Shared ras inhibitors and uses thereof

Abstract

Provided are compounds, or pharmaceutically acceptable salts thereof, capable of regulating biological processes involving Ras, alone or in combination with other therapeutic agents, pharmaceutical compositions, and protein conjugates thereof.SOLUTION: Provided is a compound having the structure of Formula I: A-L-B (Formula I) or a pharmaceutically acceptable salt thereof, wherein A is a Ras binding moiety, L is a linker, and B is a selective crosslinking group, wherein when the compound, or pharmaceutically acceptable salt thereof, is contacted with a sample containing a Ras protein, at least 20% of the Ras protein in the sample covalently reacts with the compound, or pharmaceutically acceptable salt thereof, to form a conjugate.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Application Nos. 62 / 940,947, filed November 27, 2019, 62 / 969,415, filed February 3, 2020, and 63 / 024,868, filed May 14, 2020, all of which are incorporated by reference in their entireties.

[0002] Sequence Listing The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. [Background technology]

[0003] The vast majority of small molecule drugs act by binding to functionally important pockets on target proteins, thereby regulating their activity. For example, cholesterol-lowering drugs known as statins bind to the enzyme active site of HMG-CoA reductase, thereby preventing the enzyme from engaging its substrate. The fact that many such drug / target interaction pairs are known may mislead some into believing 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 case. Current estimates suggest that only about 10% of all human proteins are targetable by small molecules. (Non-Patent Document 1) The other 90% are currently considered refractory or intractable to small molecule drug discovery as described above. Such targets are commonly referred to as "undruggable." These undruggable targets represent a vast and abundant, untapped reservoir of clinically important human proteins. Therefore, there is much interest in discovering novel molecular modalities that can control the function of such undruggable targets.

[0004] It has been well established in the literature that Ras proteins (K-Ras, H-Ras, and N-Ras) play essential roles in various human cancers and are therefore suitable targets for anticancer therapy. Dysregulation of Ras proteins due to activating mutations, overexpression, or upstream expression is common in human tumors, and activating mutations in Ras are frequently found in human cancers (see, for example, Non-Patent Document 2). Among Ras proteins, K-Ras is the most frequently mutated and therefore an important target for cancer therapy. Despite extensive small molecule drug discovery efforts against Ras in recent decades, drugs directly targeting Ras are still not available for clinical use. However, the reputation of the "undruggability" of Ras proteins by small molecules has recently been challenged (see, for example, Non-Patent Document 3). Further efforts are needed to uncover new medical treatments for cancers driven by Ras mutations, for example, by identifying new small molecule Ras inhibitors. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Bojadzic and Buchwald,Curr Top Med Chem 18(8):674-699(2019) [Non-patent document 2] Prior et al., Cancer Res 72(10):2457-2467(2012) [Non-patent document 3] Ostrem et al.,Nature 503(7477),548-551(2013) Summary of the Invention

[0006] Covalent drugs bind covalently to their biological targets. Covalent drugs have a long history in medicine and will continue to impact drug discovery and human health in the future. Biological targets with nucleophilic functional groups such as -SH, -OH, -NH2, -COOH, etc. are amenable to covalent drug discovery approaches. For example, the irreversible covalent drug ibrutinib was approved by the FDA in 2013 for the treatment of mantle cell lymphoma, and its label has since expanded.

[0007] Provided herein are compounds capable of binding to Ras proteins to form conjugates by reacting as electrophiles and forming covalent bonds with nucleophilic Ras amino acids of the Ras protein. Forming conjugates through covalent binding of the compounds of the present invention can disrupt downstream Ras signaling. The Ras protein can be a wild-type or mutant Ras protein. The amino acid can be, for example, aspartic acid, serine, or cysteine ​​of the Ras protein. In some embodiments, the compounds of the present invention form a covalent bond with an aspartic acid, serine, or cysteine ​​residue at position 12 of a mutant K-Ras, H-Ras, or N-Ras protein. In some embodiments, the compounds disclosed herein form a covalent bond with an aspartic acid residue at position 12 of K-Ras G12D. In some embodiments, the compounds disclosed herein form a covalent bond with an aspartic acid residue at position 13 of K-Ras G13D. In some embodiments, the compounds disclosed herein form a covalent bond with a serine residue at position 12 of K-Ras G12S. In some embodiments, the compounds of the invention may be useful in treating diseases and disorders in which Ras, particularly mutated Ras, plays a role, such as cancer. Additional aspects of the foregoing are further described herein.

[0008] Accordingly, provided herein are compounds having the structure of Formula I: ALB Formula I wherein A is a Ras-binding moiety, L is a linker, and B is a selective cross-linking group, or a pharmaceutically acceptable salt thereof, wherein when the compound, or a pharmaceutically acceptable salt thereof, is contacted with a sample containing Ras proteins, at least 20% of the Ras proteins in the sample covalently react with the compound, or a pharmaceutically acceptable salt thereof, to form a conjugate. Also provided is a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] Further provided is a conjugate or salt thereof comprising a Ras protein covalently bound to a selective cross-linking group, wherein the selective cross-linking group is attached to a Ras binding moiety via a linker, and the selective cross-linking group is a carbodiimide, an aminooxazoline, a chloroethylurea, an aziridine, a trifluoromethyl ketone, a boronic acid, a boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an isoEEDQ, an epoxide, an oxazolium, or a glycal.

[0010] Further provided are Ras proteins covalently linked to compounds of the invention. In some embodiments, inhibited Ras proteins covalently linked to compounds of the invention are provided. In some embodiments, wild-type Ras proteins covalently linked to compounds of the invention are provided. In some embodiments, mutant Ras proteins covalently linked to compounds of the invention are provided.

[0011] Also provided is a method for producing a conjugate, comprising contacting a Ras protein with a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt, under conditions sufficient to covalently react the compound with the Ras protein or under conditions suitable to allow conjugate formation. Also provided is a conjugate produced by such a method.

[0012] Further provided is a method of treating cancer in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.

[0013] Also provided is a method for inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.

[0014] In some embodiments, there is provided a method for treating a Ras protein-associated disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt. DETAILED DESCRIPTION OF THE INVENTION

[0015] Definition: In this application, unless otherwise clear from the context, (i) the term "a" is understood to mean "at least one," (ii) the term "or" is understood to mean "and / or," (iii) the terms "comprising" and "including" are understood to encompass the itemized components or steps, whether presented by themselves or with one or more additional components or steps, and (iv) when ranges are presented, the endpoints are included.

[0016] As used herein, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. As used herein, the term "adjacent" in the context of describing adjacent atoms means divalent atoms that are directly joined by a covalent bond.

[0017] As used herein, the term "binding" will generally be understood to mean an association between or among two or more elements (e.g., non-covalent or covalent bonds, hydrogen bonds, van der Waals interactions, hydrophobic interactions, magnetic forces, and combinations thereof). "Direct" binding involves physical contact between multiple elements or moieties, while indirect binding involves a physical interaction through physical contact with one or more intermediate elements. Binding between two or more elements can generally be assessed in any of a variety of contexts, including when the interacting elements or moieties are studied alone or in the context of a more complex system (e.g., when covalently bound or otherwise associated with a carrier element, or within a biological system or cell).

[0018] As used herein, the term "corresponding to" is often used to refer to a structural element or moiety in a compound of interest that shares a position (e.g., in three-dimensional space or relative to another element or moiety) with a position present in an appropriate reference compound. For example, in some embodiments, the term is used to refer to the position / matching of a residue within a polymer, e.g., an amino acid residue within a polypeptide or a nucleotide residue within a nucleic acid. For simplicity, residues within such polymers are often represented using a standard numbering system based on the relevant reference polymer, so that those of skill in the art will understand that, for example, a residue in a first polymer that "corresponds to" a residue at position 190 in a reference polymer is not necessarily the 190th residue in the first polymer, but rather corresponds to the residue found at position 190 of the reference polymer. Those of skill in the art will readily understand how to identify "corresponding" amino acids, including by using one or more commercially available algorithms specifically designed for polymer sequence comparison.

[0019] As used herein, the term "inhibitor" refers to a compound that i) inhibits, reduces, or decreases the effect of a protein, such as a Ras protein, or ii) inhibits, reduces, decreases, or slows one or more biological events. The term "inhibiting," or any variation thereof, includes any measurable reduction or complete inhibition to achieve a desired result. For example, there can be a reduction in activity (e.g., Ras activity) of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, compared to normal.

[0020] The term "pure" means substantially pure or substantially free from unwanted components (e.g., other compounds), contaminating materials, admixtures, or imperfections.

[0021] Those of skill in the art will understand that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, tautomers) and / or isotopic (e.g., where one or more atoms are replaced with a different isotope of that atom, such as hydrogen replaced with deuterium) forms. Unless otherwise specified, or apparent from context, the depicted structures can be understood to represent any such isomeric or isotopic forms, individually or in combination.

[0022] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise specified. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials, such as by resolution of racemic mixtures or stereoselective synthesis, are known in the art. Many geometric isomers of olefins, C=N double bonds, and the like, can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present disclosure are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0023] In some embodiments, one or more compounds described herein can exist in different tautomeric forms. Unless explicitly excluded, as is clear from the context, reference to such a compound encompasses all such tautomeric forms. In some embodiments, a tautomeric form results from the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form can be a prototropic tautomer, which is an isomeric protonation state having the same empirical formula and total charge as the referenced form. Examples of moieties that have prototropic tautomeric forms are ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. In some embodiments, the tautomeric forms are in equilibrium or can be sterically locked into one form by appropriate substitution. In certain embodiments, the tautomeric forms arise from acetal interconversion.

[0024] In some embodiments, one of ordinary skill in the art will understand that isotopes of the compounds described herein can be prepared or utilized in accordance with the present invention. "Isotopes" refers to atoms having the same atomic number but different mass numbers due to different numbers of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium. Other isotopes include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. In some embodiments, isotopic substitution (e.g., replacing hydrogen with deuterium) can alter the physicochemical properties of a molecule, such as metabolism, distribution of metabolites, or the rate of racemization of a chiral center. Methods for incorporating one or more such isotopes into a compound are known to those skilled in the art.

[0025] As is known in the art, many chemical entities can be adopted in a variety of different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates), etc. In some embodiments, the compounds of the present invention can be utilized in any such form, including any solid form. In some embodiments, the compounds described or illustrated herein can be provided or utilized in hydrate or solvate form.

[0026] At various places herein, substituents for compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1-C6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, when a compound contains multiple positions where a substituent is disclosed in a group or range, unless otherwise specified, the disclosure is intended to cover individual compounds containing each and every individual subcombination of the elements at each position, as well as groups (e.g., genera and subgenera) of compounds.

