Netherlands), DAC anti-angiogenic agent (ConjuChem, Canada), Angiocidin (InKine Pharmaceutical, USA), KM-2550 (Kyowa Hakko, Japan), SU-0879 (Pfizer, USA), CGP-79787 (Novartis, Switzerland, 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 IV (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, Alpha-5 Beta-3 Integrin, Second 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 anti-angiogenic agents (XOMA, USA), PI 88 (Progen, Australia), Silendide (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 Children's Hospital, USA), ATN 161 (Attenuon, USA), 2-Methoxyestradiol (Boston Children's Hospital, USA), ZD 6474 (AstraZeneca, UK), ZD 6126 (Angiogene Pharmaceuticals, UK), PPI 2458 (Praecis, USA), AZD 9935 (AstraZeneca, UK), AZD 2171 (AstraZeneca, UK), vatalanib (pINN) (Novartis, Switzerland and Schering AG,Germany), tissue factor pathway inhibitor (EntreMed, USA), pegaptanib (Pinn) (Gilead Sciences, USA), xantrizole (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, angiogenic agents (EntreMed, USA), urokinase plasminogen activator inhibitors (Dendreon, USA), ogluphanide (pINN) (Melmotte, USA), HIF-alfa inhibitors (Xenova, UK), CEP 5214 (Cephalon, USA), BAY RES 2622 (Bayer, Germany), angiocidin (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), tamstatin (Beth Israel Hospital, USA), truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA), Tie-2 ligand (Regeneron, USA), and thrombospondin 1 inhibitor (Allegheny Health, Education and The Research Foundation (USA) is one example.

[0232] Further examples of therapeutic agents that may be used in combination with the compounds of the present invention include agents that specifically bind to 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 domains, or soluble receptors), as well as antibodies or antigen-binding domains that specifically bind to the receptor c-Met.

[0233] Another example of therapeutic agents that may be used in combination with the compounds of the present invention is autophagy inhibitors. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil®), bafilomycin A1, 5-amino-4-imidazole carboxamidriboside (AICAR), okadaic acid, autophagy-suppressing algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Furthermore, antisense or siRNAs that inhibit the expression of proteins, including but not limited to ATG5 (which is involved in autophagy), may also be used. In some embodiments, one or more additional therapies include autophagy inhibitors.

[0234] Another example of a therapeutic agent that may be used in combination with the compounds of the present invention is an antineoplastic agent. In some embodiments, one or more additional therapies include an antineoplastic agent. Non-limiting examples of antineoplastic agents include acemannan, acralubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amiphostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, algravin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, bromodeoxyuridine, capecitabine, cermoloukin, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphate, and DA 3030 (Dong-A), daclizumab, denileukin difutox, deslorerin, dexrazoxane, dilazep, docetaxel, docosanol, doxelcalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, ederfosine, edrecolomab eflornithine, emiteflu, epirubicin, epoetin beta, etoposide phosphate, exemestane, exislind, fadrozol, filgrastim, finasteride, fludarabine phosphate, formestan, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination Combined, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin (imiquimod), interferon alpha, interferon alpha, natural type, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-NI, interferon alpha-n3, interferon alpha-con-1, interferon alpha, natural type, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, natural type interferon gamma-la, interferon gamma-lb, interleukin-1 beta, iobenguan, irinotecan, ilsoglazine,Lanreotide, LC9018 (Yakult), Leflunomide, Lenograstim, Lentinan sulfate, Letrozole, Leukocyte alpha interferon, Leuprorelin, Levamizole + Fluorouracil, Rialozol, Lovaplatin, Ronidamin, Lovastatin, Masopropyl, Melalsoprole, Metoclopramide, Mifepristone, Miltefosine, Millimostim, Mispaired double-stranded RNA, Mitoguazone, Mitractol, Mitoxantrone, Morglamostim, Nafarelin, Naloxone + Pentazocine, Naltograstim, Neda Platin, nilutamide, noscapine, novel erythropoiesis-promoting protein, NSC631570 octreotide, oprelbequin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspar gauze, pegylated interferon alpha-2b, pentosan, sodium polysulfate, pentostatin, picibanil, pirarubicin, rabbit anti-thymocyte polyclonal antibody, polyethylene glycol interferon alpha-2a, porfimer sodium, raloxifene, larcitrexed, rasbrine bodyment (rasbu riembodiment), etidronate rhenium Re186, RII retinamide, rituximab, romultide, samarium (153Sm) lexidonam, salglamostim, schizophyllan, sobuzoxane, sonelmin, strontium-89 chloride, suramin, tasonelmin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfacin, thyroid-stimulating hormone alpha, topotecan, toremifene, tositumomab-iodine-131, trastuzumab, treosulfan, Tretinoin, trilostane, trimethrexate, triptorelin, tumor necrosis factor alpha, natural type, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma solubilizing solution vaccine, barrubicin, verteporfin, vinorelbine, bilirulysine, dinostatin stimalamer or zoledronic acid; Abarelix; AE941 (Aeterna), ambamustin, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), decitabine, dexaaminoglutethimide, diazicon, EL532 (Elan),EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, gallocitabine, gastrin-17 immunogene, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin-2, iproxyfen, LDI200 (Milkhaus), religistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine-131MAb (Techniclone), polymorphoemic mucin-yttrium-90MAb (Antisoma), marimast, menogalil, mitumomab, motexafine, gadolinium, MX6 (Galderma), nelarabine, noratexed, P30 protein, pegvisomant, pemetrexed, porphyromycin, prinomast, RL0903 (Shire), rubitecan, satoraplatin, sodium phenylacetate, sparphosic acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, saliblastin, thrombopoietin, tin ethylethiopurine, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering (Institute), melanoma tumor breakdown product vaccine (New York Medical College), viral melanoma cell solubilization vaccine (Royal, Examples include Newcastle Hospital, or Valspodal.

[0235] 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®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; Atasicept; CP-870893; Lucatumumab; Dasetuzumab; Muromonab-CD3; Ipirumumab; MEDI4736 (Imfinzi (registered trademark)); MSB0010718C; AMP 224; Adalimumab (Humira®); Adtrastuzumab emtansine (Kadcyla®); Aflibercept (Eylea®); Alemtuzumab (Campath®); Basiliximab (Simulect®); Belimumab (Benlysta®); Basiliximab (Simulect®); Belimumab (Benlysta®); Brentuximab vedotin (Adcetris®); Canakinumab (Ilaris®); Certolizumab pegol (Cimzia®); Daclizumab (Zenapax®); Daratumumab (Darzale x(registered trademark)); denosumab (Prolia(registered trademark)); eculizumab (Soliris(registered trademark)); efalizumab (Raptiva(registered trademark)); gemtuzumab ozogamicin (Mylotarg(registered trademark)); golimumab (Simponi(registered trademark)); ibritumomab tiuxetan (Zevalin(registered trademark)); infliximab (Remicade(registered trademark)); motabizumab (Numax(registered trademark)); natalizumab (Tysabri(registered trademark)); obinutuzumab (Gazyva(registered trademark)); ofatumumab (Arzerra(registered trademark)); omalizumab (Xolair(registered trademark)); palivizumab (Synagis(registered trademark));Pertuzumab (Perjeta®); Pertuzumab (Perjeta®); Ranibizumab (Lucentis®); Laxibakumab (Abthrax®); Tocilizumab (Actemra®); Tositumomab; Tositumomab-i-131; Tositumomab and Tositumomab-i-131 (Bexxar®); Ustekinumab (Stelara®); AMG 102; AMG; Examples include the 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951.

[0236] The compounds described herein can be used in combination with other agents disclosed herein or other suitable agents, depending on the condition being treated. Therefore, in some embodiments, one or more compounds of this disclosure are administered concurrently with other therapies, such as those described herein. When used in combination therapy, the compounds described herein may be administered concurrently with or separately from a second agent. This combined administration may include concurrent administration of the two agents in the same dosage form, concurrent administration in separate dosage forms, and separate administration. That is, the compounds described herein and any agents described herein may be formulated together in the same dosage form and administered concurrently. Alternatively, the compounds of the present invention and any therapy described herein may be administered concurrently, with both agents existing in separate formulations. In another alternative, the compounds of this disclosure may be administered, followed by any therapy described herein, and vice versa. In some embodiments of separate administration protocols, the compounds of the present invention and any therapy described herein are administered at intervals of several minutes, several hours, or several days.

[0237] In some embodiments of any of the methods described herein, the first therapy (e.g., the compound of the present invention) and one or more additional therapies are administered simultaneously or sequentially in any order. The first therapeutic agent is administered immediately before or after one or more additional therapies, or up to 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 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, 22 hours, 23 hours, 24 hours, or up to 1-7, 1-14, 1-21, or 1-30 days before or after.

[0238] The present invention also features a kit comprising (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the present invention), and (b) a package containing instructions for carrying out any of the methods described herein. In some embodiments, the kit comprises (a) a pharmaceutical composition comprising an agent described herein (e.g., a compound of the present invention), (b) one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents), and (c) a package containing instructions for carrying out any of the methods described herein.

[0239] One aspect of the present invention, intending to treat a disease or associated symptoms using a combination of pharmaceutically active compounds that can be administered separately, further relates to combining separate pharmaceutical compositions in the form of a kit. The kit may comprise two separate pharmaceutical compositions, i.e., the compounds of the present invention, and one or more additional therapies. The kit may comprise containers for housing the separate compositions, such as divided bottles or divided foil packets. Examples of additional containers include syringes, boxes, and bags. In some embodiments, the kit may include instructions for using the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing healthcare professional.