[0027] 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"). The feature "X" (e.g., alkyl) itself is not intended to imply optionality. As described herein, certain compounds of interest can contain one or more "optionally substituted" moieties. Generally, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent, e.g., any of the substituents or groups described herein. Unless otherwise specified, an "optionally substituted" group can have a suitable substituent at each suitable position of the group. Also, when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents can be either the same or different at each position. For example, in the term "optionally substituted C-C alkyl-C-C heteroaryl," the alkyl portion, the heteroaryl portion, or both can be optionally substituted. Combinations of substituents contemplated by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that remain substantially unchanged when subjected to conditions that foresee their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0028] Suitable monovalent substituents at a substitutable carbon atom of an "optionally substituted" group are independently deuterium, halogen, -(CH)O-4R°, -(CH)O-4OR°, -O(CH)O-4R°, -O-(CH)O-4C(O)OR°, -(CH)O-4CH(OR°), -(CH)O-4SR°, -(CH)O-4Ph [optionally substituted with R°], -(CH)O(CH)O-1Ph [optionally substituted with R°], -CH=CHPh [optionally substituted with R°], -(CH)O(CH)O-1-pyridyl [optionally substituted with R°]. ], 4-8 membered saturated or unsaturated heterocyclyl (e.g., pyridyl), 3-8 membered saturated or unsaturated cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), -NO2, -CN, -N3, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2)0-4N(R°)C(O)NR°2, -N(R°)C(S)NR °2, -(CH2)0-4N(R°)C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -(CH2)0-4C (O)R°, -C(S)R°, -(CH2)0-4C(O)OR°, -(CH2)0-4-C(O)-N(R°)2, -(CH2)0-4-C(O)-N(R°)-S(O)2-R°, -C(NCN)NR °2, -(CH2)0-4C(O)SR°, -(CH2)0-4C(O)OSiR°3, -(CH2)0-4OC(O)R°, -OC(O)(CH2)0-4SR°, -SC(S)SR°, -(CH2)0 -4SC(O)R°, -(CH2)0-4C(O)NR°2, -C(S)NR°2, -C(S)SR°, -(CH2)0-4OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2)0-4SSR°, -(CH2)0-4S(O)2R°, -(CH2)0-4S(O)2OR°, -(CH2)0-4OS(O)2R° , -S(O)2NR°2, -(CH2)0-4S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(OR°)R°, -C(NOR°)NR°2, -C(NH)NR°2,-P(O)R°, -P(O)R°, -P(O)(OR°), -OP(O)R°, -OP(O)(OR°), -OP(O)(OR°), -SiR°, -(Ci-4 straight or branched chain alkylene)ON(R°), or -(Ci-4 straight or branched chain alkylene)C(O)ON(R°), wherein each R° is optionally substituted as defined below and independently represents hydrogen, -Ci-6 aliphatic, -CHPh, -O(CH)o-lPh, -CH-(5-6 membered heteroaryl ring) ), or a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independently occurring R° together with the atom(s) between them form a 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0029] Suitable monovalent substituents on R° (or the ring formed by taking two independently occurring R° together with the atoms between them) are independently halogen, —(CH)O-R ● ,-(Halo R ● ), -(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 or branched alkylene)C(O)OR ● or -SSR ●wherein each R ● It is unsubstituted or, where preceded by "halo," is substituted only with one or more halogens, independently selected from 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 a saturated carbon atom of R° include =0 and =S.

[0030] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2))2-3O-, or -S(C(R * 2) 2-3S-, wherein each R * is selected from hydrogen, a C1-C6 aliphatic, which may be substituted as defined below, or an unsubstituted 5-6 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2-3O-, wherein each R * is selected from hydrogen, a C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0031] R * Suitable substituents on the aliphatic group include -R ● , (Halo R ● ), -OH, -OR ● , -O(HaloR ●), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, wherein each R ● is unsubstituted or, where preceded by "halo", substituted only with 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.

[0032] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † wherein each R † are independently hydrogen, C1-6 aliphatic, unsubstituted -OPh, which may be substituted as defined below, or an unsubstituted 3-6 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the definition above, two independently occurring R † together with the intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] R † Suitable substituents on the aliphatic group are independently halogen, —R ● ,-(Halo R ● ), -OH, -OR● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, where preceded by "halo", substituted only with 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. R † Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0034] As used herein, the term "alkyl" refers to a saturated, straight- or branched-chain monovalent hydrocarbon group containing 1 to 20 (e.g., 1 to 10, or 1 to 6) carbons. In some embodiments, alkyl groups are unbranched (i.e., straight-chain), and in some embodiments, alkyl groups are branched. Alkyl groups are exemplified by, but not limited to, methyl, ethyl, n- and isopropyl, n-, sec-, iso- and tert-butyl, and neopentyl.

[0035] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by removing two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like. x -C y "Alkylene" refers to an alkylene group having x to y carbons. Exemplary values ​​of x are 1, 2, 3, 4, 5, and 6, and exemplary values ​​of y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C6). 10 , C2-C 20 , C2-C6, C2-C 10 , or C2-C 20In some embodiments, the alkylene can be further substituted with 1, 2, 3, or 4 substituents as defined herein for an alkyl group.

[0036] As used herein, the term "alkenyl," unless otherwise specified, represents a monovalent straight or branched chain group of 2 to 20 carbons (e.g., 2 to 6, or 2 to 10 carbons) containing one or more carbon-carbon double bonds, and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyl includes both cis and trans isomers. As used herein, the term "alkenylene," unless otherwise specified, represents a divalent straight or branched chain group of 2 to 20 carbons (e.g., 2 to 6, or 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0037] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain group of 2 to 20 carbon atoms (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons) containing a carbon-carbon triple bond, and is exemplified by ethynyl, 1-propynyl, and the like.

[0038] As used herein, the term "amino" refers to -N(R † )2. As used herein, the term "amino acid" refers to a molecule having a side chain, an amino group, and an acidic group (e.g., -COH or -SOH), where the amino acid is attached to the parent molecular group by the side chain, the amino group, or the acidic group (e.g., the side chain). As used herein, the term "amino acid" in its broadest sense refers to any compound or substance that can be incorporated into a polypeptide chain, for example, by the formation of one or more peptide bonds. In some embodiments, an amino acid has the general structure HN-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. A "standard amino acid" refers to any of the 20 standard L-amino acids commonly found in naturally occurring peptides. A "non-standard amino acid" refers to any amino acid other than the standard amino acids, whether synthetically prepared or obtained from a natural source. In some embodiments, amino acids, including the carboxy- or amino-terminal amino acids in a polypeptide, can contain structural modifications compared to the general structures described above. For example, in some embodiments, an amino acid can be modified by methylation, amidation, acetylation, or substitution relative to the general structure. In some embodiments, such modifications can, for example, alter the circulating half-life of a polypeptide containing the modified amino acid compared to one containing another identical unmodified amino acid. In some embodiments, such modifications do not significantly alter the relevant activity of a polypeptide containing the modified amino acid compared to one containing another identical unmodified amino acid. As will be clear from the context, in some embodiments, the term "amino acid" is used to refer to a free amino acid, and in some embodiments, the term "amino acid" is used to refer to an amino acid residue of a polypeptide. In some embodiments, an amino acid is attached to the parent molecular group by a carbonyl group, with the side chain or amino group attached to the carbonyl group. In some embodiments, the amino acid is an α-amino acid.In certain embodiments, the amino acid is a β-amino acid. In some embodiments, the amino acid is a γ-amino acid. Exemplary side chains include optionally substituted alkyl, aryl, heterocyclyl, alkaryl, alkheterocyclyl, aminoalkyl, carbamoylalkyl, and carboxyalkyl. Exemplary 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, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.

[0039] As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system formed by carbon atoms, each ring being aromatic. Examples of aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl. An aryl ring can be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms can be optionally substituted.

[0040] As used herein, the term "C" represents a bond. For example, part of the term -N(C(O)-(C-C alkylene-H)- includes -N(C(O)-(C alkylene-H)-, which is also represented by -N(C(O)-H)-.

[0041] As used herein, the terms "carbocyclic" and "carbocyclyl" refer to a monovalent, optionally substituted C-C 12"Carbocyclic" refers to a monocyclic, bicyclic, or tricyclic ring structure, which may be optionally bridged, fused, or spirocyclic, in which all rings are formed by carbon atoms and at least one ring is non-aromatic. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups. Examples of carbocyclyl groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decalinyl, and the like. A carbocyclic ring can be attached to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms can be optionally substituted.

[0042] As used herein, the term "carbonyl" refers to a C(O) group, which can also be represented as C=O. As used herein, the term "carboxyl" means -COH, (C=O)(OH), COOH, or C(O)OH.

[0043] As used herein, the term "cyano" refers to a -CN group. As used herein, the term "cycloalkyl" refers to a monovalent saturated cyclic hydrocarbon group, which, unless otherwise specified, may be bridged, fused, or spirocyclic, optionally fused, having 3 to 8 carbons, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexyl, and the like.

[0044] The term "diyl," when used in the name of a chemical compound, refers to a divalent radical. As used herein, the term "diastereomers" means stereoisomers that are not mirror images of each other and are not superimposable with respect to one another.

[0045] As used herein, "enantiomer" means each individual optically active form of a compound of the present invention having an optical purity or enantiomeric excess (as measured by standard methods in the art) of 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%.

[0046] The term "halo" as used herein refers to a halogen selected from bromine, chlorine, iodine, or fluorine. As used herein, the term "heteroalkyl" refers to an "alkyl" group (as defined herein) in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom). The heteroatom can occur at the center or end of the radical.

[0047] As used herein, the term "heteroaryl" refers to a monovalent monocyclic or polycyclic ring system containing at least one fully aromatic ring, i.e., they contain 4n+2 pi electrons in the monocyclic or polycyclic ring system and at least one ring heteroatom selected from N, O, or S in the aromatic ring. Exemplary unsubstituted heteroaryl groups are those of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heteroaryl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings are fused to one or more aryl or carbocyclic rings, such as phenyl or cyclohexane rings. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 4-azaindolyl, etc. A heteroaryl ring can be attached to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any ring atom can be optionally substituted. In some embodiments, a heteroaryl is substituted with 1, 2, 3, or 4 substituents.

[0048] As used herein, the term "heterocyclyl" refers to a monovalent monocyclic, bicyclic, or polycyclic ring system, which may be bridged, fused, 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 heterocyclyl groups are those of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heterocyclyl" also refers to heterocyclic compounds having bridged polycyclic structures in which one or more carbons or heteroatoms bridge two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group. The term "heterocyclyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings are fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, such as an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, a pyridine ring, or a pyrrolidine ring. Examples of heterocyclyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, decahydronaphthyridinyl, or the like. A heterocyclic ring can be attached to its pendant group at any ring atom that results in a stable structure, and unless otherwise specified, any of the ring atoms can be optionally substituted.

[0049] As used herein, the term "haloalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more of the same or different halo moieties. As used herein, the term "hydroxyalkyl" refers to an alkyl moiety substituted on one or more carbon atoms with one or more --OH moieties.

[0050] As used herein, "isomer" refers to any tautomer, stereoisomer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention can have one or more chiral centers or double bonds and therefore 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)). In accordance with the present invention, the chemical structures depicted herein, and hence the compounds of the invention, may be present in all their corresponding stereoisomers, i.e., stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomeric pure), as well as in any other form. The present invention encompasses both enantiomeric and stereoisomeric mixtures (e.g., racemates). Enantiomeric and stereoisomeric mixtures of the compounds of the invention can typically be resolved into their component 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 stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0051] As used herein, "nitro" refers to the group --NO.sub.2. As used herein, the term "oxo" refers to =O. As used herein, the term "stereoisomer" refers to all possible different isomeric forms and structural forms that a compound (e.g., a compound of any formula described herein) may possess, in particular all possible stereochemical and structural isomeric forms of the basic molecular structure, all diastereomers, enantiomers, or conformational isomers. Some compounds of the present invention can exist in different tautomeric forms, all of the latter being within the scope of the present invention.

[0052] As used herein, the term "sulfonyl" refers to the group -S(O)2-. Those of skill in the art reading this disclosure will understand that certain compounds described herein can be provided or utilized in any of a variety of forms, such as, for example, salt forms, protected forms, prodrug forms, ester forms, isomeric forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a particular compound may refer to a particular form of that compound. In some embodiments, reference to a particular compound may refer to that 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 that compound from a racemic mixture of that compound, a particular salt of a compound may be considered a different form from another salt form of that compound, a preparation containing a structural isomer of a double bond ((Z) or (E)) may be considered a different form from one containing the other structural isomer of that double bond ((E) or (Z)), a preparation in which one or more atoms are isotopically different from those present in a reference preparation may be considered a different form, etc.

[0053] The term "Ras protein" refers to a protein from the Ras family of related GTPase proteins, including K-Ras, H-Ras, and N-Ras. The Ras protein may be a wild-type protein or a mutant protein. In some embodiments, the Ras protein is not a wild-type protein.

[0054] K-Ras is encoded by the K-RAS gene. The term "K-Ras" also refers to natural variants of wild-type K-Ras proteins, such as proteins having at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) to the amino acid sequence of wild-type K-Ras, as set forth in SEQ ID NO: 1.

[0055] SEQ ID NO: 1 MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ RVEDAFYTLV REIRQYRLKK ISKEEKTPGC VKIKKCIIM H-Ras is encoded by the H-RAS gene. The term "H-Ras" also refers to natural variants of wild-type H-Ras proteins, such as proteins having at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) to the amino acid sequence of wild-type H-Ras, as set forth in SEQ ID NO: 2.

[0056] SEQ ID NO: 2 MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHQYREQI KRVKDSDDVP MVLVGNKCDL AARTVESRQA QDLARSYGIP YIETSAKTRQ GVEDAFYTLV REIRQHKLRK LNPPDESGPG CMSCKCVLS N-Ras is encoded by the N-RAS gene. The term "N-Ras" also refers to natural variants of wild-type N-Ras proteins, such as proteins that have at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity or more) to the amino acid sequence of wild-type N-Ras, as set forth in SEQ ID NO: 3.

[0057] SEQ ID NO: 3 MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNSKSF ADINLYREQI KRVKDSDDVP MVLVGNKCDL PTRTVDTKQA HELAKSYGIP FIETSAKTRQ GVEDAFYTLV REIRQYRMKK LNSSDDGTQG CMGLPCVVM A given Ras protein can bind either GDP or GTP. In response to cellular exposure to specific growth-promoting stimuli, RAS is induced to exchange its bound GDP for GTP. Upon GTP binding, RAS is "switched on," allowing it to interact with and activate other proteins (its "downstream targets"). Ras itself has a very low intrinsic ability to hydrolyze GTP back to GDP, thereby returning itself to its off state. To switch RAS off, an exogenous protein called a GTPase-activating protein (GAP) is required, which interacts with RAS and greatly accelerates the conversion of GTP to GDP. Any mutation in Ras that interacts with GAP or affects its ability to convert GTP back to GDP results in sustained activation of the protein, resulting in sustained signals to the cell that tell it to continue growing and dividing. Because these signals lead to cell growth and division, overactive RAS signaling can ultimately lead to cancer. Methods for measuring the GDP- or GTP-bound state of Ras proteins are known in the art.

[0058] As used herein, the term "mutant Ras protein" refers to a Ras protein containing at least one mutation in which an amino acid in the corresponding wild-type Ras protein is mutated to a different amino acid, e.g., glycine is mutated to aspartic acid, serine, or cysteine. As used herein, the term "mutation" refers to any modification of a nucleic acid or polypeptide that results in an alteration of the nucleic acid or polypeptide. The term "mutation" can include, for example, point mutations, deletions, or insertions of single or multiple residues within a polynucleotide, and includes alterations occurring within the protein-coding region of a gene, as well as alterations in regions outside the protein-coding region, such as, but not limited to, regulatory or promoter sequences, as well as amplifications, or chromosomal breaks or translocations.

[0059] Examples of mutant Ras proteins include, but are not limited to, K-Ras G12D, K-Ras G13D, and K-Ras G12S. In some embodiments, mutations contemplated by the present invention include those associated with oncogenic activity. In some embodiments, mutations contemplated by the present invention include: (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof; (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof; and (c) the following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof.

[0060] Compounds and conjugates of the present invention Provided herein are compounds capable of binding to Ras proteins to form conjugates by reacting as electrophiles and forming covalent bonds with nucleophilic Ras amino acids of the Ras protein. In some embodiments, the compounds of the present invention may be useful in treating diseases and disorders in which Ras, particularly mutated Ras, plays a role, such as cancer. The compounds described or depicted herein, whether explicitly stated or not, can be provided or utilized in salt form, e.g., pharmaceutically acceptable salt form, unless explicitly stated to the contrary.

[0061] The covalent binding of the compound of the present invention to Ras can be reversible or irreversible.The irreversible covalent binding to GDP-bound Ras or GTP-bound Ras can be measured by methods known to those skilled in the art, for example, by mass spectrometry.For example, to measure the binding to GTP or GDP-Ras, the compound of the present invention can be incubated with Ras loaded with appropriate nucleotides, and then crosslinking is measured by mass spectrometry.An exemplary protocol is provided below in the Examples.

[0062] Furthermore, covalent binding of the compounds of the present invention to Ras may disrupt the conformation of Ras, thereby restricting or preventing the binding of Ras to effector proteins, including SOS and RAF. Ras-RAF disruption assays are known to those skilled in the art, for example, as described by Lim et al., Angew. Chem. Int. Ed. 53:199 (2014). By disrupting Ras binding to effector proteins, compounds may disrupt downstream signaling, resulting in growth inhibition or apoptosis induction. These effects can be measured in cell culture after compound treatment by monitoring the activation status of downstream effectors (e.g., the phosphorylation status of ERK), performing cell viability assays, and measuring caspase-3 activity in cell lysates.

[0063] Some compounds disclosed herein, including boronic acids and trifluoromethyl ketones, can form reversible covalent bonds with Ras. For example, as described by Adams et al., Cancer Invest. 22:304 (2004), boronic acids are known to interact with serine and threonine residues. Aspartic acid residues can also form reversible covalent bonds with boronic acids or other electrophiles, such as trifluoromethyl ketones.

[0064] Thus, the present disclosure features compounds of formula I: ALB Formula I wherein A is a Ras-binding moiety; L is a linker, B is a selective crosslinking group; or a pharmaceutically acceptable salt thereof.] In some embodiments, when the compound, or a pharmaceutically acceptable salt thereof, is contacted with a sample containing Ras proteins, at least 20% of the Ras proteins in the sample covalently react with the compound, or a pharmaceutically acceptable salt thereof, to form a conjugate. In some embodiments, when the compound, or a pharmaceutically acceptable salt thereof, is contacted with a sample containing Ras proteins, at least 20% (e.g., at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%) of the Ras proteins in the sample covalently react with the compound, or a pharmaceutically acceptable salt thereof, to form a conjugate (e.g., form a conjugate comprising a Ras-binding moiety, a linker, and a Ras protein).

[0065] Ras proteins are described herein. Thus, the Ras protein can be wild-type or mutant. The Ras protein can be a human Ras protein. The wild-type Ras protein can be K-Ras, H-Ras, or N-Ras. In some embodiments, the Ras protein is not a wild-type protein. In some embodiments, the Ras protein is a mutant Ras protein, such as K-Ras G12D, K-Ras G13D, or K-Ras G12S. Other Ras mutants are described herein. In some embodiments, the sample containing the Ras protein is a sample containing an isolated Ras protein in a solution, for example, a buffer solution. In some embodiments, the sample containing the Ras protein is a sample containing cells expressing the Ras protein.

[0066] The compounds of the present invention, or pharmaceutically acceptable salts thereof, comprise a Ras-binding moiety. As used herein, "Ras-binding moiety" refers to a moiety that binds to a Ras protein. In some embodiments, the Ras-binding moiety comprises a group of atoms (e.g., 5-20 atoms, 5-10 atoms, 10-20 atoms, 20-30 atoms, 30-40 atoms) that bind to a Ras protein. In some embodiments, one or more atoms of the Ras-binding moiety do not bind to a Ras protein.

[0067] The Ras protein can bind to a single atom in the Ras binding moiety. Alternatively, or in addition, the Ras protein can bind to two or more atoms in the Ras binding moiety. In another alternative, the Ras protein is bound to a group that mimics the natural ligand of the Ras protein, and the group that mimics the natural ligand of the Ras protein is bound to the Ras binding moiety. In these examples, the binding is usually, but not limited to, by non-covalent interaction of the Ras protein with the Ras binding moiety.

[0068] In some embodiments, the Ras binding moiety binds to the GDP-bound form of a Ras protein. In some embodiments, the Ras binding moiety binds to the GTP-bound form of a Ras protein. In some embodiments, the Ras binding moiety binds to both the GDP-bound and GTP-bound forms of a Ras protein.

[0069] In some embodiments, the Ras-binding moiety is a human H-Ras-binding moiety, a human N-Ras-binding moiety, or a human K-Ras-binding moiety. In some embodiments, the Ras-binding moiety is a K-Ras-binding moiety. In some embodiments, the K-Ras-binding moiety binds to a residue in the K-Ras Switch-II binding pocket of a K-Ras protein, for example, a residue in the K-Ras protein corresponding to V7, V8, V9, G10, A11, D12, K16, P34, T58, A59, G60, Q61, E62, E63, Y64, S65, R68, D69, Y71, M72, F78, I92, H95, Y96, Q99, I100, R102, or V103 of human wild-type K-Ras (SEQ ID NO: 1). In some embodiments, the Ras-binding moiety is an H-Ras-binding moiety that binds to a residue in the H-Ras Switch-II binding pocket of an H-Ras protein. In some embodiments, the Ras-binding moiety is an N-Ras-binding moiety that binds to a residue in the N-Ras Switch-II binding pocket of an N-Ras protein.

[0070] In some embodiments, the Ras binding moiety comprises the structure of any one of Formulas II-V, described below. In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of Formula II:

[0071] [ka]

[0072] wherein m is 0, 1, 2, or 3; W 1 is N or C, and C is optionally attached to a linker via an optionally substituted C-C alkylene bridge or an optionally substituted C-C heteroalkylene bridge; Each R 1 are independently CN, halo, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 1is attached to the linker via a C1-C3 alkylene bridge or a C1-C3 heteroalkylene bridge, and R 2 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl. In some embodiments of Formula II, W 1 is N or C, and C is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge.

[0073] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of formula II-1:

[0074] [ka]

[0075] wherein m is 0, 1, 2, or 3; Each R 1 are independently CN, halo, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 1 is attached to the linker via a C1-C3 alkylene bridge or a C1-C3 heteroalkylene bridge, and R 2 is an optionally substituted C6-C 10 aryl or optionally substituted C2-C9 heteroaryl; or a pharmaceutically acceptable salt thereof.] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the following structure:

[0076] [ka]

[0077] [Wherein W2 is hydrogen or hydroxy.] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of formula II-1a:

[0078] [ka]

[0079] [In the formula, R 1a , R 1b , and R 2a are independently hydrogen, CN, halo, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; or a pharmaceutically acceptable salt thereof.] In some embodiments, R 1a is halo (e.g., chloro). In some embodiments, R 1b is halo (e.g., fluoro). In some embodiments, R 2a is halo (e.g., fluoro).