[0240] Numbered embodiments [1] Compounds having the structure of formula I, or pharmaceutically acceptable salts thereof: [ka] [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH3)C(O)-(CH2)-[wherein amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-6 member heteroarylenes, B is -CH(R 9 )-or>C=CR 9 R 9’ [In the formula, carbon is -N(R 11 )[bonded to the carbonyl carbon of C(O)-], optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes, G is an arbitrarily substituted C1-C4 alkylene, an arbitrarily substituted C1-C4 alkenylene, an arbitrarily substituted C1-C4 heteroalkylene, -C(O)O-CH(R 6 )-[In the formula, the second C is -C(R 7 R 8 )- is bonded. ], -C(O)NH-CH(R 6 )-[In the formula, the second C is -C(R 7 R 8 )- is bonded to it. ], optionally substituted C1-C4 heteroalkylenes, or 3-8 member heteroarylenes, L does not exist, or it is a linker. W is hydrogen, cyano, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 3-8 member heteroaryl. X 1 This is an optionally substituted C1-C2 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-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2. Each R' is independently H or an optionally substituted C1-C4 alkyl group. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 Independently, C or N, Y 5 is CH, CH2, or N, Y 6 It is C(O), CH, CH2, or N, R 1This is a cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R 1 and R 2 These combine with the atoms to which they bond, forming optionally substituted 3-14 member heterocycloalkyl groups. R 2 R is either absent, or contains hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5 or 6-membered heteroaryl. 3 It does not exist, or R 2 and R 3 These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R 4 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1 to 3 halogens. R 5 These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens. R 6 R is hydrogen or methyl, 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 8This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 These combine with the carbon atoms they bond to, forming C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, R 7a and R 8a These are independently hydrogen, halos, or optionally substituted C1-C3 alkyl groups, or they combine with the carbon they bond to to form a carbonyl group. R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 9This is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl. R 9 And L combine with the atoms to which they are bonded to form optionally substituted 3-14 member heterocycloalkyl groups. R 9’ is a hydrogen- or optionally substituted C1-C6 alkyl group, R 10 These are hydrogen, halo, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl. R 10a is hydrogen or halo, R 11 is hydrogen or a C1-C3 alkyl group, and R 16 [It is hydrogen or a C1-C3 alkyl group.]

[0241] [2] The compounds described in paragraph [1], or pharmaceutically acceptable salts thereof, wherein G is an optionally substituted C1-C4 heteroalkylene.

[0242] [3] The compounds described in paragraph [1] or [2], or pharmaceutically acceptable salts thereof, wherein the above compound has the structure of formula Ic: [ka] [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH3)C(O)-(CH2)-[wherein amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-6 member heteroarylenes, B is -CH(R 9 )-[In the formula, carbon is -N(R 11)[bonded to the carbonyl carbon of C(O)-], optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. 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-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2. Each R' is independently H or an optionally substituted C1-C4 alkyl group. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 Independently, C or N, Y 5 and Y 6 They are independently CH or N, R 1These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 R is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, 3 It does not exist, or R 2 and R 3 These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R 4 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1 to 3 halogens. R 5 These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens. R 6 R is hydrogen or methyl, 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 8This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 These combine with the carbon atoms they bond to, forming C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 9 This is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl. R 10 is hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl, and R 11[It is hydrogen or a C1-C3 alkyl group.]

[0243] [4]X 2 A compound described in any one of paragraphs [1] to [3], or a pharmaceutically acceptable salt thereof, wherein NH is NH.

[0244] [5]X 3 A compound described in any one of paragraphs [1] to [4], or a pharmaceutically acceptable salt thereof, wherein is CH.

[0245] [6]R 11 A compound described in any one of paragraphs [1] to [5], or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

[0246] [7]R 11 A compound described in any one of paragraphs [1] to [5], wherein the compound is a C1-C3 alkyl group, or a pharmaceutically acceptable salt thereof.

[0247] [8]R 11 The compounds described in paragraph [7], or pharmaceutically acceptable salts thereof, wherein the compound is methyl.

[0248] [9] Compounds described in any one of paragraphs [1] to [6], or pharmaceutically acceptable salts thereof, having the structure of formula Id: [ka] [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH3)C(O)-(CH2)-[wherein amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-6 member heteroarylenes, B is -CH(R 9)-[wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. n is 0, 1, or 2. R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R', C(O)OR', C(O)N(R')2, S(O)R', S(O)2R', or S(O)2N(R')2. Each R' is independently H or an optionally substituted C1-C4 alkyl group. Y 1 is C, CH, or N, Y 2 , Y 3 , Y 4 , and Y 7 Independently, C or N, Y 5 and Y 6 They are independently CH or N, R 1 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R2 R is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, 3 It does not exist, or R 2 and R 3 These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R 4 It is either absent, or a methyl atom optionally substituted with hydrogen, halogen, cyano, or 1 to 3 halogens. R 5 These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens. R 6 R is hydrogen or methyl, 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 8 This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7 and R 8 These combine with the carbon atoms they bond to, forming C=CR 7’ R 8’, forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl, and R 10 [These are hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.]

[0249]

[10] X 1 The compounds described in any one of paragraphs [1] to [9], or pharmaceutically acceptable salts thereof, wherein the C1-C2 alkylene is optionally substituted.

[0250]

[11] X 1 The compounds described in paragraph

[10] , or pharmaceutically acceptable salts thereof, wherein methylene is present.

[0251]

[12] R 5 A compound described in any one of paragraphs [1] to

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

[0252]

[13] R 5 The compounds described in any one of paragraphs [1] to

[11] , or pharmaceutically acceptable salts thereof, which are C1-C4 alkyl groups optionally substituted with halogens.

[0253]

[14] R 5 The compounds described in paragraph

[13] , or pharmaceutically acceptable salts thereof, wherein the compound is methyl.

[0254]

[15] Y 4 A compound described in any one of paragraphs [1] to

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

[0255]

[16] R 4 A compound described in any one of paragraphs [1] to

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

[0256]

[17] Y 5 A compound described in any one of paragraphs [1] to

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

[0257]

[18] Y 6 A compound described in any one of paragraphs [1] to

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

[0258]

[19] Y 1 A compound described in any one of paragraphs [1] to

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

[0259]

[20] Y 2 A compound described in any one of paragraphs [1] to

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

[0260]

[21] Y 3 A compound described in any one of paragraphs [1] to

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

[0261]

[22] R 3A compound described in any one of paragraphs [1] to

[21] , or a pharmaceutically acceptable salt thereof, which does not exist.

[0262]

[23] Y 7 A compound described in any one of paragraphs [1] to

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

[0263]

[24] Compounds described in any one of paragraphs [1]-[6] or [9]-

[23] , or pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula Ie: [ka] [In the formula, A is -N(H or CH3)C(O)-(CH2)-[In the formula, amino nitrogen is -CH(R 10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-6 member heteroarylenes, B is -CH(R 9 )-[wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. R 1These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 R is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, 3 It does not exist, or R 2 and R 3 These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R 5 These are C1-C4 alkyl, cyano, hydroxy, or C1-C4 alkoxy, cyclopropyl, or cyclobutyl compounds optionally substituted with hydrogen or halogens. R 6 R is hydrogen or methyl, 7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or R 6 and R 7 These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 8 This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R7 and R 8 These combine with the carbon atoms they bond to, forming C=CR 7’ R 8’ , forming C=N(OH), C=N(O-C1-C3 alkyl), C=O, C=S, C=NH, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl, R 7’ is hydrogen, halogen, or optionally substituted C1-C3 alkyl, and R 8’ This can be hydrogen, halogen, hydroxyl, cyano, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-8 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R 7’ and R 8’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R 9 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3- to 6-membered cycloalkyl, or an optionally substituted 3- to 7-membered heterocycloalkyl, and R 10 [These are hydrogen, hydroxyl, C1-C3 alkoxy, or C1-C3 alkyl.]

[0264]

[25] R 6 A compound described in any one of paragraphs [3] to

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

[0265]

[26] R 2A compound described in any one of paragraphs [1] to

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

[0266]

[27] R 2 The compounds described in paragraph

[26] , or pharmaceutically acceptable salts thereof, wherein the C1-C6 alkyl group is optionally substituted.

[0267]

[28] R 2 The compounds described in paragraph

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

[0268]

[29] R 7 The compounds described in any one of paragraphs [1] to

[28] , or pharmaceutically acceptable salts thereof, wherein the C1-C3 alkyl is optionally substituted.

[0269]

[30] R 7 The compounds described in paragraph

[29] , or pharmaceutically acceptable salts thereof, wherein the compound is a C1-C3 alkyl group.

[0270]

[31] R 8 The compounds described in any one of paragraphs [1] to

[30] , or pharmaceutically acceptable salts thereof, wherein the C1-C3 alkyl is optionally substituted.

[0271]

[32] R 8 The compounds described in paragraph

[31] , or pharmaceutically acceptable salts thereof, wherein the compound is a C1-C3 alkyl group.

[0272]

[33] Compounds described in any one of paragraphs [1] to

[32] , or pharmaceutically acceptable salts thereof, having the structure of formula If: [ka] [In the formula, A is -N(H or CH3)C(O)-(CH2)-[In the formula, amino nitrogen is -CH(R10 )- bonded to a carbon atom, optionally substituted 3-6 member cycloalkylenes, optionally substituted 3-6 member heterocycloalkylenes, optionally substituted 6 member arylenes, or optionally substituted 5-6 member heteroarylenes, B is -CH(R 9 )-[wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. R 1 These are cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl. R 2 These are C1-C6 alkyl or 3-6 member cycloalkyl groups. R 7 It is a C1-C3 alkyl group, R 8 It is a C1-C3 alkyl group, and R 9 This is an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group.

[0273]

[34] R 1 A compound described in any one of paragraphs [1] to

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

[0274]

[35] R 1 The compounds described in paragraph

[34] , or pharmaceutically acceptable salts thereof, wherein the compound is an optionally substituted six-membered aryl or an optionally substituted six-membered heteroaryl.

[0275]

[36] Compounds described in any one of paragraphs [1] to

[35] , or pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula Ig: [ka] [In the formula, 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 5- to 6-membered heteroarylene.] B is -CH(R 9 )-[wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. R 2These are C1-C6 alkyl or 3-6 member cycloalkyl groups. R 7 It is a C1-C3 alkyl group, R 8 It is a C1-C3 alkyl group, R 9 This is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl. X e is N, CH, or CR 17 And, X f is N or CH, R 12 is an optionally substituted C1-C6 alkyl group, or an optionally substituted C1-C6 heteroalkyl group, and R 17 This is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl.

[0276]

[37] X e N is X f The compounds described in paragraph

[36] , or pharmaceutically acceptable salts thereof, wherein CH is CH.

[0277]

[38] X e CH is, X f The compounds described in paragraph

[36] , or pharmaceutically acceptable salts thereof, wherein N is N.

[0278]

[39] X e CR 17 X f The compounds described in paragraph

[36] , or pharmaceutically acceptable salts thereof, wherein N is N.

[0279]

[40] R 12The compounds described in any one of paragraphs

[36] to

[39] , or pharmaceutically acceptable salts thereof, which are optionally substituted C1-C6 heteroalkyl groups.

[0280]

[41] R 12 but [ka] The compound described in any one of paragraphs

[36] to

[40] , or a pharmaceutically acceptable salt thereof.

[0281]

[42] Compounds described in any one of paragraphs [1] to

[41] , or pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula Ih: [ka] [In the formula, 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 5- to 6-membered heteroarylene.] B is -CH(R 9 )-[wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. R 2These are C1-C6 alkyl or 3-6 member cycloalkyl groups. R 7 It is a C1-C3 alkyl group, R 8 It is a C1-C3 alkyl group, R 9 This is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted 3-6 member cycloalkyl, or an optionally substituted 3-7 member heterocycloalkyl. X e CH, or CR 17 And, R 17 This is an optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl.