[0080] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the following structure:

[0081] [ka]

[0082] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the following structure:

[0083] [ka]

[0084] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of Formula II-2:

[0085] [ka]

[0086] wherein m is 0, 1, 2, or 3; W 1 is C attached to the linker via an optionally substituted C-C alkylene bridge or an optionally substituted C-C heteroalkylene bridge; Each R 1 are independently CN, halo, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 1 is attached to the linker via a C1-C3 alkylene bridge or a C1-C3 heteroalkylene bridge, and R 2 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl. In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of Formula III:

[0087] [ka]

[0088] wherein n is 0, 1, 2, 3, 4, 5, or 6;

[0089] [ka]

[0090] represents a single or double bond, X is N or CR', where R' is hydrogen, or R' is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; V is CHR 5 , CR5R 5 , OR 5 , NHR5 , or NR 5a R 5b and Each R 3 is independent,

[0091] [ka]

[0092] optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; or R 3 is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; R 4 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl; Each R 5 is independently an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted —C1-C6 alkyl-C2-C9 heteroaryl, or an optionally substituted —C1-C6 alkyl-C2-C9 heterocyclyl, and Each R 5a and R 5b are independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted —C1-C6 alkyl-C2-C9 heteroaryl, or optionally substituted —C1-C6 alkyl-C2-C9 heterocyclyl; or R 5a and R 5b combine with the nitrogen atom to which they are attached to form an optionally substituted C2-C9 heterocyclyl; provided that if R' is attached to the linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, then R3 is not attached to the linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; and Furthermore, however, R 3 is attached to the linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, then R' is not attached to the linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge. In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of formula III-1:

[0093] [ka]

[0094] wherein n is 0, 1, 2, 3, 4, 5, or 6; X is N or CR', where R' is hydrogen, or R' is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; V is CHR 5 , C.R. 5 R 5 , OR 5 , NHR 5 , or NR 5a R 5b and Each R 3 are independently optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; or R 3 is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; R 4 is an optionally substituted C6-C10 aryl, or optionally substituted C2-C9 heteroaryl; Each R 5 is independently an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted —C1-C6 alkyl-C2-C9 heteroaryl, or an optionally substituted —C1-C6 alkyl-C2-C9 heterocyclyl, and Each R 5a and R 5b is independently an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted —C1-C6 alkyl-C2-C9 heteroaryl, or an optionally substituted —C1-C6 alkyl-C2-C9 heterocyclyl; However, when R' is attached to the linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, R 3 is not attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, and Furthermore, however, R 3 is attached to the linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, then R' is not attached to the linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge. In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of formula III-1a:

[0095] [ka]

[0096] wherein n is 0, 1, 2, 3, 4, 5, or 6; V is CHR 5 , C.R. 5 R 5 , OR 5 , or NHR5 , or NR 5a R 5b and Each R 3 are independently optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; or R 3 is attached to the linker via a C1-C3 alkylene bridge or a C1-C3 heteroalkylene bridge; R 4 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl; Each R 5 are independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkyl-C2-C9 heteroaryl, or optionally substituted C1-C6 alkyl-C2-C9 heterocyclyl, and Each R 5a and R 5b are independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted -C1-C6 alkyl-C2-C9 heteroaryl, or optionally substituted -C1-C6 alkyl-C2-C9 heterocyclyl. In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of formula III-1b:

[0097] [ka]

[0098] [In the formula, R 4 is an optionally substituted C6-C 10 is a bicyclic aryl, and R 5 is an optionally substituted C1-C6 alkyl-C2-C9 heteroaryl, or an optionally substituted C1-C6 alkyl-C2-C9 heterocyclyl. In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of formula III-2:

[0099] [ka]

[0100] wherein n is 0, 1, 2, or 3; X is N or CR', where R' is hydrogen, or R' is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; V is CHR 5 , C.R. 5 R 5 , OR 5 , NHR 5 , or NR 5a R 5b and Each R 3 teeth

[0101] [ka]

[0102] and R 4 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl; Each R 5 is independently an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted —C1-C6 alkyl-C2-C9 heteroaryl, or an optionally substituted —C1-C6 alkyl-C2-C9 heterocyclyl, and Each R 5a and R 5bare independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted —C1-C6 alkyl-C2-C9 heteroaryl, or optionally substituted —C1-C6 alkyl-C2-C9 heterocyclyl; or R 5a and R 5b combine with the nitrogen atom to which they are attached to form an optionally substituted C2-C9 heterocyclyl; However, when R' is attached to the linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, R 3 is not attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge. In some embodiments, the Ras, Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of formula III-2a:

[0103] [ka]

[0104] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of formula III-3:

[0105] [ka]

[0106] wherein n is 0, 1, 2, 3, 4, 5, or 6;

[0107] [ka]

[0108] represents a single or double bond, X is N or CR', where R' is hydrogen, or R' is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; V is NR 5a R 5b and Each R 3 is independent,

[0109] [ka]

[0110] optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; or R 3 is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; R 4 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl; R 5a and R 5b combine with the nitrogen atom to which they are attached to form an optionally substituted C2-C9 heterocyclyl; However, when R' is attached to the linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, R 3 is not attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, and Furthermore, however, R 3 is attached to the linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, then R' is not attached to the linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge. In some embodiments, R 4 teeth,

[0111] [ka]

[0112] is. In some embodiments, R 4 teeth,

[0113] [ka]

[0114] is. In some embodiments, R 4 teeth,

[0115] [ka]

[0116] is. In some embodiments, V is CHR 5 or CR 5 R 5 In some embodiments, V is OR 5 , NHR 5 , or NR 5a R 5b In some embodiments, V is OR 5 In some embodiments, V is O 5 where R 5 is an optionally substituted C1-C6 alkyl or an optionally substituted C1-C6 heteroalkyl. In some embodiments, V is OR 5 where R 5 is an optionally substituted -C1-C6 alkyl-C2-C9 heteroaryl, or an optionally substituted -C1-C6 alkyl-C2-C9 heterocyclyl. In some embodiments, V is NHR 5 , or NR 5a R 5bIn some embodiments, V is NR 5a R 5b where R 5a and R 5b are combined with the nitrogen atom to which they are attached to form an optionally substituted C2-C9 heterocyclyl.

[0117] In some embodiments, V is

[0118] [ka]

[0119] is. In some embodiments, V is

[0120] [ka]

[0121] is. In some embodiments, V is

[0122] [ka]

[0123] is. In some embodiments, V is

[0124] [ka]

[0125] is. In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the following structure:

[0126] [ka]

[0127] [ka]

[0128] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of formula IV:

[0129] [ka]

[0130] wherein o is 0, 1, or 2; X 1 , X 2 , and X 3 are each independently N, CH, or CR 6 and Each R 6 are independently halo, CN, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 6 is attached to the linker via a C1-C3 alkyl bridge or a C1-C3 heteroalkyl bridge, and R 7 and R 8 are independently an optionally substituted C-C 10 aryl or optionally substituted C2-C9 heteroaryl; or a pharmaceutically acceptable salt thereof.] In some embodiments, X 1 , X 2 , and X 3 and X is N. In some embodiments, X and X are each CH or CR 6 and X1 is N.

[0131] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of formula IVa:

[0132] [ka]

[0133] [In the formula, R 6 is hydrogen, halo, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, and R 7 and R 8 are independently an optionally substituted C-C 10 aryl or optionally substituted C2-C9 heteroaryl; or a pharmaceutically acceptable salt thereof.] In some embodiments, Formula IV has the following structure:

[0134] [ka]

[0135] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of formula IVb:

[0136] [ka]

[0137] [In the formula, R 6 , R 7a , R 8a , and R 8b are independently hydrogen, halo, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; or a pharmaceutically acceptable salt thereof.] In some embodiments, R 6a is halo (e.g., fluoro). In some embodiments, R 7a is halo (e.g., fluoro). In some embodiments, R 8a is an optionally substituted C1-C6 alkyl (e.g., methyl). In some embodiments, R 8bis optionally substituted C1-C6 alkyl (e.g., isopropyl).

[0138] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the following structure:

[0139] [ka]

[0140] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the structure of Formula V:

[0141] [ka]

[0142] wherein p is 0, 1, 2, or 3; R 9 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl; Each R 10 are independently halo, CN, hydroxy, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl, or R 10 is attached to the linker via a C1-C3 alkylene or C1-C3 heteroalkylene bridge, and R 11 is an optionally substituted C2-C9 heteroaryl or an optionally substituted C2-C9 heterocyclyl; or a pharmaceutically acceptable salt thereof.] In some embodiments, the Ras binding moiety (e.g., K-Ras binding moiety) comprises the following structure:

[0143] [ka]

[0144] In some embodiments, the Ras binding moiety is selected from the group consisting of WO2020216190, WO2020178282, WO2020146613, WO2020118066, WO2020113071, WO2020106647, WO2020102730, WO2020101736, WO2020097537, WO2020086739, WO2020081282, WO2020050890, WO2020047192, WO2020035031, WO2020028706, WO2019 241157, WO2019232419, WO2019217691, WO2019217307, WO2019215203, WO2019213526, WO2019213516, WO2019155399, WO2019150305, WO2019110751, WO2019099524, WO2019051291, WO2018218070, WO2018218071, WO2018218069, WO2018217651, WO2018206539, WO201814 3315, WO2018140600, WO2018140599, WO2018140598, WO2018140514, WO2018140513, WO2018140512, WO2018119183, WO2018112420, WO 2018068017, WO2018064510, WO2017201161, WO2017172979, WO2017100546, WO2017087528, WO2017058807, WO2017058805, WO20170587 28, WO2017058902, WO2017058792, WO2017058768, WO2017058915, WO2017015562, WO2016168540, WO2016164675, WO2016049568, WO2016049524, WO2015054572, WO2014152588, WO2014143659, and WO2013155223, which Ras-binding moieties are incorporated herein by reference. In light of the disclosure herein, as well as general knowledge, one skilled in the art will understand how the crosslinking groups of the compounds in these references can be replaced with the selective crosslinking groups of the present invention.

[0145] The compounds of the present invention, or pharmaceutically acceptable salts thereof, include a linker between the Ras-binding moiety (e.g., A in Formula I) and the selective crosslinking group (e.g., B in Formula I). ​​As used herein, "linker" refers to a divalent organic moiety connecting moiety A to moiety B in a compound of Formula I such that the resulting compound achieves an IC50 of 2 μM or less in the Ras-RAF disruption assay protocol described in Lim et al., Angew. Chem. Int. Ed. 53:199 (2014). In some embodiments, the linker positions the reactive atom of B about 0.5 to about 1.1 nm (about 5 to about 11 angstroms) from the nearest atom of A. In some embodiments, the linker positions the reactive atom of B 4 to 9 atoms from the nearest atom of A. 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 comprises 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.

[0146] The term "reactive," when used in conjunction with a selective crosslinking group, refers to an electrophilic atom that reacts rapidly or at a practical rate under conventional conditions of organic synthesis or under physiological conditions to form a covalent bond with a nucleophilic functional group on a Ras protein, such as a carboxyl, hydroxyl, or thiol group. This is in contrast to atoms that either do not react or require strong catalysts or impractical reaction conditions to react (i.e., "nonreactive" or "inert" groups).

[0147] As used herein, "functional group" refers to an organic moiety within a Ras protein that is capable of forming a covalent bond with a selective cross-linking group, as described herein. Functional groups can be nucleophilic or electrophilic, as these terms are known in the art. Non-limiting examples of nucleophilic functional groups include carboxyl, hydroxyl, and thiol groups. Non-limiting examples of Ras amino acids having nucleophilic functional groups include aspartic acid, glutamic acid, serine, threonine, tyrosine, cysteine, and lysine.

[0148] In some embodiments, the linker has the structure of Formula VI: -A 1 -(B 1 ) a -(C 1 ) b -(B 2 ) c -(D)-(B 3 ) d -(C 2 ) e -(B 4 ) f -A 2 - Equation VI [In the formula, A 1 is the bond between the linker and the Ras binding moiety, and A 2 is the bond between the selective crosslinking group and the linker, and B 1 , B 2 , B 3 , and B 4 are each independently selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NRN, where NRN is hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C 6-12 Aryl, or optionally substituted C 1-7 Heteroalkyl, C 1 and C 2are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; a, b, c, d, e, and f are each independently 0 or 1; D is an optionally substituted C 1-10 Alkylene, optionally substituted C 2-10 Alkenylene, optionally substituted C 2-10 Alkynylene, optionally substituted C 2-6 Heterocyclylene, optionally substituted C 2-6 Heteroarylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 6-12 Arylene, optionally substituted C-C 10 Polyethylene glycol or optionally substituted C 1-10 heteroalkylene, or A 1 -(B 1 ) a -(C 1 ) b -(B 2 ) c -(B 3 ) d -(C 2 ) e -(B 4 ) f -A 2 It is a chemical bond that connects to .