[0282]

[43] Compounds described in any one of paragraphs [1] to

[42] , or pharmaceutically acceptable salts thereof, wherein the compound has the structure of formula II: [ka] [In the formula, 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 5- to 6-membered heteroarylene.] B is -CH(R 9 )-[wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 hydroxyalkyl, optionally substituted C1-C4 aminoalkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 guanidinoalkyl, optionally substituted 3-11 member heterocycloalkyl with C0-C4 alkyl, optionally substituted 3-8 member cycloalkyl, or optionally substituted 3-8 member heteroaryl. R 2 These are C1-C6 alkyl or 3-6 member cycloalkyl groups. R 7 It is a C1-C3 alkyl group, R 8 It is a C1-C3 alkyl group, and R 9 This is an optionally substituted C1-C6 alkyl group, an optionally substituted C1-C6 heteroalkyl group, an optionally substituted 3- to 6-membered cycloalkyl group, or an optionally substituted 3- to 7-membered heterocycloalkyl group.

[0283]

[44] A is an optionally substituted six-membered arylene, the compound described in any one of paragraphs [1] to

[43] , or a pharmaceutically acceptable salt thereof.

[0284]

[45] A is a compound described in paragraph

[44] , or a pharmaceutically acceptable salt thereof, wherein A has the following structure: [ka] [In the formula, R 13 [These are hydrogen, hydroxyl, amino, cyano, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl.]

[0285]

[46] R 13 The compounds described in paragraph

[45] , or pharmaceutically acceptable salts thereof, wherein the compound is hydrogen.

[0286]

[47] R 13The compounds described in paragraph

[45] , or pharmaceutically acceptable salts thereof, wherein is hydroxyl.

[0287]

[48] ​​A is an optionally substituted 5-6 member heteroarylene, the compound described in any one of paragraphs [1] to

[43] , or a pharmaceutically acceptable salt thereof.

[0288]

[49] A [ka] The compounds described in paragraph

[48] , or pharmaceutically acceptable salts thereof.

[0289]

[50] A [ka] The compounds described in paragraph

[49] , or pharmaceutically acceptable salts thereof.

[0290]

[51] B is -CHR 9 - The compound described in any one of paragraphs [1] to

[50] , or a pharmaceutically acceptable salt thereof.

[0291]

[52] R 9 The compounds described in paragraph

[51] , or pharmaceutically acceptable salts thereof, wherein the compound is optionally substituted with a C1-C6 alkyl group or optionally substituted with a 3- to 6-membered cycloalkyl group.

[0292]

[53] R 9 but [ka] The compounds described in paragraph

[52] , or pharmaceutically acceptable salts thereof.

[0293]

[54] R 9 but [ka] The compounds described in paragraph

[53] , or pharmaceutically acceptable salts thereof.

[0294]

[55] The compounds described in any one of paragraphs [1] to

[50] , or pharmaceutically acceptable salts thereof, wherein B is an optionally substituted six-membered arylene.

[0295]

[56] The compounds described in

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

[0296]

[57] B [ka] The compounds described in paragraph

[56] , or pharmaceutically acceptable salts thereof.

[0297]

[58] A compound described in any one of paragraphs [1] to

[50] , or a pharmaceutically acceptable salt thereof, in which B is absent.

[0298]

[59] R 7 A compound described in any one of paragraphs [1] to

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

[0299]

[60] R 8 A compound described in any one of paragraphs [1] to

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

[0300]

[61] The compound described in any one of paragraphs [1] to

[60] , wherein the 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 This is the bond between the linker and B; A 2 This is the bond between W and the linker; B 1 B 2 B 3 , and B 4 These are, independently, an arbitrarily substituted C1-C2 alkylene, an arbitrarily substituted C1-C3 heteroalkylene, O, S, and NR. N Selected from; R N C is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C3 cycloalkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted C1-C7 heteroalkyl; C 1 and C 2 Each is independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; f, g, h, i, j, and k are each independently 0 or 1; D 1 This is an arbitrarily substituted C1-C 10 Alkylene, optionally substituted C2-C 10 Alkenylene, optionally substituted C2-C 10 Alkynylene, optionally substituted 3-14 member heterocycloalkylene, optionally substituted 5-10 member heteroarylene, optionally substituted 3-8 member cycloalkylene, optionally substituted 6-10 member arylene, optionally substituted C2-C 10 Polyethylene glycolen, or optionally substituted C1-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 It is a chemical bond that connects two things together.

[0301]

[62] A compound described in any one of paragraphs [1] to

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

[0302]

[63] The compound described in paragraph

[62] , or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of formula IIa: [ka] [In the formula, X a It does not exist, or it is N. R 14 It is either absent, or is hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C3 cycloalkyl, and L 2 It does not exist, or it is -C(O)-, -SO2-, an arbitrarily substituted C1-C4 alkylene, or an arbitrarily substituted C1-C4 heteroalkylene. X a , R 14 , or L 2 At least one of these exists.

[0303]

[64] The compound described in paragraph

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

[0304]

[65] The compound described in paragraph

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

[0305]

[66] The compounds described in any one of paragraphs [1] to

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

[0306]

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

[61] or

[66] , wherein the linker has the structure of formula IIb, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, o is either 0 or 1, X b is C(O) or SO2, R 15 is a hydrogen- or optionally substituted C1-C6 alkyl group, 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 It either does not exist, or it is -C(O)-, -SO2-, an arbitrarily substituted C1-C4 alkylene, or an arbitrarily substituted C1-C4 heteroalkylene.

[0307]

[68] The compound described in paragraph

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

[0308]

[69] A compound described in any one of paragraphs [1] to

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

[0309]

[70] A compound described in any one of paragraphs [1] to

[68] , wherein W is an optionally substituted amino, or a pharmaceutically acceptable salt thereof.

[0310]

[71] The compounds described in paragraph

[70] , or pharmaceutically acceptable salts thereof, wherein W is -NHCH3 or -N(CH3)2.

[0311]

[72] A compound described in any one of paragraphs [1] to

[68] , wherein W is an optionally substituted amide, or a pharmaceutically acceptable salt thereof.

[0312]

[73] W [ka] The compounds described in paragraph

[72] , or pharmaceutically acceptable salts thereof.

[0313]

[74] A compound described in any one of paragraphs [1] to

[68] , wherein W is optionally substituted C1-C4 alkoxy, or a pharmaceutically acceptable salt thereof.

[0314]

[75] The compounds described in paragraph

[74] , or pharmaceutically acceptable salts thereof, wherein W is methoxy or isopropoxy.

[0315]

[76] A compound described in any one of paragraphs [1] to

[68] , wherein W is optionally substituted with a C1-C4 alkyl group, or a pharmaceutically acceptable salt thereof.

[0316]

[77] The compounds described in paragraph

[76] , or pharmaceutically acceptable salts thereof, wherein W is methyl, ethyl, isopropyl, tert-butyl, or benzyl.

[0317]

[78] A compound described in any one of paragraphs [1] to

[68] , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted C1-C4 hydroxyalkyl.

[0318]

[79] W [ka] The compounds described in paragraph

[78] , or their pharmaceutically acceptable salts.

[0319]

[80] A compound described in any one of paragraphs [1] to

[68] , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted C1-C4 aminoalkyl.

[0320]

[81] W [ka] The compounds described in paragraph

[80] , or pharmaceutically acceptable salts thereof.

[0321]

[82] A compound described in any one of paragraphs [1] to

[68] , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted C1-C4 haloalkyl.

[0322]

[83] W [ka] The compounds described in paragraph

[82] , or pharmaceutically acceptable salts thereof.

[0323]

[84] A compound described in any one of paragraphs [1] to

[68] , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted C1-C4 guanidinoalkyl.

[0324]

[85] W [ka] The compounds described in paragraph

[84] , or pharmaceutically acceptable salts thereof.

[0325]

[86] A compound described in any one of paragraphs [1] to

[68] , or a pharmaceutically acceptable salt thereof, wherein W is a 3- to 11-membered heterocycloalkyl group optionally substituted with a C0-C4 alkyl group.

[0326]

[87] W [ka] [ka] [ka] [ka] [ka] The compounds described in paragraph

[86] , or pharmaceutically acceptable salts thereof.

[0327]

[88] A compound described in any one of paragraphs [1] to

[68] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3- to 8-membered cycloalkyl group.

[0328]

[89] W [ka] The compounds described in paragraph

[88] , or pharmaceutically acceptable salts thereof.

[0329]

[90] A compound described in any one of paragraphs [1] to

[68] , or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3- to 8-membered heteroaryl.

[0330]

[91] W [ka] The compounds described in paragraph

[90] , or pharmaceutically acceptable salts thereof.

[0331]

[92] A compound described in any one of paragraphs [1] to

[68] , wherein W is optionally substituted with a 6- to 10-membered aryl, or a pharmaceutically acceptable salt thereof.

[0332]

[93] The compounds described in paragraph

[92] , or pharmaceutically acceptable salts thereof, wherein W is phenyl, 4-hydroxyphenyl, or 2,4-methoxyphenyl.

[0333]

[94] Compounds listed in Table 1 or 2, or pharmaceutically acceptable salts thereof.

[0334]

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

[94] , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0335]

[96] A method for treating cancer in a subject requiring treatment for cancer, the method comprising administering to the subject a therapeutically effective amount of a compound described in any one of paragraphs [1] to

[94] , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in paragraph

[95] .

[0336]

[97] The method according to paragraph

[96] , wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer, or uterine cancer.

[0337]

[98] The method described in paragraph

[97] , wherein the cancers described above include a Ras mutation.

[0338]

[99] The method according to paragraph

[98] , wherein the Ras mutation is located at position 12, 13, or 61.

[0339]

[0100] The method according to paragraph

[98] , wherein the Ras mutation is K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, or K-Ras Q61L.

[0340]

[0101] A method for treating a subject in a subject requiring treatment for a Ras protein-related disease, the method comprising administering to the subject a therapeutically effective amount of a compound described in any one of paragraphs [1] to

[94] , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in paragraph

[95] .

[0341]

[0102] A method for inhibiting Ras protein in cells, the method comprising contacting the cells with a therapeutically effective amount of a compound described in any one of paragraphs [1] to

[94] , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in paragraph

[95] .

[0342]

[0103] The method according to paragraph

[0101] or

[0102] , wherein the Ras protein is K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, or K-Ras Q61L.