[0149] In some embodiments, the linker comprises a heteroaryl group, such as a phenyl group or a pyridyl group. Non-limiting examples of such linkers include:

[0150] [ka]

[0151] In some embodiments, the linker comprises a heterocyclyl group, for example, a 3-8 membered heterocyclyl group. In some embodiments, the linker comprises a cycloalkyl group, for example, a 3-8 membered carbocyclyl group.

[0152] In some embodiments, the linker is an optionally substituted heterocyclyl group, e.g., an optionally substituted 3- to 8-membered heterocyclyl group. In some embodiments, the linker is an optionally substituted cycloalkyl group, e.g., an optionally substituted 3- to 8-membered carbocyclyl group.

[0153] In some embodiments, the linker is as exemplified by any of Formulas VIIa-VIII. In these structures, when a nitrogen group is in position B, the nitrogen is part of the selective crosslinking group. When a carbon atom is in position B, the carbon atom is part of the linker.

[0154] In some embodiments, compound ALB, or a pharmaceutically acceptable salt thereof, has the formula VIIa o or VIIb o It has any one of the following structures:

[0155] [ka]

[0156] wherein q and r are independently 0, 1, or 2; X 1 is N or CH, and R 12 , R 13 , R 14 , and R 14a are independently hydrogen, oxo, optionally substituted C-C alkyl, optionally substituted C-C heteroalkyl, or -CO-optionally substituted C-C alkyl; R 14 When is not oxo, R 14 optionally includes a bond to A. In some embodiments, R 12 , R 13 , R 14 , and R 14a and is not simultaneously oxo. 12 , R 13 , R 14 , and R 14aOnly one of the is oxo.

[0157] In some embodiments, compound ALB, or a pharmaceutically acceptable salt thereof, has the structure of any one of formulas VIIa or VIIb.

[0158] [ka]

[0159] wherein q and r are independently 0, 1, or 2; X 1 is N or CH, R 12 and R 13 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, and R 14 is hydrogen, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 14 optionally includes a bond to A.

[0160] See also Formula VIIe below for an explanation of the linker moiety in these formulas. In some embodiments, the ALB, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0161] [ka]

[0162] [In the formula, R x is an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge attached to A (see also WO2018 / 206539)].

[0163] In some embodiments, ALB, or a pharmaceutically acceptable salt thereof,

[0164] [ka]

[0165] is. In some embodiments, -LB is

[0166] [ka]

[0167] is selected from the group consisting of: In some embodiments, ALB, or a pharmaceutically acceptable salt thereof, has the structure of Formula VIIc or Formula VIId:

[0168] [ka]

[0169] wherein s, t, u, and v are independently 0, 1, or 2; X 3 is N or CH, and R 15 and R 16 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl. See also Formula VIIf below for an explanation of the linker moiety in these formulas.

[0170] In some embodiments, ALB, or a pharmaceutically acceptable salt thereof,

[0171] [ka]

[0172] is. In some embodiments, the linker is acyclic. For example, the linker has the structure of Formula VIII:

[0173] [ka]

[0174] [In the formula, R 17 is hydrogen or optionally substituted C1-C6 alkyl, and L 2 is an optionally substituted C1-C4 alkylene, or an optionally substituted C3-C6 cycloalkyl. In some embodiments, the linker is selected from the group consisting of:

[0175] [ka]

[0176] [In the formula, R y is an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge attached to A (see WO2018 / 206539)].

[0177] In some embodiments, the linker has the following structure:

[0178] [ka]

[0179] The compounds of the present invention, or pharmaceutically acceptable salts thereof, comprise a selective crosslinking group. As used herein, a "selective crosslinking group" refers to a group that, under conventional conditions of organic synthesis or physiological conditions, exhibits preferential crosslinking reactivity with one or more nucleophilic functional groups of a Ras protein, relative to other nucleophilic functional groups present on the Ras protein. For example, in some embodiments, the selective crosslinking group reacts preferentially with carboxyl groups, hydroxyl groups, or thiol groups, or a combination thereof, relative to other nucleophilic functional groups on the Ras protein. For example, in some embodiments, the selective crosslinking group reacts preferentially with carboxyl groups. In some embodiments, the selective crosslinking group reacts preferentially with hydroxyl groups. In some embodiments, the selective crosslinking group reacts preferentially with thiol groups. In some embodiments, the selective crosslinking group reacts preferentially with carboxyl groups and hydroxyl groups. In some embodiments, the selective crosslinking group reacts preferentially with carboxyl groups and thiol groups. In some embodiments, the selective crosslinking group reacts preferentially with hydroxyl groups and thiol groups. In some embodiments, the selective crosslinking group reacts preferentially with thiol groups. Non-limiting examples of moieties that are "selective crosslinking groups" include, for example, carbodiimides, aminooxazolines, chloroethylureas, aziridines, trifluoromethylketones, boronic acids, boronic esters, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinolines (EEDQ), isoEEDQ or other EEDQ derivatives, epoxides, oxazoliums, or glycals. In some embodiments, the selective crosslinking group is a carbodiimide, aminooxazoline, chloroethylureas, aziridines, trifluoromethylketones, boronic acids, boronic esters, epoxides, or glycals. In some embodiments, the selective crosslinking group is a carbodiimide, aminooxazoline, chloroethylureas, or aziridines.

[0180] In some embodiments, the selective crosslinking group is a C-O bond-forming selective crosslinking group. In some embodiments, the selective crosslinking group is a C-S bond-forming selective crosslinking group. In some embodiments, the selective crosslinking group has the structure of or is included in any one of Formulas IX-XVIII.

[0181] In some embodiments, the selective crosslinking group has the structure of Formula IX:

[0182] [ka]

[0183] [In the formula, R 18 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl. In some embodiments, the selective crosslinking group is selected from the group consisting of:

[0184] [ka]

[0185] [ka]

[0186] In some embodiments, the selective crosslinking group is a structure of formula Xa or Xb:

[0187] [ka]

[0188] [In the formula, X 5 is O or S, X 5’ is O or S, X 5a is not present or NR19 and X 5a’ is N, said N being a ring atom of an optionally substituted C2-C9 heterocyclyl group; R 19 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; and R 20 , R 21 , R 22 , R 23 , R 20’ , R 21’ , R 22’ , and R 23’ are independently hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, the selective crosslinking group is selected from the group consisting of:

[0189] [ka]

[0190] In some embodiments, the selective crosslinking group is of the structure of formula XIa or XIb:

[0191] [ka]

[0192] [In the formula, X 6 is O or S, X 6’ is O or S, X 6a is not present or NR 24 and X 6a’ is N, said N being a ring atom of an optionally substituted C2-C9 heterocyclyl group; X 7 and X 7’ are O, S, or NR, respectively. 29 and R 24 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; and R 25 , R 26 , R 27 , R 28 , R 29 , R 25’ , R 26’ , R 27’ , and R 28’ are independently hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, the selective crosslinking group is selected from the group consisting of:

[0193] [ka]

[0194] In some embodiments, the selective crosslinking group is a structure of formula XIIa, XIIb, XIIc, XIId, or XIIe:

[0195] [ka]

[0196] wherein X is absent or NR 30 and X' is N, said N being a ring atom of an optionally substituted C2-C9 heterocyclyl group; Y is C(O), C(S) (i.e., C=S), SO, or optionally substituted C-C alkyl; Z' is C(O) or SO2; Z'' is -CH2- or C(O), q is 0, 1, or 2; Each R x are independently hydrogen, CN, C(O)R y , CO2R y, C(O)NR y R y , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; Each R y are independently hydrogen, optionally substituted C-C alkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; R z is hydrogen or CH3, R 30 is hydrogen or optionally substituted C1-C6 alkyl; R 31 is hydrogen, -C(O)R 32 , -SO2R 33 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; and R 32 and R 33 are independently hydrogen, optionally substituted C-C alkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl. In some embodiments, R 31 and R x At least two of R are hydrogen. 31 is CH3, C(O)CH3, SO2CH3, CH2-C6H5, or CH2CH2OCH3.

[0197] In some embodiments, the selective crosslinking group is selected from the group consisting of:

[0198] [ka]

[0199] In some embodiments, the selective crosslinking group is selected from the group consisting of:

[0200] [ka]

[0201] In some embodiments, the selective crosslinking group is selected from the group consisting of:

[0202] [ka]

[0203] In some embodiments, the selective crosslinking group is selected from the group consisting of:

[0204] [ka]

[0205] In some embodiments, the compound of the invention has the following structure:

[0206] [ka]

[0207] In some embodiments, the compound of the invention has the following structure:

[0208] [ka]

[0209] [In the formula, R 31is absent, hydrogen, C(O)CH3, SO2CH3, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C3 alkyl-C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C1-C3 alkyl-C2-C9 heterocyclyl; R 56 is CH3 or Cl, R z is hydrogen, optionally substituted C1-C3 alkyl, Each R x are independently hydrogen, CO2CH3, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, and Z''' is N or O.] In some embodiments, the compound of the invention has the following structure:

[0210] [ka]

[0211] [In the formula, R 31 is hydrogen, CH3, C(O)CH3, SO2CH3, CH2-C6H5, or CH2CH2OCH3.] In some embodiments, the compound of the invention has the following structure:

[0212] [ka]

[0213] [In the formula, R 31is absent, hydrogen, C(O)CH3, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C3 alkyl-C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C1-C3 alkyl-C2-C9 heterocyclyl; R z is hydrogen, optionally substituted C1-C3 alkyl, R x is hydrogen, CO2CH3, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, and Z''' is N or O.] In some embodiments, the selective crosslinking group is an optionally substituted aziridine. In some embodiments, the selective crosslinking group is an optionally substituted epoxide.

[0214] In some embodiments, the selective crosslinking group is

[0215] [ka]

[0216] [ka]

[0217] is. In some embodiments, the selective crosslinking group is

[0218] [ka]

[0219] is. In some embodiments, the selective crosslinking is

[0220] [ka]

[0221] is. In some embodiments, the selective crosslinking group has the structure of Formula XIV:

[0222] [ka]

[0223] [In the formula, R 34 and R 35 is independently an optionally substituted C1-C6 alkyl, or R 34 and R 35 combine with the boron to which they are attached to form an optionally substituted heterocyclyl. In some embodiments, the selective crosslinking group is a structure of Formula XV:

[0224] [ka]

[0225] wherein w is 1 or 2; R 36 is hydrogen or optionally substituted C1-C6 alkyl, and Each R 37 and R 38 are independently hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, the selective crosslinking group is selected from the group consisting of:

[0226] [ka]

[0227] In some embodiments, the selective crosslinking group has the structure of Formula XVI:

[0228] [ka]

[0229] [In the formula, X 8 Does not exist or is O, S, NR 40 , or CH2, X 9 O, NR 41 , S, S(O), or S(O)2; R 39 is an optionally substituted C1-C6 alkyl, and R 40 and R 41 are independently hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, the selective crosslinking group is

[0230] [ka]

[0231] is. In some embodiments, the selective crosslinking group has the structure of Formula XVII:

[0232] [ka]

[0233] [In the formula, X 10 Does not exist or is O, S, NR 43 , or CH2, X 11 O, NR 44 , S, S(O), or S(O)2; R 42 is an optionally substituted C1-C6 alkyl, and R 43 and R 44are independently hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, the selective crosslinking group is

[0234] [ka]

[0235] is. In some embodiments, the selective crosslinking group has the structure of Formula XVIII:

[0236] [ka]

[0237] [In the formula, R 45 is hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, the selective crosslinking group is

[0238] [ka]

[0239] is. In some embodiments, the selective crosslinking group has the structure of Formula XIX:

[0240] [ka]

[0241] [In the formula, R 46 and R 47 are independently hydrogen, optionally substituted C-C alkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl. In some embodiments, the compounds of the invention have the structure of formula XX or XXI:

[0242] [ka]

[0243] wherein Y is C(O), C(S), SO, or optionally substituted C-C alkyl; Z' is C(O) or SO2; q is 0, 1, or 2; x is 0, 1, 2, or 3, Each R X are independently hydrogen, CN, C(O)R y , CO2R y , C(O)NR y R y , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; Each R y are independently hydrogen, optionally substituted C-C alkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; Each R 48 are independently CN, halo, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 49 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl; R 50 is hydrogen or C1-C6 alkyl, R 51 is hydrogen, CN, or C1-C6 alkyl; R 54 is hydrogen, -C(O)R32, -SO2R 33, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; and R 55 is hydrogen or optionally substituted C1-C6 alkyl. In some embodiments, R 51 , R 54 , and R x are hydrogen atoms.

[0244] In some embodiments, the compounds of the invention have the structure of Formula XXII or XXIII:

[0245] [ka]

[0246] wherein X is hydrogen or hydroxy. In some embodiments, the selective crosslinking group is an epoxide having the formula:

[0247] [ka]

[0248] In some embodiments, the compound of the present invention is selected from Table 1:

[0249] [Table 1-1]

[0250] [Table 1-2]

[0251] [Table 1-3]

[0252] [Table 1-4]

[0253] [Table 1-5]

[0254] [Table 1-6]

[0255] [Table 1-7]

[0256] [Table 1-8]

[0257] [Table 1-9]

[0258] [Table 1-10]

[0259] In some embodiments, the compound of the present invention is selected from Table 2a:

[0260] [Table 2-1]

[0261] [Table 2-2]

[0262] [Table 2-3]

[0263] [Table 2-4]

[0264] [Table 2-5]

[0265] [Table 2-6]

[0266] [Table 2-7]

[0267] [Table 2-8]

[0268] [Table 2-9]

[0269] In some embodiments, the compound of the present invention is selected from Table 2b:

[0270] [Table 3-1]

[0271] [Table 3-2]

[0272] [Table 3-3]

[0273] [Table 3-4]

[0274] [Table 3-5]

[0275] [Table 3-6]

[0276] In some embodiments, the compound of the invention is selected from Table 2c:

[0277] [Table 4-1]

[0278] [Table 4-2]

[0279] In some embodiments, the compound of the present invention is selected from Table 2d:

[0280] [Table 5-1]

[0281] [Table 5-2]

[0282] [Table 5-3]

[0283] [Table 5-4]

[0284] [Table 5-5]

[0285] [Table 5-6]

[0286] [Table 5-7]

[0287] [Table 5-8]

[0288] [Table 5-9]

[0289] [Table 5-10]

[0290] [Table 5-11]

[0291] [Table 5-12]

[0292] [Table 5-13]

[0293] In some embodiments, the compound of the invention is selected from Table 2e:

[0294] [Table 6-1]

[0295] [Table 6-2]

[0296] [Table 6-3]

[0297] [Table 6-4]

[0298] [Table 6-5]

[0299] [Table 6-6]

[0300] In some embodiments, the compound of the invention is selected from Table 2f:

[0301] [Table 7-1]

[0302] [Table 7-2]

[0303] [Table 7-3]

[0304] [Table 7-4]

[0305] Table 7-5

[0306] Table 7-6

[0307] Table 7-7

[0308] Table 7-8

[0309] Table 7-9

[0310] Table 7-10

[0311] Table 7-11

[0312] Table 7-12

[0313] Table 7-13

[0314] Table 7-14

[0315] In any embodiment herein, such an embodiment may be any of WO2020216190, WO2020178282, WO2020146613, WO2020118066, WO2020113071, WO2020106647, WO2020102730, WO2020101736, WO2020097537, WO2020086739, WO2020081282, WO2020050890, WO2020047192, WO2020035031, WO20202 0028706, WO2019241157, WO2019232419, WO2019217691, WO2019217307, WO2019215203, WO2019213526, WO2019213516, WO2019155 399, WO2019150305, WO2019110751, WO2019099524, WO2019051291, WO2018218070, WO2018217651, WO2018218071, WO2018218069, WO2018206539, WO2018143315, WO2018140600, WO2018140599, WO2018140598, WO2018140514, WO2018140513, WO2018140512, WO20 18119183, WO2018112420, WO2018068017, WO2018064510, WO2017201161, WO2017172979, WO2017100546, WO2017087528, WO201705 8807, WO2017058805, WO2017058728, WO2017058902, WO2017058792, WO2017058768, WO2017058915, WO2017015562, WO2016168540, WO2016164675, WO2016049568, WO2016049524, WO2015054572, WO2014152588, WO2014143659, or WO2013155223, or McGregor This does not include the compounds disclosed in [Chem. Chem., 2017].

[0316] Further provided are Ras proteins comprising a covalent bond to a compound of the invention. In some embodiments, a conjugate, or salt thereof, is provided, in which the Ras protein is covalently linked to a Ras binding moiety via a linker and a selective cross-linker (as these terms are defined herein), wherein the covalent bond is between the selective cross-linker and the Ras protein.

[0317] In some embodiments, the conjugate, or a salt thereof, has the structure of Formula XIX: A-LB-C Formula XIX wherein A is a Ras binding moiety, e.g., a compound of Formula II, Formula III, Formula IV, or Formula V; LB is a linker, e.g., a linker of formula VI, VIIe, VIIf, or VIII attached to a selective crosslinking group, and C is a Ras protein, and C is covalently bound to B.] In some embodiments of the conjugate or salt thereof, the selective crosslinking group binds to a Ras protein, such as a human mutant K-Ras protein, a human mutant H-Ras protein, or a human mutant N-Ras protein, by covalently binding to the carboxyl group of the Ras protein. In some embodiments, the Ras protein is K-Ras G12D, K-Ras G13D, or K-Ras G12S. In some embodiments, the carboxyl group of the residue of the Ras protein is the carboxyl group of an aspartic acid residue at a mutant position corresponding to position 12 or 13 of human wild-type K-Ras (SEQ ID NO: 1).

[0318] In some embodiments, the conjugate or salt thereof comprises a Ras protein covalently linked to a selective crosslinking group, the selective crosslinking group being attached to the Ras binding moiety via a linker, and the selective crosslinking group being a carbodiimide, aminooxazoline, chloroethylurea, aziridine, trifluoromethyl ketone, boronic acid, boronic ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), iso-EEDQ, epoxide, oxazolium, or glycal. In some embodiments, the selective crosslinking group is a carbodiimide, aminooxazoline, chloroethylurea, aziridine, trifluoromethyl ketone, boronic acid, boronic ester, epoxide, or glycal. In some embodiments, the selective crosslinking group is a carbodiimide, aminooxazoline, chloroethylurea, or aziridine.

[0319] In some embodiments, the conjugate or salt thereof comprises a linker selected from the group consisting of: (a) -A 1 -(B 1 ) a -(C 1 ) b -(B 2 ) c -(D)-(B 3 ) d -(C 2 ) e -(B 4 ) f -A 2 - Equation VI [In the formula, A 1 is the bond between the linker and the Ras binding moiety, and A 2 is the bond between the selective crosslinking group and the linker, and B 1 , B 2 , B 3 , and B 4 are each independently an optionally substituted C1-C2 alkylene, an optionally substituted C1-C3 heteroalkylene, O, S, and NR N Selected from R Nis hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C 6-12 Aryl, or optionally substituted C 1-7 Heteroalkyl, C 1 and C 2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; a, b, c, d, e, and f are each independently 0 or 1; D is an optionally substituted C 1-10 Alkylene, optionally substituted C 2-10 Alkenylene, optionally substituted C 2-10 Alkynylene, optionally substituted C 2-6 Heterocyclylene, optionally substituted C 2-6 Heteroarylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 6-12 Arylene, optionally substituted C-C 10 Polyethylene glycol or optionally substituted C 1-10 heteroalkylene, or A 1 -(B 1 ) a -(C 1 ) b -(B 2 ) c -(B 3 ) d -(C 2 ) e -(B 4 ) f -A 2 It is a chemical bond that connects (b)

[0320] [ka]

[0321] wherein q and r are independently 0, 1, or 2; X 1and X 2 are independently N or CH; R 12 and R 13 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, and R 14 is hydrogen, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 14 optionally includes a bond to A. (c)

[0322] [ka]

[0323] wherein s, t, u, and v are independently 0, 1, or 2; X 3 and X 4 are independently N or CH, and R 15 and R 16 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, and (d)

[0324] [ka]

[0325] where R 17 is hydrogen or optionally substituted C1-C6 alkyl, and L 2 is an optionally substituted C1-C4 alkylene or an optionally substituted C3-C6 cycloalkylene. Further provided is a method for producing a conjugate, comprising contacting a Ras protein with a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of such a compound or salt, under conditions sufficient to covalently react the compound with the Ras protein. Also provided is a method for producing a conjugate, comprising contacting a Ras protein with a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of such a compound or salt, under conditions suitable to allow conjugate formation. Also provided is a conjugate produced by such a method.

[0326] Synthesis method The compounds described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic, or enzymatic processes.

[0327] The compounds of the present invention can be prepared by a number of methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present disclosure can be synthesized using the methods described below and in the Examples below, along with synthetic methods known in the art of synthetic organic chemistry, or variations thereof that will be appreciated by those skilled in the art. These methods include, but are not limited to, the methods described below and in the Examples section.

[0328] The following scheme illustrates a synthetic route for attaching a selective cross-linking group (B) to an intermediate consisting of a Ras binding moiety and a linker (AL). Although only one AL is shown, WO2020216190, WO2020178282, WO2020146613, WO2020118066, WO2020113071, WO2020106647, WO2020102730, WO2020101736, WO2020097537, WO2020086739, WO2020081282, WO2020050890, WO2020047192, WO2020035031, WO2020028706, WO2019241157, WO2019 232419, WO2019217691, WO2019217307, WO2019215203, WO2019213526, WO2019213516, WO2019155399, WO2019150305, WO2019110751, WO2 019099524, WO2019051291, WO2018218070, WO2018217651, WO2018218071, WO2018218069, WO2018206539, WO2018143315, WO2018140600, WO2018140599, WO2018140598, WO2018140514, WO2018140513, WO2018140512, WO2018119183, WO2018112420, WO2018068017, WO20180645 10, WO2017201161, WO2017172979, WO2017100546, WO2017087528, WO2017058807, WO2017058805, WO2017058728, WO2017058902, WO20170 Any suitable Ras-binding moiety and linker can be selected, such as those derived from the structures described in WO2015054572, WO2014152588, WO2014143659, and WO2013155223, which Ras-binding moieties are incorporated herein by reference.In view of the disclosure herein, as well as general knowledge, one skilled in the art will understand how the bridging groups of the compounds in these references can be replaced with the selective bridging groups of the present invention.

[0329] Reaction Scheme 1

[0330] [ka]

[0331] As shown in Scheme 1, compounds of type 4 can be prepared by reaction of an appropriate amine, such as compound 1, with a carboxylic acid, such as compound 2, in the presence of a standard amide coupling reagent, followed by trityl deprotection under acidic conditions.