[0343]

[0104] The method according to paragraph

[0102] or

[0103] , wherein the cells are cancer cells.

[0344]

[0105] The method according to paragraph

[0104] , wherein the cancer cells are pancreatic cancer cells, colorectal cancer cells, non-small cell lung cancer cells, gastric cancer cells, esophageal cancer cells, ovarian cancer cells, or uterine cancer cells.

[0345]

[0106] The method or use of any one of paragraphs

[96] to

[0105] , further comprising administering an additional anti-cancer treatment.

[0346]

[0107] The method according to paragraph

[0106] , wherein the additional anticancer treatment 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.

[0347]

[0108] The method according to paragraph

[0106] or

[0107] , wherein the additional anti-cancer treatment described above is an SHP2 inhibitor.

[0348] Examples This disclosure is further illustrated by the following examples and synthesis examples, which should not be considered to limit the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate specific embodiments and are not intended to imply any limitation on the scope of this disclosure. It should also be understood that various other embodiments, modifications, and equivalents can be taken, which themselves may be suggested to those skilled in the art, without departing from the spirit of this disclosure or the appended claims.

[0349] Chemical Synthesis The following examples and definitions used elsewhere in this specification are as follows: CH2Cl2, DCM: Methylene chloride, Dichloromethane CH3CN, MeCN: Acetonitrile CuI: Copper(I) iodide DIPEA: Diisopropylethylamine DMF: N,N-dimethylformamide æ:ethyl acetate h: time H2O: Water HCl: Hydrochloric acid K3PO4: Potassium phosphate (tribasic acid) MeOH: methanol Na2SO4: Sodium sulfate NMP: N-methylpyrrolidone Pd(dppf)Cl2:[1,1′-bis(diphenylphosphin)ferrocene]dichloropalladium(II)

[0350] Equipment Mass spectrometry data were acquired using a Shimadzu LCMS-2020, Agilent 1260LC-6120 / 6125MSD, Shimadzu LCMS-2010EV, or Waters Acquity UPLC equipped with either a QDa or SQ detector 2. Samples were injected in liquid phase into a C18 reversed phase. Compounds were eluted from the column using an acetonitrile gradient and fed to the mass spectrometer. Initial data analysis was performed using either an Agilent ChemStation, Shimadzu LabSolutions, or Waters MassLynx. NMR data were obtained using a Bruker AVANCE III HD 400MHz or Bruker Ascend. Data was collected using either a 500MHz instrument or a Varian 400MHz instrument, and the raw data was analyzed using either TopSpin or Mestrelab Mnova.

[0351] Synthesis of intermediates Intermediate 1: Synthesis of 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]indole-3-yl)-2,2-dimethylpropan-1-ol [ka]

[0352] Step 1. Under an N2 atmosphere at 0°C, 137 mL of 1 M SnCl4 in DCM was slowly added to a mixture of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoyl chloride (65 g, 137 mmol, crude) with DCM (120 mL). After stirring the mixture at 0°C for 30 minutes, a solution of 5-bromo-1H-indole (26.8 g, 137 mmol) in DCM (40 mL) was added dropwise. After stirring the mixture at 0°C for 45 minutes, it was diluted with siRNA (300 mL), washed with brine (100 mL x 4), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1-(5-bromo-1H-indole-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (55 g, 75% yield). LCMS(ESI): m / z [M+Na]C 29 H 32 Calculated value for BrNO2SiNa: 556.1; measured value: 556.3.

[0353] Step 2. Under an N2 atmosphere at 0°C, LiBH4 (6.1 g, 281 mmol) was added to a mixture of 1-(5-bromo-1H-indole-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (50 g, 93.6 mmol) with THF (100 mL). The mixture was heated to 60°C and stirred for 20 hours, then MeOH (10 mL) and siRNA were added. The mixture was washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (50 mL), cooled to 10°C, and zirzine (9.5 g, 37.4 mmol) and TsOH·H2O (890 mg, 4.7 mmol) were added. The mixture was stirred at 10°C for 2 hours and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1-(5-bromo-1H-indole-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (41 g, 84% yield). LCMS(ESI): m / z [M+H]C 29 H34 Calculated value for BrNOSi: 519.2; Measured value: 520.1; 1 H NMR(400MHz, CDCl3)δ 7.96 (s, 1H), 7.75 - 7.68 (m, 5H), 7.46 - 7.35 (m, 6H), 7.23 - 7.19 (m, 2H), 6.87 (d, J = 2.1 Hz, 1H), 3.40 (s, 2H), 2.72 (s, 2H), 1.14 (s, 9H), 0.89 (s, 6H).

[0354] Step 3. 1-(5-bromo-1H-indole-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-1-one (1.5 g, 2.9 mmol) and I2 (731 mg, 2.9 mmol) were mixed with THF (15 mL) and AgOTf (888 mg, 3.5 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours, then diluted with siRNA (200 mL), washed with saturated Na2S2O3 (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (900 mg, 72% yield) as a solid. 1 H NMR (400MHz, DMSO-d6)δ 11.70 (s, 1H), 7.68 (d, J = 1.3 Hz, 1H), 7.64 - 7.62 (m, 4H), 7.46 - 7.43 (m, 6H), 7.24 - 7.22 (d, 1H), 7.14 - 7.12 (dd, J = 8.6, 1.6 Hz, 1H), 3.48 (s, 2H), 2.63 (s, 2H), 1.08 (s, 9H), 0.88 (s, 6H).

[0355] Step 4. Under an Ar atmosphere at 0°C, (4S,5S)-2-chloro-2-methyl-1-(4-methylbenzenesulfonyl)-4,5-diphenyl-1,3-diaza-2-lutenacyclopentancymene (3.9 g, 6.0 mmol) was added in several portions to a mixture of HCOOH (66.3 g, 1.44 mol) and TEA (728 mg, 7.2 mol). The mixture was heated to 40°C and stirred for 15 minutes, then cooled to room temperature, and 1-(3-bromopyridine-2-yl)ethanone (120 g, 600 mmol) was added in small portions. The mixture was heated to 40°C and stirred for a further 2 hours, after which the solvent was concentrated under reduced pressure. Brine (2 L) was added to the residue, the mixture was extracted with ELISA (4 × 700 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain (1S)-1-(3-bromopyridine-2-yl)ethanol (100g, 74% yield) as oil. LCMS (ESI): m / z [M+H]C7H8BrNO Calculated value: 201.1; Measured value: 201.9.

[0356] Step 5. At 0°C, (1S)-1-(3-bromopyridine-2-yl)ethanol (100g, 495 mmol) was mixed with DMF (1 L) and added in small quantities to a stirred mixture. NaH (60% dispersion of oil) (14.25g, 594 mmol) was added. The mixture was stirred at 0°C for 1 hour. MeI (140.5g, 990 mmol) was added dropwise at 0°C, and the mixture was warmed to room temperature and stirred for 2 hours. The mixture was cooled to 0°C and saturated NH4Cl (5 L) was added. The mixture was extracted with ELISA (3 × 1.5 L), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (90g, 75% yield) as oil. LCMS(ESI): m / z [M+H]C8H 10 Calculated value for BrNO: 215.0; measured value: 215.9.

[0357] Step 6. Under an Ar atmosphere at room temperature, 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (90 g, 417 mmol) and Pd(dppf)Cl2 (30.5 g, 41.7 mmol) were stirred with toluene (900 mL), to which bis(pinacolato)diborone (127 g, 500 mmol) and KOAc (81.8 g, 833 mmol) were added in fractions. The mixture was heated to 100 °C and stirred for 3 hours. The filtrate was concentrated under reduced pressure, and the residue was purified by Al2O3 column chromatography to obtain 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100 g, 63% yield) as a semi-solid. LCMS(ESI): m / z [M+H]C 14 H 22 Calculated value for BNO3: 263.2; Measured value: 264.1.

[0358] Step 7. 5-Bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2-iodo-1H-indole (140 g, 217 mmol) and 2-[(1S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100 g, 380 mmol) were stirred with 1,4-dioxane (1.4 L). Under an Ar atmosphere at room temperature, K2CO3 (74.8 g, 541 mmol), Pd(dppf)Cl2 (15.9 g, 21.7 mmol), and H2O (280 mL) were added in fractions. The mixture was heated to 85°C, stirred for 4 hours, then cooled, H2O (5 L) was added, and the mixture was extracted with SiO2 (3 × 2 L). The combined organic layers were washed with brine (2 × 1 L), dried over anhydrous sodium 2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]-1H-indole (71 g, 45% yield) as a solid. LCMS(ESI): m / z [M+H]C 37 H 43Calculated value for BrN2O2Si: 654.2; measured value: 655.1.

[0359] Step 8. Under an N2 atmosphere at 0°C, 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]-1H-indole (71 g, 108 mmol) was stirred with DMF (0.8 L), to which Cs2CO3 (70.6 g, 217 mmol) and EtI (33.8 g, 217 mmol) were added in fractions. The mixture was warmed to room temperature and stirred for 16 hours, then H2O (4 L) was added, and the mixture was extracted with SiO2 (3 × 1.5 L). The combined organic layers were washed with brine (2 × 1 L), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]indole (66 g, 80% yield) as oil. LCMS(ESI): m / z [M+H]C 39 H 47 Calculated value for BrN2O2Si: 682.3; measured value: 683.3.

[0360] Step 9. Under an N2 atmosphere at room temperature, 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]indole (66 g, 97 mmol) was added in fractions to a stirred mixture of TBAF (172.6 g, 660 mmol) and THF (660 mL). The mixture was heated to 50°C and stirred for 16 hours, then cooled and diluted with H2O (5 L), and extracted with ethyl acetate (3 × 1.5 L). The combined organic layers were washed with brine (2 × 1 L), dried over anhydrous Na2SO4, and filtered. After filtration, the filtrate was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]indole-3-yl)-2,2-dimethylpropan-1-ol (30 g, 62% yield) as a solid. LCMS(ESI): m / z [M+H]C 23 H 29 Calculated value for BrN2O2: 444.1; measured value: 445.1.

[0361] Intermediate 1. Alternative synthesis via the Fischer indole pathway.