[0332] Reaction Scheme 2

[0333] [ka]

[0334] As shown in Scheme 2, compounds of type 4 can be prepared by reductive amination of an appropriate amine, such as compound 1, with an aldehyde, such as compound 2, followed by trityl deprotection under acidic conditions.

[0335] Reaction Scheme 3

[0336] [ka]

[0337] Compounds of type 3 can be prepared by reaction of an appropriate amine, such as compound 1, with vinylsulfonyl chloride, followed by dibromination and elimination of the alkene using a suitable amine base, as shown in Scheme 3. Reaction of compounds of type 3 with a suitable primary amine produces compounds of type 4, which can be converted to compounds of type 5 in the presence of a base.

[0338] Reaction Scheme 4

[0339] [ka]

[0340] As shown in Scheme 4, compounds of type 3 can be prepared by reaction of an appropriate amine, such as compound 1, with a suitable alkyl halide or other leaving group, such as compounds of type 2.

[0341] Reaction Scheme 5

[0342] [ka]

[0343] As shown in Scheme 5, compounds of type 3 can be prepared by reaction of an appropriate amine, such as compound 1, with sulfuryl chloride and an amine, such as compound 2. Reaction Scheme 6

[0344] [ka]

[0345] As shown in Scheme 6, compounds of type 3 can be prepared by reaction of an appropriate amine, such as compound 1, with phosgene and an amine, such as compound 2. Pharmaceutical compositions and methods of administration As used herein, the term "pharmaceutical composition" refers to an active compound formulated with one or more pharmaceutically acceptable excipients. In some embodiments, the compound is present in a unit dose suitable for administration in a treatment regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, the pharmaceutical composition can be specially formulated for administration in solid or liquid form, including oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and those targeted for systemic absorption, pills, powders, granules, pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation; topical application, e.g., as a cream, ointment, or sustained-release patch, or spray applied to the skin, lungs, or oral cavity; vaginal or rectal administration, e.g., as a pessary, cream, or foam; sublingual; intraocular; transdermal; or suitable for nasal, pulmonary, and other mucosal surfaces.

[0346] As used herein, "pharmaceutically acceptable excipient" refers to any inert ingredient (e.g., a vehicle capable of suspending or dissolving an active compound) that is toxic and non-inflammatory in a subject. Typical excipients include, for example, anti-adhesives, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydration water. Excipients include, but are not limited to, optionally substituted butylated hydroxyl toluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxyl propyl cellulose, optionally substituted hydroxyl propyl methylcellulose, 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, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those skilled in the art are familiar with the variety of agents and materials useful as excipients.

[0347] The compounds described herein or depicted herein, whether explicitly stated or not, can be provided or utilized in salt form, e.g., pharmaceutically acceptable salt form, unless explicitly stated to the contrary. As used herein, the term "pharmaceutically acceptable salt" refers to those salts of the compounds described herein that are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, etc., within the normal scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. 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.

[0348] The compounds of the present invention can have ionic groups, allowing them to be prepared as pharmaceutically acceptable salts. These salts can be acid addition salts with inorganic or organic acids, or in the case of the acidic form of the compounds of the present invention, salts can be prepared from inorganic or organic bases. Frequently, 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, such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, or tartaric acid for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, etc. for forming base salts, are well known in the art. Methods for preparing suitable salts are well established in the art.

[0349] Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-(optionally substituted)hydroxy-ethanesulfonate, and the like. Included are sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.

[0350] As used herein, the term "subject" refers to any member of the animal kingdom. In some embodiments, "subject" refers to a human at any stage of development. In some embodiments, "subject" refers to a human patient. In some embodiments, "subject" refers to a non-human animal at any stage of development. In some embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, or pig). In some embodiments, the subject includes, but is not limited to, a mammal, a bird, a reptile, an amphibian, a fish, or an insect. In some embodiments, the subject can be a transgenic animal, a genetically modified animal, or a clone.

[0351] As used herein, the term "dosage form" means a physically discrete unit of an active compound (e.g., a therapeutic or diagnostic agent) for administration to a subject. Each unit contains a predetermined amount of active agent. In some embodiments, such amount is a unit dose (or a whole fraction thereof) appropriate for administration according to a dosing regimen (i.e., using a therapeutic dosing regimen) that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population. Those skilled in the art will understand that the total amount of a therapeutic composition or compound administered to a particular subject will be determined by one or more attending physicians and may involve the administration of multiple dosage forms.

[0352] As used herein, the term "dosing regimen" refers to a collection of unit doses (usually two or more) administered individually to a subject, usually separated by a period of time. In some embodiments, a given therapeutic compound has a recommended dosing regimen, which may involve one or more administrations. In some embodiments, a dosing regimen includes multiple doses, each separated from the other by the same length of time period; in some embodiments, a dosing regimen includes multiple doses and at least two different time periods separating the individual doses. In some embodiments, all doses within a dosing regimen are the same unit dose. In some embodiments, different doses within a dosing regimen are different amounts. In some embodiments, a dosing regimen includes a first dose at a first dosage amount, followed by one or more additional doses at a second dosage amount that is different from the first dosage amount. In some embodiments, a dosing regimen includes a first dose at a first dosage amount, followed by one or more additional doses at a second dosage amount that is the same as the first dosage amount. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered across relevant populations (ie, is a therapeutic dosing regimen).

[0353] By "therapeutic regimen" is meant a dosing regimen in which administration across a relevant population correlates with a desired or beneficial therapeutic outcome. The term "treatment" (plus "treat" or "treating"), in its broadest sense, refers to any administration of a substance (e.g., a provided composition) that partially or completely ameliorates, 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, characteristics, or causes of a particular disease, disorder, or condition. In some embodiments, such treatment can be administered to a subject who does not exhibit signs of the associated disease, disorder, or condition, or who exhibits only early signs of a disease, disorder, or condition. Alternatively, or in addition, in some embodiments, such treatment can be administered to a subject who exhibits established signs of one or more of the associated diseases, disorders, or conditions. In some embodiments, treatment can be in a subject who has been diagnosed as suffering from the associated disease, disorder, or condition. In some embodiments, treatment may be in subjects known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the relevant disease, disorder or condition.

[0354] The term "therapeutically effective amount" refers to an amount sufficient to treat a disease, disorder, or condition when administered to a population suffering from or suspected of having the disease, disorder, or condition in accordance with a therapeutic dosing regimen. In some embodiments, a therapeutically effective amount is an amount that reduces the occurrence 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 "therapeutically effective amount" does not actually require that successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount can be an amount that, when administered to subjects in need of such treatment, results in a specific, desired pharmacological response in a significant number of subjects. It is specifically understood that certain subjects may, in fact, be "refractory" to a "therapeutically effective amount." By way of example only, refractory subjects may have low bioavailability such that clinical efficacy is not obtainable. In some embodiments, reference to a therapeutically effective amount can be a reference to the amount measured in one or more specific tissues (e.g., tissues affected by a disease, disorder, or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). One of skill in the art will understand that in some embodiments, a therapeutically effective amount can be formulated or administered in a single dose. In some embodiments, a therapeutically effective amount can be formulated or administered in multiple doses, for example, as part of a dosing regimen.

[0355] For use as a therapeutic agent in a subject, the compounds of the present invention, or pharmaceutically acceptable salts thereof, can be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the method of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or therapy, the compounds, or pharmaceutically acceptable salts thereof, are formulated in a manner consistent with these parameters. Summaries of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0356] The compounds described herein, or pharmaceutically acceptable salts thereof, can be present in a total amount of 1 to 95% by weight of a composition, such as a pharmaceutical composition. The composition can be provided in a dosage form suitable for intraarticular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesical, intraurethral, ​​intrathecal, epidural, otic, or ocular administration, or for injection, inhalation, or direct contact with nasal, urogenital, reproductive, or oral mucosa. Thus, the pharmaceutical composition can be in the form of, for example, a tablet, capsule, pill, powder, granule, suspension, emulsion, solution, gel, including hydrogel, paste, ointment, cream, plaster, drenching agent, osmotic delivery device, suppository, enema, injectable solution, implant, spray, preparation suitable for iontophoretic delivery, or aerosol. The composition can be formulated according to conventional pharmaceutical practice.

[0357] The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be prepared and used as pharmaceutical compositions comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient known in the art. In some embodiments, the composition comprises at least two different pharmaceutically acceptable excipients or carriers.

[0358] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a preparation comprising a compound described herein) to a subject or system. Administration to an animal subject (e.g., a human) can be by any suitable route. For example, in some embodiments, administration can be bronchial (including bronchial infusion), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, intranasal, oral, rectal, subcutaneous, sublingual, topical, intratracheal (including intratracheal infusion), transdermal, intravaginal, and intravitreal.

[0359] The formulation can be prepared in a manner suitable for systemic administration or local or topical administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection), or can be prepared for transdermal, transmucosal, or oral administration. The formulation generally includes a diluent, and may also include an adjuvant, a buffer, a preservative, etc. The compound or its pharmaceutically acceptable salt can also be administered in a liposome composition or as a microemulsion.

[0360] For injection, the preparations can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol, etc. Such compositions can also contain amounts of nontoxic auxiliary substances (e.g., wetting agents or emulsifying agents), pH buffering agents, etc., such as sodium acetate, sorbitan monolaurate, etc.

[0361] Various sustained release systems for drugs have also been devised, see for example U.S. Patent No. 5,624,677, incorporated herein by reference. Systemic administration can also include relatively non-invasive methods such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration.Oral administration is also suitable for the compound of the present invention or its pharmaceutically acceptable salt.Suitable forms include syrups, capsules, and tablets, as understood in the art.

[0362] Each compound of the combination therapy described herein, or a pharmaceutically acceptable salt thereof, can be formulated in a variety of ways known in the art, for example, the first and second agents of the combination therapy can be formulated together or separately.

[0363] Individually or separately formulated agents can be packaged together as a kit. Non-limiting examples include, but are not limited to, a kit containing two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit can include any components that aid in administering a unit dose to a subject, such as a vial for reconstituting a powder form, a syringe for injection, a customized IV delivery system, an inhaler, etc. In addition, a unit dose kit can contain instructions for preparing or administering the composition. The kit can be manufactured as a single-use unit dose for a subject, multiple uses for a specific subject (at a fixed concentration or where the potency of the individual compounds, or pharmaceutically acceptable salts thereof, changes as treatment progresses), or the kit can contain multiple doses (bulk packaging) suitable for administration to multiple subjects. The components of the kit can be assembled into a carton, blister pack, bottle, tube, etc.

[0364] Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, optionally substituted hydroxylpropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and smoothing agents, glidants, and antiadherents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0365] The two or more compounds can be mixed in a tablet, capsule, or other vehicle, or can be fractionated. In one example, a first compound is contained inside the tablet and a second compound is present on the outside, with a substantial portion of the second compound being released before the release of the first compound.

[0366] Formulations for oral use can be provided as chewable tablets, or as hard 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 soft gelatin capsules in which the active ingredient can be mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets can be prepared using the ingredients described above under tablets and capsules in a conventional manner, for example, using a mixer, a fluidized bed device, or a spray-drying device.

[0367] Dissolution or diffusion controlled release can be achieved by suitable coating of the compound on tablets, capsules, pellets, or granules, or by incorporating the compound or its pharmaceutically acceptable salt into a suitable matrix. The sustained release coating can include one or more of the above-mentioned coating materials, or, for example, shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethyl cellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-(optionally substituted) hydroxyl methacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate, or polyethylene glycol. In sustained-release matrix formulations, the matrix material can also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, Carbopol 934, silicone, glyceryl tristearate, acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbons.

[0368] Liquid forms into 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.