[0362] [ka]

[0363] Step 1: Under an N2 atmosphere, at -10°C, n-BuLi (2.5M, 333mL, 833 mmol in hexane) was added dropwise to a mixture of i-PrMgCl (2M, in THF, 0.5L) over 15 minutes. The mixture was stirred at -10°C for 30 minutes, and then a solution of 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (180g, 833 mmol) in THF (0.5L) was added dropwise at -10°C over 30 minutes. The resulting mixture was warmed to -5°C and stirred for 1 hour, and then a solution of 3,3-dimethyloxane-2,6-dione (118g, 833 mmol) in THF (1.2L) was added dropwise at -5°C over 30 minutes. The mixture was heated to 0°C and stirred for 1.5 hours. Then, HCl from a pre-pooled 4M 1,4-dioxane (0.6 L) was added at 0°C to quench the mixture and adjust the pH to approximately 5. The mixture was diluted with ice water (3 L) and extracted with ethyl acetate (3 × 2.5 L). The combined organic layers were dried over anhydrous sodium 2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]-2,2-dimethyl-5-oxopentanoic acid (87 g, 34% yield) as a solid. LCMS(ESI): m / z [M+H]C 15 H 21 Calculated value for NO4: 279.2; Measured value: 280.1.

[0364] Step 2. Under an N2 atmosphere at room temperature, 78 g of 5-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]-2,2-dimethyl-5-oxopentanoic acid (279 mmol) was added in a mixture with 0.78 L of EtOH, to which 68.7 g of (4-bromophenyl)hydrazine hydrochloride (307 mmol) was added in fractions. The mixture was heated to 85°C and stirred for 2 hours, then cooled to room temperature, after which 69.8 mL of 4 M HCl (in 1,4-dioxane, 279 mmol) was added dropwise. The mixture was heated to 85°C and stirred for a further 3 hours, then concentrated under reduced pressure, and the residue was dissolved in 0.78 L of TFA. The mixture was heated to 60°C, stirred for 1.5 hours, concentrated under reduced pressure, and the pH of the residue was adjusted to approximately 5 with saturated NaHCO3, after which it was extracted with SiO2 (3 × 1.5 L). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3-(5-bromo-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]-1H-indole-3-yl)-2,2-dimethylpropanoic acid and ethyl(S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropanoate (78 g, crude). LCMS(ESI): m / z [M+H]C 21 H 23 Calculated value for BrN2O3: 430.1, and C 23 H 27 Calculated value for BrN2O3: 458.1; measured values: 431.1 and 459.1.

[0365] Procedure 3. Under an N2 atmosphere, at 0 °C, Cs2CO3 (449 g, 1.38 mol) was added portionwise to a mixture of 3-(5-bromo-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]-1H-indol-3-yl)-2,2-dimethylpropanoic acid and ethyl (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoate (198 g, 459 mmol) in DMF (1.8 L). Next, a solution of EtI (215 g, 1.38 mmol) in DMF (200 mL) was added dropwise at 0 °C. The mixture was warmed to room temperature and stirred for 4 hours, then diluted with brine (5 L) and extracted with EtOAc (3 × 2.5 L). The combined organic layers were washed with brine (2 × 1.5 L), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridin-3-yl]indol-3-yl)-2,2-dimethylpropanoate (160 g, 57% yield) as a solid. LCMS (ESI): m / z [M+H]C 25 H 31 Calculated for BrN2O3: 486.2; found 487.2.

[0366] Step 4. Under an N2 atmosphere at 0°C, LiBH4 (28.6 g, 1.3 mol) was added to a mixture of ethyl 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]indole-3-yl)-2,2-dimethylpropanoate (160 g, 328 mmol) with THF (1.6 L). The mixture was heated to 60°C for 16 hours, cooled, and quenched with pre-pooled (0°C) NH4Cl aqueous solution (5 L). The mixture was extracted with ELISA (3 × 2 L), the combined organic layers were washed with brine (2 × 1 L), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain two atropisomers of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)pyridine-3-yl)-1H-indole-3-yl)-2,2-dimethylpropan-1-ol (as a single atropisomer) (60 g, 38% yield, and 40 g, 26% yield), both as solids. LCMS(ESI) m / z:[M+H]C 23 H 29 Calculated value for BrN2O2: 444.1; measured value: 445.2.

[0367] Intermediate 2 and Intermediate 4. Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)hexahydropyridazine-3-carboxylate [ka]

[0368] Step 1. Imidazole (4.6 g, 67.8 mmol) and TIPSCl (7.8 g, 40.7 mmol) were added to a mixture of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (10.0 g, 33.9 mmol) with DCM (100 mL). The mixture was stirred overnight at room temperature, then diluted with DCM (200 mL) and washed with H2O (150 mL x 3). The organic layer was dried over anhydrous Na2SO4 and filtered. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain (S)-methyl 2-(tert-butoxycarbonylamino)-3-(3-(triisopropylsilyloxy)phenyl)-propanoate (15.0 g, 98% yield) as oil. LCMS(ESI): m / z [M+Na]C 24 H 41 Calculated value for NO5SiNa: 474.3; measured value: 474.2.

[0369] Step 2. A mixture of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(3-(triisopropylsilyloxy)phenyl)-propanoate (7.5 g, 16.6 mmol), PinB2 (6.3 g, 24.9 mmol), [Ir(OMe)(COD)]2 (1.1 g, 1.7 mmol), and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (1.3 g, 5.0 mmol) was purged with Ar (×3), then THF (75 mL) was added, and the mixture was sealed under an Ar atmosphere. The mixture was heated to 80°C and stirred for 16 hours, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain (S)-methyl 2-(tert-butoxycarbonylamino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(triisopropylsilyloxy)phenyl)-propanoate (7.5 g, 78% yield) as a solid. LCMS(ESI): m / z [M+Na]C 30 H 52Calculated value for BNO7SiNa: 600.4; measured value 600.4; 1H NMR (300 MHz, CD3OD) δ 7.18 (s, 1H), 7.11 (s, 1H), 6.85 (s, 1H), 4.34 (m, 1H), 3.68 (s, 3H), 3.08 (m, 1H), 2.86 (m, 1H), 1.41 - 1.20 (m, 26H), 1.20 - 1.01 (m, 22H), 0.98 - 0.79 (m, 4H).

[0370] Step 3. At 0 °C, an aqueous solution (35 mL) of LiOH (840 mg, 34.4 mmol) was added to a mixture of triisopropylsilyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoate (4.95 g, 6.9 mmol) and MeOH (53 mL). The mixture was stirred at 0 °C for 2 hours, then acidified with 1 M HCl to a pH of about 5 and extracted with EtOAc (250 mL × 2). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoic acid (3.7 g, 95% yield), which was used directly in the next step without further purification. LCMS (ESI): m / z [M+NH4]C 29 H 50 Calculated value for BNO7SiNH4: 581.4; measured value 581.4.

[0371] Step 4. At 0°C, a mixture of methyl(S)-hexahydropyridazine-3-carboxylate (6.48 g, 45.0 mmol) and DCM (200 mL) was mixed with NMM (41.0 g, 405 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoic acid (24 g, 42.6 mmol) in DCM (50 mL), followed by HOBt (1.21 g, 9.0 mmol) and EDCI hydrochloride (12.9 g, 67.6 mmol). The mixture was heated to room temperature and stirred for 16 hours, then diluted with DCM (200 mL) and washed with H2O (3 × 150 mL). The organic layer was dried over anhydrous Na2SO and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain methyl(S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)hexahydropyridazine-3-carboxylate (22 g, 71% yield) as oil. LCMS(ESI): m / z [M+H]C 35 H 60 Calculated value for BN3O8Si: 689.4; Measured value: 690.5.

[0372] Intermediate 3. Synthesis of (S)-tert-butyl 3-methyl-2-((S)-N-methylpyrrolidine-3-carboxamide)butanoate [ka]

[0373] Step 1. At room temperature, HATU (7.8 g, 20.4 mmol) and DIPEA (5 mL) were added to a mixture of (S)-1-(tert-butoxycarbonyl)pyrrolidone-3-carboxylic acid (2.2 g, 10.2 mmol) with DMF (10 mL). After stirring at room temperature for 10 minutes, a solution of tert-butylmethyl-L-valinate (3.8 g, 20.4 mmol) in DMF (10 mL) was added. The mixture was stirred at room temperature for 3 hours, and then diluted with DCM (40 mL) and H2O (30 mL). The aqueous layer and organic layer were separated, the organic layer was washed with H2O (3 × 30 mL) and brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain (S)-tert-butyl 3-(((S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidone-1-carboxylate (3.2 g, 82% yield) as oil. LCMS(ESI): m / z [M+Na]C 20 H 36 Calculated value for N2O5Na: 407.3; measured value: 407.2.

[0374] Step 2. A mixture of (S)-tert-butyl 3-(((S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidone-1-carboxylate (3.2 g, 8.4 mmol) with DCM (13 mL) and TFA (1.05 g, 9.2 mmol) was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure to obtain (S)-tert-butyl 3-methyl-2-((S)-N-methylpyrrolidine-3-carboxamide)butanoate (2.0 g, 84% yield) as oil. LCMS(ESI) m / z:[M+H]C 15 H 28 Calculated value for N2O3: 284.2; measured value: 285.2.

[0375] Intermediate 5. tert-butyl((6 3S ,4 S )-1 1 -ethyl-1 2 -(2-(( S)-1-methoxyethyl)pyridine-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 Synthesis of hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridadina-2(1,3)-benzenacycloundecafan-4-yl)carbamate.

[0376] [ka] Step 1. Under an Ar atmosphere at room temperature, 3-(5-bromo-1-ethyl-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]indole-3-yl)-2,2-dimethylpropan-1-ol (30g, 67mmol) and methyl(3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 To a stirred mixture of (-yl)-5-[(triisopropylsilyl)oxy]phenyl]propanoyl]-1,2-diadinane-3-carboxylate (55.8 g, 80.8 mmol) and 1,4-dioxane (750 mL), Na2CO3 (17.9 g, 168.4 mmol), Pd(DtBPF)Cl2 (4.39 g, 6.7 mmol), and H2O (150.00 mL) were added in fractions. The mixture was heated to 85°C and stirred for 3 hours, then cooled and diluted with H2O (2 L), and extracted with siRNA (3 × 1 L). The combined organic layer was washed with brine (2 × 500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain methyl(3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl]propanoyl]-1,2-diadinane-3-carboxylate (50 g, 72% yield) as a solid. LCMS(ESI): m / z [M+H]C 52 H 77 Calculated value for N5O8Si: 927.6; measured value: 928.8.

[0377] Step 2. At room temperature, methyl(3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl]propanoyl]-1,2-diadinane-3-carboxylate (50 g, 54 mmol) was mixed with DCE (500 mL) and trimethyltin hydroxide (48.7 g, 269 mmol) was added in fractions. The mixture was heated to 65 °C and stirred for 16 hours, then filtered, and the filtrate was washed with DCM (3 × 150 mL). The filtrate was concentrated under reduced pressure to obtain (3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl]propanoyl]-1,2-diadinane-3-carboxylic acid (70g, crude), which was used directly in the next step without further purification. LCMS(ESI):m / z:[M+H]C 51 H 75 Calculated value for N5O8Si: 913.5; Measured value: 914.6.

[0378] Step 3. Under an N2 atmosphere at 0°C, (3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-[2-[(1S)-1-methoxyethyl]pyridine-3-yl]indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl]propanoyl]-1,2-diadinane-3-carboxylic acid (70 g) was stirred with DCM (5 L) to which DIPEA (297 g, 2.3 mol), HOBT (51.7 g, 383 mmol), and EDCI (411 g, 2.1 mol) were added in fractions. The mixture was warmed to room temperature and stirred for 16 hours, then diluted with DCM (1 L), washed with brine (3 × 1 L), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain tert-butyl((6) 3 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridine-3-yl)-10,10-dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 H-8-oxa-1(5,3)-indola-6(1,3)-pyridadina-2(1,3)-benzenacycloundecafan-4-yl)carbamate (36 g, 42% yield) was obtained as a solid. LCMS(ESI): m / z [M+H]C 51 H 73 Calculated value for N5O7Si: 895.5; measured value: 896.5.

[0379] Intermediate 6. Synthesis of tert-butyl N-[(8S,14S)-21-iodo-18,18-dimethyl-9,15-dioxo-4-[(triisopropylsilyl)oxy]-16-oxa-10,22,28-triazapentacyclo[18.5.2.1^[2,6].1^[10,14].0^[23,27]]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaen-8-yl]carbamate. [ka]

[0380] Step 1. This reaction was carried out in five batches in parallel, on the scale described below.

[0381] To each of two 2 L round-bottom flasks, a solution of 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-1H-indole (100 g, 192 mmol) and TBAF (301.4 g, 1.15 mol) in THF (1.15 L) was added at room temperature. The resulting mixture was heated to 50°C and stirred for 16 hours, after which the mixture was concentrated under reduced pressure. The combined residue was diluted with H2O (5 L) and extracted with ethyl acetate (3 × 2 L). The combined organic layer was washed with brine (2 × 1.5 L), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3-(5-bromo-1H-indole-3-yl)-2,2-dimethylpropan-1-ol (310 g, crude) as a solid. LCMS(ESI): m / z [M+H]C 13 H 16 Calculated values ​​for BrNO: 281.0 and 283.0; measured values: 282.1 and 284.1.

[0382] Step 2. This reaction was carried out in two batches in parallel, on the scale described below.

[0383] Under an N2 atmosphere at 0°C, 3-(5-bromo-1H-indole-3-yl)-2,2-dimethylpropan-1-ol (135 g, 478 mmol) and TEA (145.2 g, 1.44 mol) were mixed with DCM (1.3 L) and Ac2O (73.3 g, 718 mmol) were added in fractions. The resulting mixture was stirred at 0°C for 10 minutes and then washed with H2O (3 × 2 L). The organic layers from each experiment were combined, washed with brine (2 × 1 L), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 3-(5-bromo-1H-indole-3-yl)-2,2-dimethylpropyl acetate (304 g, 88% yield) as a solid. 1 H NMR (400MHz, DMSO-d6)δ 11.16 - 11.11 (m, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.19 - 7.12 (m, 2H), 3.69 (s, 2H), 2.64 (s, 2H), 2.09 (s, 3H), 0.90 (s, 6H).

[0384] Step 3. This reaction was carried out in four batches in parallel, on the scale described below.

[0385] In a 2 L round-bottom flask, under an Ar atmosphere at room temperature, methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-[(triisopropylsilyl)oxy]phenyl]propanoate (125 g, 216 mmol), 1,4-dioxane (1 L), H2O (200 mL), 3-(5-bromo-1H-indole-3-yl)-2,2-dimethylpropyl acetate (73.7 g, 227 mmol), K2CO3 (59.8 g, 433 mmol), and Pd(dtbpf)Cl2 (7.05 g, 10.8 mmol) were added. The resulting mixture was heated to 65°C and stirred for 2 hours, then diluted with H2O (10 L) and extracted with ethyl acetate (3 × 3 L). The combined organic layers were washed with brine (2 × 2 L), dried over anhydrous sodium 2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain methyl(2S)-3-(3-[3-[3-(acetoxy)-2,2-dimethylpropyl]-1H-indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (500 g, 74% yield) as oil. LCMS(ESI): m / z [M+Na]C 39 H 58 Calculated value for N2O7SiNa: 717.4; measured value: 717.3.

[0386] Step 4. This reaction was carried out in three batches in parallel, on the scale described below.

[0387] A mixture of methyl(2S)-3-(3-[3-[3-(acetoxy)-2,2-dimethylpropyl]-1H-indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (150 g, 216 mmol) and NaHCO3 (21.76 g, 259 mmol) was stirred with THF (1.5 L). Under a nitrogen atmosphere at 0°C, a THF solution of AgOTf (66.5 g, 259 mmol) was added. A THF solution of I2 (49.3 g, 194 mmol) was added dropwise over 1 hour at 0°C, and the resulting mixture was stirred for a further 10 minutes at 0°C. The combined experimental product was diluted with an aqueous solution of Na2S2O3 (5 L) and extracted with ELISA (3 × 3 L). The combined organic layers were washed with brine (2 × 1.5 L), dried over anhydrous sodium 2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain methyl(2S)-3-(3-[3-[3-(acetyloxy)-2,2-dimethylpropyl]-2-iodo-1H-indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (420 g, 71% yield) as oil. LCMS(ESI): m / z [M+Na]C 39 H 57 Calculated value for IN2O7SiNa: 843.3; measured value: 842.9.

[0388] Step 5. This reaction was carried out in three batches in parallel, on the scale described below.

[0389] Methyl(2S)-3-(3-[3-[3-(acetyloxy)-2,2-dimethylpropyl]-2-iodo-1H-indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (140 g, 171 mmol), MeOH (1.4 L), and K3PO4 (108.6 g, 512 mmol) were added to a 2 L round-bottom flask at 0°C. The mixture was warmed to room temperature and stirred for 1 hour. The combined experimental product was then diluted with H2O (9 L) and extracted with ELISA (3 × 3 L). The combined organic layers were washed with brine (2 x 2 L), dried over anhydrous sodium 2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl]propanoate (438 g, crude) as a solid. LCMS(ESI): m / z [M+Na]C 37 H 55 Calculated value for IN2O6SiNa: 801.3; measured value: 801.6.

[0390] Step 6. This reaction was carried out in three batches in parallel on the scale described below.

[0391] Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl]propanoate (146 g, 188 mmol) was mixed with THF (1.46 L) and stirred. An aqueous solution of LiOH (22.45 g, 937 mmol) (937 mL) was added dropwise at 0°C. The resulting mixture was warmed to room temperature and stirred for 1.5 hours [Note: LC-MS showed 15% de-TIPS product]. The mixture was acidified to pH 5 with 1 M HCl (1 M), and the combined product was extracted with ELISA (3 × 3 L). The combined organic layers were washed with brine (2 x 2 L), dried over anhydrous sodium 2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl]propanoic acid (402 g, crude) as a solid. LCMS(ESI): m / z [M+Na]C 36 H 53 Calculated value for IN2O6SiNa: 787.3; measured value: 787.6.

[0392] Step 7. (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl]propanoic acid (340 g, 445 mmol) and methyl(3S)-1,2-diadinane-3-carboxylate (96.1 g, 667 mmol) were stirred with DCM (3.5 L), to which NMM (225 g, 2.2 mol), EDCI (170 g, 889 mmol), and HOBt (12.0 g, 88.9 mmol) were added dropwise at 0°C. The mixture was warmed to room temperature and stirred for 16 hours, then washed with H2O (3 × 2.5 L) and brine (2 × 1 L), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain methyl(3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl]propanoyl]-1,2-diadinane-3-carboxylate (310 g, 62% yield) as oil. LCMS(ESI): m / z [M+H]C 42 H 63 Calculated value for IN4O7Si: 890.4; Measured value: 890.8.

[0393] Step 8. This reaction was carried out in three batches in parallel, on the scale described below.

[0394] Under an N2 atmosphere at 0°C, methyl(3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl]propanoyl]-1,2-diadinane-3-carboxylate (85.0 g, 95.4 mmol) was mixed with THF (850 mL) and to each mixture, an aqueous solution of LiOH (6.85 g, 286 mmol) (410 mL) was added dropwise. The mixture was stirred at 0°C for 1.5 hours [Note: LCMS showed 15% de-TIPS product], then acidified to pH 5 with 1 M HCl, and the combined product was extracted with ELISA (3 × 2 L). The combined organic layers were washed with brine (2 × 1.5 L), dried over anhydrous sodium 2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain (3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indole-5-yl]-5-[(triisopropylsilyl)oxy]phenyl]propanoyl]-1,2-diadinane-3-carboxylic acid (240 g, crude) as a solid. LCMS(ESI): m / z [M+H]C 41 H 61 Calculated value for IN4O7Si: 876.3; measured value: 877.6.

[0395] Step 9. This reaction was carried out in two batches in parallel, on the scales described below.

[0396] Under an atmosphere of N2 at 0 °C, to a stirred mixture of (3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl]-5-[(triisopropylsilyl)oxy]phenyl]propanoyl]-1,2-diazinane-3-carboxylic acid (120 g, 137 mmol) and DCM (6 L) were added DIPEA (265 g, 2.05 mol), EDCI (394 g, 2.05 mol), and HOBT (37 g, 274 mmol) in portions. The mixture was warmed to room temperature and stirred overnight, then the combined experimental materials were washed with H2O (3 × 6 L) and brine (2 × 6 L), dried over anhydrous Na2SO4, and filtered. After filtration, the filtrate was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain tert-butyl N-[(8S,14S)-21-iodo-18,18-dimethyl-9,15-dioxo-4-[(triisopropylsilyl)oxy]-16-oxa-10,22,28-triazapentacyclo[18.5.2.1^[2,6].1^[10,14].0^[23,27]]nonacosa-1(26),2,4,6(29),20,23(27),24-heptaene-8-yl]carbamate (140 g, 50% yield) as a solid. LCMS (ESI): m / z [M+H]C 41 H 59 Calculated for C41H62IN4O6Si: 858.9; Found 858.3.

[0397] Intermediate 7. (6 3S ,4S)-4-amino-1 1 -ethyl-2 5 -hydroxy-1 2 -(4-(methoxymethyl)pyridin-3-yl)-10,10-dimethyl-6 1 ,,6 2 ,,6 3 ,,6 4 ,,6 5 ,,6 6 -hexahydro-1 1 H-8-oxa-1(5,3)-indolazina-6(1,3)-pyridazina-2(1,3)-benzacycloundecaphane-5,7-dione synthesis [ka]

[0398] Step 1. Under an Ar atmosphere at room temperature, a mixture of 3-bromo-4-(methoxymethyl)pyridine (1.00 g, 5.0 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.51 g, 5.9 mmol), and KOAc (1.21 g, 12.3 mmol) with toluene (10 mL) was mixed with Pd(dppf)Cl2 (362 mg, 0.5 mmol). The mixture was heated to 110 °C, stirred overnight, and then concentrated under reduced pressure to obtain 4-(methoxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, which was used directly in the next step without further purification. LCMS(ESI): m / z [M+H]C 13 H 20 Calculated value for BNO3: 249.2; Measured valu...

Claims

1. Structure of formula I: 【Chemistry 1】 [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH) ３ )C(O)-(CH ２ )-[wherein amino nitrogen is -CH(R １０ ) - bonded to a carbon atom, optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or optionally substituted 5- to 6-membered heteroarylenes, B is -CH(R ９ ) - or > C = CR ９ R ９’ [In the formula, carbon is -N(R １１ ) those bonded to the carbonyl carbon of C(O)-, optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes, G is optionally substituted 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 )- [wherein the second C is bonded to -C(R ７ R ８ ).], -C(O)NH-CH(R ６ )- [wherein the second C is bonded to -C(R ７ R ８ ).], optionally substituted C １ -C ４ heteroalkylene, or 3- to 8-membered heteroarylene, and L does not exist, or it is a linker. W is hydrogen, cyano, optionally substituted amino, optionally substituted C １ -C ４ alkoxy, optionally substituted C １ -C ４ Hydroxyalkyl, optionally substituted C １ -C ４ aminoalkyl, optionally substituted C １ -C ４ Haloalkyl, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ４ Guanidinoalkyl, C ０ -C ４ A 3- to 11-membered heterocycloalkyl group optionally substituted with alkyl, an optionally substituted 3- to 8-membered cycloalkyl group, an optionally substituted 6- to 10-membered aryl group, or an optionally substituted 3- to 8-membered heteroaryl group. X １ is an arbitrarily substituted 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, or optionally substituted C １ -C ４ Alkyl, optionally substituted C ２ -C ４ Alkenyl, optionally substituted C ２ -C ４ Alkinyl, 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 optionally substituted with C. １ -C ４ It is alkyl, Y １ is C, CH, or N, Y ２ , Y ３ , Y ４ , and Y ７ They are independently C or N, Y ５ CH, CH ２ , or N, Y ６ C(O), CH, CH ２ , or N, R １ C is a cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-6 member cycloalkenyl, optionally substituted 3-6 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted 5-10 member heteroaryl, or R １ and R ２ These combine with the atoms to which they bond to form optionally substituted 3- to 14-membered heterocycloalkyl groups. R ２ is either nonexistent, or a hydrogen atom, or a C atom that is arbitrarily substituted. １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, R ３ It does not exist, or R ２ and R ３ These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R ４ It is either absent, or is a methyl atom optionally substituted with hydrogen, halogen, cyano, or one to three halogens. R ５ C is optionally substituted with hydrogen and halogens. １ -C ４ Alkyl, cyano, hydroxy, or C １ -C ４ It is an alkoxy, cyclopropyl, or cyclobutyl, R ６ R is hydrogen or methyl, ７ is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, or, R ６ and R ７ combine 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- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or R ７ and R ８ These combine with the carbon atoms they bond to, resulting in C=CR ７’ R ８’ , C=N(OH), C=N(OC １ -C ３ Forming alkyl, C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R ７ａ and R ８ａ These are independently hydrogen, halo, and optionally substituted C. １ -C ３ They are alkyl groups, or they combine with the carbon they are bonded to to form a carbonyl group. R ７’ C is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, R ８’ C is a hydrogen, halogen, hydroxyl, cyano, or 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 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R ７’ and R ８’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R ９ is hydrogen, F, and optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group, an optionally substituted 3-6 member cycloalkyl group, or an optionally substituted 3-7 member heterocycloalkyl group. R ９ And L combine with the atoms to which they are bonded to form optionally substituted 3- to 14-membered heterocycloalkyl groups. R ９’ is hydrogen or optionally substituted C １ -C ６ It is alkyl, R １０ is hydrogen, halo, hydroxyl, C １ -C ３ Alkoxy, or C １ -C ３ It is alkyl, R １０ａ is hydrogen or halo, R １１ is hydrogen or C １ -C ３ It is alkyl, and R １６ is hydrogen or C １ -C ３ It is alkyl. A compound having, or a pharmaceutically acceptable salt thereof.

2. The above compound has the structure of formula Ic: 【Chemistry 2】 [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH) ３ )C(O)-(CH ２ )-[wherein amino nitrogen is -CH(R １０ ) - bonded to a carbon atom, optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or optionally substituted 5- to 6-membered heteroarylenes, B is -CH(R ９ )-[In the formula, carbon is -N(R １１ ) those bonded to the carbonyl carbon of C(O)-, optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or 5- to 6-membered heteroarylenes, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino acids, optionally substituted C １ -C ４ alkoxy, optionally substituted C １ -C ４ Hydroxyalkyl, optionally substituted C １ -C ４ aminoalkyl, optionally substituted C １ -C ４ Haloalkyl, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ４ Guanidinoalkyl, C ０ -C ４ A 3- to 11-membered heterocycloalkyl group optionally substituted with alkyl, an optionally substituted 3- to 8-membered cycloalkyl group, or an optionally substituted 3- to 8-membered heteroaryl group. X ２ is O or NH, X ３ is N or CH, n is 0, 1, or 2. R is hydrogen, cyano, or optionally substituted C １ -C ４ Alkyl, optionally substituted C ２ -C ４ Alkenyl, optionally substituted C ２ -C ４ Alkinyl, 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 optionally substituted with C. １ -C ４ It is alkyl, Y １ is C, CH, or N, Y ２ , Y ３ , Y ４ , and Y ７ They are independently C or N, Y ５ and Y ６ These are independently CH or N, R １ C is a cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-6 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, R ３ It does not exist, or R ２ and R ３ These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R ４ It is either absent, or is a methyl atom optionally substituted with hydrogen, halogen, cyano, or one to three halogens. R ５ C is optionally substituted with hydrogen and halogens. １ -C ４ Alkyl, cyano, hydroxy, or C １ -C ４ It is an alkoxy, cyclopropyl, or cyclobutyl, R ６ R is hydrogen or methyl, ７ is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, or, R ６ and R ７ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R ８ C is a hydrogen, halogen, hydroxyl, cyano, or 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 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R ７ and R ８ These combine with the carbon atoms they bond to, resulting in C=CR ７’ R ８’ , C=N(OH), C=N(OC １ -C ３ Forming alkyl, C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R ７’ C is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, R ８’ C is a hydrogen, halogen, hydroxyl, cyano, or 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 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R ７’ and R ８’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R ９ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group, an optionally substituted 3-6 member cycloalkyl group, or an optionally substituted 3-7 member heterocycloalkyl group. R １０ is hydrogen, hydroxyl, C １ -C ３ Alkoxy, or C １ -C ３ It is alkyl, and R １１ is hydrogen or C １ -C ３ It is alkyl. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

3. The above compound has the structure of formula Id: 【Transformation 3】 [In the formula, the dotted lines indicate 0, 1, 2, 3, or 4 non-adjacent double bonds.] A is -N(H or CH) ３ )C(O)-(CH ２ )-[wherein amino nitrogen is -CH(R １０ ) - bonded to a carbon atom, optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or optionally substituted 5- to 6-membered heteroarylenes, B is -CH(R ９ )- [wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino acids, optionally substituted C １ -C ４ alkoxy, optionally substituted C １ -C ４ Hydroxyalkyl, optionally substituted C １ -C ４ aminoalkyl, optionally substituted C １ -C ４ Haloalkyl, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ４ Guanidinoalkyl, C ０ -C ４ A 3- to 11-membered heterocycloalkyl group optionally substituted with alkyl, an optionally substituted 3- to 8-membered cycloalkyl group, or an optionally substituted 3- to 8-membered heteroaryl group. n is 0, 1, or 2. R is hydrogen, cyano, or optionally substituted C １ -C ４ Alkyl, optionally substituted C ２ -C ４ Alkenyl, optionally substituted C ２ -C ４ Alkinyl, 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 optionally substituted with C. １ -C ４ It is alkyl, Y １ is C, CH, or N, Y ２ , Y ３ , Y ４ , and Y ７ They are independently C or N, Y ５ and Y ６ These are independently CH or N, R １ C is a cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-6 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, R ３ It does not exist, or R ２ and R ３ These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R ４ It is either absent, or is a methyl atom optionally substituted with hydrogen, halogen, cyano, or one to three halogens. R ５ C is optionally substituted with hydrogen and halogens. １ -C ４ Alkyl, cyano, hydroxy, or C １ -C ４ It is an alkoxy, cyclopropyl, or cyclobutyl, R ６ R is hydrogen or methyl, ７ is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, or, R ６ and R ７ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R ８ C is a hydrogen, halogen, hydroxyl, cyano, or 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 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R ７ and R ８ These combine with the carbon atoms they bond to, resulting in C=CR ７’ R ８’ , C=N(OH), C=N(OC １ -C ３ Forming alkyl, C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R ７’ C is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, R ８’ C is a hydrogen, halogen, hydroxyl, cyano, or 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 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R ７’ and R ８’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R ９ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group, an optionally substituted 3-6 member cycloalkyl group, or an optionally substituted 3-7 member heterocycloalkyl group, and R １０ is hydrogen, hydroxyl, C １ -C ３ Alkoxy, or C １ -C ３ It is alkyl. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, having the above.

4. The above compound has the structure of formula Ie: 【Chemistry 4】 [In the formula, A is -N(H or CH ３ )C(O)-(CH ２ )-[wherein amino nitrogen is -CH(R １０ ) - bonded to a carbon atom, optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or optionally substituted 5- to 6-membered heteroarylenes, B is -CH(R ９ )- [wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino acids, optionally substituted C １ -C ４ alkoxy, optionally substituted C １ -C ４ Hydroxyalkyl, optionally substituted C １ -C ４ aminoalkyl, optionally substituted C １ -C ４ Haloalkyl, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ４ Guanidinoalkyl, C ０ -C ４ A 3- to 11-membered heterocycloalkyl group optionally substituted with alkyl, an optionally substituted 3- to 8-membered cycloalkyl group, or an optionally substituted 3- to 8-membered heteroaryl group. R １ C is a cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-6 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. R ２ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted 3-6 member cycloalkyl, optionally substituted 3-7 member heterocycloalkyl, optionally substituted 6 member aryl, optionally substituted 5 or 6 member heteroaryl, R ３ It does not exist, or R ２ and R ３ These combine with the atoms to which they bond to form optionally substituted 3-8 member cycloalkyl groups or optionally substituted 3-14 member heterocycloalkyl groups. R ５ C is optionally substituted with hydrogen and halogens. １ -C ４ Alkyl, cyano, hydroxy, or C １ -C ４ It is an alkoxy, cyclopropyl, or cyclobutyl, R ６ R is hydrogen or methyl, ７ is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, or, R ６ and R ７ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R ８ C is a hydrogen, halogen, hydroxyl, cyano, or 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 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R ７ and R ８ These combine with the carbon atoms they bond to, resulting in C=CR ７’ R ８’ , C=N(OH), C=N(OC １ -C ３ Forming alkyl, C=O, C=S, C=NH, optionally substituted 3-6 member cycloalkyl, or optionally substituted 3-7 member heterocycloalkyl, R ７’ C is hydrogen, halogen, or optionally substituted C １ -C ３ It is alkyl, R ８’ C is a hydrogen, halogen, hydroxyl, cyano, or 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 member cycloalkyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 5-10 member heteroaryl, or optionally substituted 6-10 member aryl, or R ７’ and R ８’ These combine with the carbon atoms to which they are bonded to form optionally substituted 3-6 member cycloalkyl groups, or optionally substituted 3-7 member heterocycloalkyl groups. R ９ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group, an optionally substituted 3-6 member cycloalkyl group, or an optionally substituted 3-7 member heterocycloalkyl group, and R １０ is hydrogen, hydroxyl, C １ -C ３ Alkoxy, or C １ -C ３ It is alkyl. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, having the above.

5. The above compound has the structure of formula If: 【Transformation 5】 [In the formula, A is -N(H or CH ３ )C(O)-(CH ２ )-[wherein amino nitrogen is -CH(R １０ ) - bonded to a carbon atom, optionally substituted 3- to 6-membered cycloalkylenes, optionally substituted 3- to 6-membered heterocycloalkylenes, optionally substituted 6-membered arylenes, or optionally substituted 5- to 6-membered heteroarylenes, B is -CH(R ９ )- [wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino acids, optionally substituted C １ -C ４ alkoxy, optionally substituted C １ -C ４ Hydroxyalkyl, optionally substituted C １ -C ４ aminoalkyl, optionally substituted C １ -C ４ Haloalkyl, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ４ Guanidinoalkyl, C ０ -C ４ A 3- to 11-membered heterocycloalkyl group optionally substituted with alkyl, an optionally substituted 3- to 8-membered cycloalkyl group, or an optionally substituted 3- to 8-membered heteroaryl group. R １ C is a cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyls, optionally substituted 3-6 member cycloalkyls, optionally substituted 3-6 member cycloalkenyls, optionally substituted 3-6 member heterocycloalkyls, optionally substituted 6-10 member aryls, or optionally substituted 5-10 member heteroaryls. R ２ C １ -C ６ Alkyl or 3-6 member cycloalkyl, R ７ C １ -C ３ It is alkyl, R ８ C １ -C ３ It is alkyl, and R ９ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ These are heteroalkyl groups, optionally substituted 3- to 6-membered cycloalkyl groups, or optionally substituted 3- to 7-membered heterocycloalkyl groups. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, having the above.

6. R １ A compound according to any one of claims 1 to 5, wherein is a 5- to 10-membered heteroaryl, or a pharmaceutically acceptable salt thereof.

7. R １ The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein the compound is an optionally substituted six-membered aryl or an optionally substituted six-membered heteroaryl.

8. The above compound has the structure of formula Ig: 【Transformation 6】 [In the formula, 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 5- to 6-membered heteroarylene.] B is -CH(R ９ )- [wherein the formula, carbon is bonded to the carbonyl carbon of -NHC(O)-], optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5- to 6-membered heteroarylene, L does not exist, or it is a linker. W is hydrogen, optionally substituted amino acids, optionally substituted C １ -C ４ alkoxy, optionally substituted C １ -C ４ Hydroxyalkyl, optionally substituted C １ -C ４ aminoalkyl, optionally substituted C １ -C ４ Haloalkyl, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ４ Guanidinoalkyl, C ０ -C ４ A 3- to 11-membered heterocycloalkyl group optionally substituted with alkyl, an optionally substituted 3- to 8-membered cycloalkyl group, or an optionally substituted 3- to 8-membered heteroaryl group. R ２ C １ -C ６ Alkyl or 3-6 member cycloalkyl, R ７ C １ -C ３ It is alkyl, R ８ C １ -C ３ It is alkyl, R ９ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ A heteroalkyl group, an optionally substituted 3-6 member cycloalkyl group, or an optionally substituted 3-7 member heterocycloalkyl group. X ｅ is N, CH, or CR １７ And, X ｆ is N or CH, R １２ is an arbitrarily substituted C １ -C ６ Alkyl or optionally substituted C １ -C ６ It is heteroalkyl, and R １７ is an arbitrarily substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ These are heteroalkyl groups, optionally substituted 3-6 member cycloalkyl groups, optionally substituted 3-6 member cycloalkenyl groups, optionally substituted 3-6 member heterocycloalkyl groups, optionally substituted 6-10 member aryl groups, or optionally substituted 5-10 member heteroaryl groups. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having the above.

9. A is a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. A is an optionally substituted 5-6 member heteroarylene, the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

11. B is -CHR ９ - The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R ９ However, C is arbitrarily substituted. １ -C ６ The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl or optionally substituted 3- to 6-membered cycloalkyl.

13. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein B is an optionally substituted six-membered arylene.

14. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein B is absent.

15. The aforementioned 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 This is the bond between the linker and B; A ２ This is the bond between W and the linker; B １ , B ２ , B ３ , and B ４ Each of these is independently and arbitrarily substituted C １ -C ２ Alkylene, optionally substituted C １ -C ３ Heteroalkylenes, O, S, and NR Ｎ Selected from; R Ｎ is hydrogen, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ３ Cycloalkyl, optionally substituted C ２ -C ４ Alkenyl, optionally substituted C ２ -C ４ Alkynyl, optionally substituted 3-14 member heterocycloalkyl, optionally substituted 6-10 member aryl, or optionally substituted C １ -C ７ It is heteroalkyl; C １ and C ２ Each is 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 substituted C １ -C １０ Alkylene, optionally substituted C ２ -C １０ Alkenylene, optionally substituted C ２ -C １０ Alkynylene, optionally substituted 3-14 member heterocycloalkylenes, optionally substituted 5-10 member heteroarylenes, optionally substituted 3-8 member cycloalkylenes, optionally substituted 6-10 member arylenes, optionally substituted C ２ -C １０ Polyethylene glycolen, 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 It is a chemical bond that connects two things. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1 to 15, wherein the linker is acyclic, or a pharmaceutically acceptable salt thereof.

17. The linker has the structure of formula IIa: 【Transformation 7】 [In the formula, X ａ It does not exist, or it is N. R １４ Either it does not exist, or hydrogen, or arbitrarily substituted C １ -C ６ Alkyl or optionally substituted C １ -C ３ It is a cycloalkyl, and L ２ It does not exist, or -C(O)-, -SO ２ -, arbitrarily substituted C １ -C ４ Alkylene, or optionally substituted C １ -C ４ It is a heteroalkylene, X ａ , R １４ , or L ２ At least one of these exists. A compound according to claim 16, or a pharmaceutically acceptable salt thereof, having the above.

18. The compound according to any one of claims 1 to 15, wherein the linker is a cyclic group or contains a cyclic group, or a pharmaceutically acceptable salt thereof.

19. The linker has the structure of formula IIb: 【Transformation 8】 [In the formula, o is either 0 or 1, X ｂ is C(O) or SO ２ And, R １５ is hydrogen or optionally substituted C １ -C ６ It is alkyl, 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 It does not exist, or -C(O)-, -SO ２ -, arbitrarily substituted C １ -C ４ Alkylene, or optionally substituted C １ -C ４ It is a heteroalkylene. A compound according to any one of claims 1 to 15 or 17, or a pharmaceutically acceptable salt thereof, having the above.

20. A compound according to any one of claims 1 to 19, wherein W is hydrogen, or a pharmaceutically acceptable salt thereof.

21. A compound according to any one of claims 1 to 19, wherein W is an optionally substituted amino acid, or a pharmaceutically acceptable salt thereof.

22. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted amide.

23. W is arbitrarily replaced by C １ -C ４ A compound according to any one of claims 1 to 19, which is an alkoxy, or a pharmaceutically acceptable salt thereof.

24. W is arbitrarily replaced by C １ -C ４ A compound according to any one of claims 1 to 19, which is alkyl, or a pharmaceutically acceptable salt thereof.

25. W is arbitrarily replaced by C １ -C ４ A compound according to any one of claims 1 to 19, which is a hydroxyalkyl compound, or a pharmaceutically acceptable salt thereof.

26. W is arbitrarily replaced by C １ -C ４ A compound according to any one of claims 1 to 19, which is an aminoalkyl compound, or a pharmaceutically acceptable salt thereof.

27. W is arbitrarily replaced by C １ -C ４ A compound according to any one of claims 1 to 19, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

28. W is arbitrarily replaced by C １ -C ４ A compound according to any one of claims 1 to 19, which is a guanidinoalkyl compound, or a pharmaceutically acceptable salt thereof.

29. W is C ０ -C ４ A compound according to any one of claims 1 to 19, wherein the compound is an alkyl or an optionally substituted 3 to 11-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

30. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3- to 8-membered cycloalkyl group.

31. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 3 to 8-membered heteroaryl compound.

32. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein W is an optionally substituted 6- to 10-membered aryl group.

33. Compounds listed in Table 1 or 2, or pharmaceutically acceptable salts thereof.

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

35. A method for treating cancer in a subject requiring cancer treatment, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34.

36. The method according to claim 35, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer, or uterine cancer.

37. The method according to claim 36, wherein the cancer includes a Ras mutation.

38. The method according to claim 37, wherein the Ras mutation is located at position 12, 13, or 61.

39. The method according to claim 37, wherein the Ras mutation is K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G12S, K-Ras G13C, K-Ras G13D, or K-Ras Q61L.

40. A method for treating a Ras protein-related disorder in a subject requiring treatment for the disorder, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34.

41. The method or use according to any one of claims 35 to 40, further comprising administering an additional anti-cancer treatment.

42. The method according to claim 41, wherein the additional anticancer treatment 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.

43. The method according to claim 41 or 42, wherein the additional anti-cancer treatment is an SHP2 inhibitor.

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