[0369] Generally, when administered to humans, the oral dose of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or any combination thereof, depends on the properties of the compound and can be readily determined by those skilled in the art. Typically, such doses are usually about 0.001 mg to 2000 mg per day, preferably about 1 mg to 1000 mg per day, and more preferably about 5 mg to 500 mg per day. Doses of up to 200 mg per day may be required.

[0370] In some embodiments, the pharmaceutical composition can further comprise an additional compound with antiproliferative activity. Depending on the administration method, the compound or its pharmaceutically acceptable salt is formulated into a suitable composition that allows easy delivery. Each compound of the combination therapy, or its pharmaceutically acceptable salt, can be formulated in various ways known in the art. For example, the first agent and the second agent of the combination therapy can be formulated together or separately. Preferably, the first agent and the second agent are formulated together for simultaneous or nearly simultaneous administration of the agents.

[0371] It will be understood that the compounds and pharmaceutical compositions of the present invention can be formulated and utilized in combination therapy, i.e., the compounds and pharmaceutical compositions can be formulated or administered simultaneously with, prior to, or after one or more other desired therapeutic agents or medical procedures. The particular combination of therapies (therapeutics or procedures) used in a combination regimen will take into account the compatibility of the desired therapeutic agents or procedures and the desired therapeutic effect to be achieved. Furthermore, it will be understood that the therapies used may achieve a desired effect on the same disease or may achieve a different effect (e.g., control of any adverse effects).

[0372] As described herein, administration of each agent in the combination therapy can independently be from one to four times daily for one day to one year, and even for the life of the subject. Chronic long-term administration may be indicated.

[0373] How to use In some embodiments, the present invention discloses methods for treating a disease or disorder characterized by ectopic Ras activity due to a Ras mutation. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, or small cell lung cancer. In some embodiments, the ectopic Ras activity is due to a Ras G12D mutation. In some embodiments, the ectopic Ras activity is due to a K-Ras G12D mutation. In some embodiments, the ectopic Ras activity is due to a Ras G13D mutation. In some embodiments, the ectopic Ras activity is due to a K-Ras G13D mutation. In some embodiments, the ectopic Ras activity is due to a Ras G12S mutation. In some embodiments, the ectopic Ras activity is due to a K-Ras G12S mutation. Other Ras mutations are described herein.

[0374] Also provided is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, pancreatic cancer, appendix cancer, melanoma, acute myeloid leukemia, small intestine cancer, ampullary cancer, germ cell cancer, 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. Also provided is a method for treating a Ras protein-associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt. In some embodiments, the cancer comprises a Ras mutation, such as the Ras mutations described herein. In some embodiments, the Ras mutation is K-Ras G12D, K-Ras G13D, or K-Ras G12S.

[0375] In some embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and the methods provided herein can be used to treat a wide variety of cancers, including, for example, tumors such as 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 comprising such compounds or salts, and the methods of the present invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, uterine, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, pharyngeal, ovarian, prostate, and thyroid cancer and sarcoma. Other cancers include, for example: Heart, for example, nonepithelial malignant tumors (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung, e.g., bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, non-epithelial malignant tumor, lymphoma, chondroitin hamartoma, mesothelioma; Gastrointestinal, e.g., esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet cell tumor, glucagonoma, gastrinoma, carcinoid tumor, VIP tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary organs, e.g., kidney (adenocarcinoma, Wilms' tumor, (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, non-epithelial carcinoma), testicle (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriomas, non-epithelial carcinoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); Liver, e.g., hepatocarcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract, e.g., gallbladder cancer, ampullary cancer, cholangiocarcinoma; Bone, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign cartilage tumor, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system, e.g., skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningiomas, meningiosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pineal tumors), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors, neurofibromatosis type I, spinal neurofibromas, meningiomas, gliomas, non-epithelial malignant tumors); Gynecological, e.g., uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), fallopian tube (epithelial carcinoma); Hematological, e.g., blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; Adrenal gland, e.g., neuroblastoma.

[0376] Also provided is a method for inhibiting Ras protein in a cell, comprising contacting the cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. Also provided is a method for inhibiting RAF-Ras binding, comprising contacting the cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. The cell may be a cancer cell. The cancer cell may be, for example, a colorectal cancer cell, a non-small cell lung cancer cell, a pancreatic cancer cell, an appendix cancer cell, a melanoma cell, an acute myeloid leukemia cell, a small intestine cancer cell, an ampullary cancer cell, a germ cell cancer cell, a cervical cancer cell, a cancer cell of unknown primary origin, an endometrial cancer cell, an esophagogastric cancer cell, a GI neuroendocrine cancer cell, an ovarian cancer cell, a sex cord-stromal tumor cancer cell, a hepatobiliary cancer cell, or a bladder cancer cell. In some embodiments, the cancer is an appendix cancer, an endometrial cancer, or a melanoma.

[0377] Combination therapy The present disclosure also provides methods of combination therapy in which agents known to regulate other pathways, or other components of the same pathway, or even a set of overlapping targets, are used in combination with the compounds of the present disclosure, or pharmaceutically acceptable salts thereof. In one aspect, such therapies include, but are not limited to, combinations of one or more compounds of the present disclosure with antiproliferative agents, chemotherapeutic agents, therapeutic antibodies, and radiation therapy, which result in synergistic or additive therapeutic effects. Examples of other pharmaceutical agents that may be combined with the compounds described herein, or pharmaceutically acceptable salts thereof, include pharmaceutical agents for treating the same indication. Other examples of pharmaceutical agents that may be combined with the compounds described herein, or pharmaceutically acceptable salts thereof, include pharmaceutical agents for treating different but related or associated symptoms or indications.

[0378] As used herein, the term "combination therapy" refers to a situation in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more compounds, such as compounds of the present invention). In some embodiments, two or more compounds may be administered simultaneously. In some embodiments, such compounds may be administered sequentially. In some embodiments, such compounds are administered in overlapping dosing regimens. In some embodiments, a combination therapeutic regimen employs two therapeutic agents, a compound of the present invention and a second therapeutic agent selected from the therapeutic agents described herein. In some embodiments, a combination therapeutic regimen employs three therapeutic agents, a compound of the present invention and two therapeutic agents selected from the therapeutic agents described herein. In some embodiments, a combination therapeutic regimen employs four or more therapeutic agents, a compound of the present invention and three therapeutic agents selected from the therapeutic agents described herein. For example, the combination therapy may involve a Ras inhibitor, a MEK inhibitor, and an SHP2 inhibitor described herein; a Ras inhibitor, a MEK inhibitor, and an SOS1 inhibitor described herein; or a Ras inhibitor, a PDL-1 inhibitor, and an SHP2 inhibitor.

[0379] In this Combination Therapy section, all references to the agents mentioned, whether explicitly stated or not, are incorporated by reference. In some embodiments, the compound of the present invention can be used in combination with an EGFR inhibitor.In some embodiments, the compound of the present invention can be used in combination with an inhibitor of downstream members of receptor tyrosine kinase (RTK) / growth factor receptor, such as SHP2 inhibitor, SOS1 inhibitor, Raf inhibitor, MEK inhibitor, ERK inhibitor, PI3K inhibitor, PTEN inhibitor, AKT inhibitor or mTORC1 inhibitor.Examples of these inhibitors are shown below.

[0380] In some embodiments, the compounds of the present invention can be used in combination with a second Ras inhibitor.In some embodiments, the Ras inhibitor targets Ras in its active or GTP-bound state.In some embodiments, the Ras inhibitor targets Ras in its inactive or GDP-bound state, for example, AMG 510, MRTX1257, MRTX849, JNJ-74699157, LY3499446, or ARS-1620.

[0381] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds of the present disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, antiangiogenic agents, and antiandrogens. Non-limiting examples include chemotherapeutic agents, cytotoxic agents, non-peptide small molecules such as Gleevec™ (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex® (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex®, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin Antibiotics such as cin, keramicin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, and enocitabine Pyrimidine analogues such as vin and floxuridine; androgens such as calsterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elfomitine; elliptinium acetate; etoglucide; gallium nitrate; hydroxybenzoates Urea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2''-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa;Taxanes such as paclitaxel and docetaxel; retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0382] Suitable chemotherapy cell modulating agents include, for example, antiestrogens such as tamoxifen (Nolvadex®), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; Also included are antihormonal agents that act to regulate or inhibit hormone action in tumors, such as tabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda®; ibandronate; camptothecin-11 (CPT-11); the topoisomerase inhibitor RFS 2000; and difluoromethylornithine (DMFO).

[0383] If desired, the compounds or pharmaceutical compositions of the present disclosure can be administered in combination with other drugs, such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfalazine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, anti-tumor drugs, tumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle non-specific anticancer drugs, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, eclulind, ferruginol, forodesin, fosfestol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucansone, lurtotecan, mafosfamide, mitozolomide, nafo It may be used in combination with commonly prescribed anticancer drugs such as xyzidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosquidar.

[0384] The present disclosure further relates to a method of using the compounds or pharmaceutical compositions provided herein in combination with radiation therapy to inhibit abnormal cell growth or treat hyperproliferative diseases in mammals.Technologies for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.The administration of the compounds of the present disclosure in this combination therapy can be determined as described herein.

[0385] Radiation therapy can be administered by one of several methods or a combination of methods, including, but not limited to, external beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by spatially confined radioactive material inserted into the body at or near the site of a tumor or other proliferative tissue disease. The term is intended to include, but is not limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Radiation sources suitable for use as cell conditioning agents of the present disclosure include both solid and liquid sources. By way of non-limiting example, the radiation source can be a radionuclide such as 1-125, 1-131, Yb-169, Ir-192, 1-125 as a solid source, or other radionuclide that emits photons, beta particles, gamma rays, or other therapeutic rays. The radioactive material can also be any solution of the radionuclide(s), e.g., a fluid made from a solution of 1-125 or 1-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of a solid radionuclide, such as Au-198 or Y-90. Additionally, the radionuclide(s) can be embodied in a gel or radioactive microspheres.

[0386] The compounds or pharmaceutical compositions of the present disclosure can be used in combination with an amount of one or more substances selected from an anti-angiogenic agent, a signal transduction inhibitor, an anti-proliferative agent, a glycolysis inhibitor, or an autophagy inhibitor.

[0387] Antiangiogenic agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, can be used in combination with the compounds of the present disclosure and the pharmaceutical compositions described herein. Antiangiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, EP0818442, EP1004578, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, EP606046, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO1999007675, EP1786785, EP1181017, US20090012085, US5863949, US5861510, and EP0780386. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 or MMP-9 relative to other matrix metalloproteinases (i.e., MMP-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 useful in the present disclosure are AG-3340, RO 32-3555, and RS13-0830.

[0388] The compound may be used in combination with acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, bromodeoxyuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine octophosphate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab Eflornithine, emiteflu, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopin, 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 alphacon-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, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin,Levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mispaired double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein, NSC631570, octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel , pamidronate, pegaspargase, peginterferon alfa-2b, pentosan, sodium polysulfate, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium etidronate Re186, RII retinamide, rituximab, romurtide, samarium (153Sm) lexidronam, sargramostim, schizophrenia Filan, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyroid-stimulating hormone alpha, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, native form, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin roxithromycin, verteporfin, vinorelbine, viruzin, zinostatin stimalamer or zoledronic acid; abarelix; AE941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL532 (Elan), EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine,Gastrin-17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin-2, iproxifen, LDI200 (Milkhaus), religistim, lintuzumab, 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-131 MAb (Techniclone), polymorphic epithelial mucin-yttrium-90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin, gadolinium, MX6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, saliblastin, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering) Institute), melanoma oncolysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal, It can also be used in combination with other anti-tumor agents, such as valspodar (Newcastle Hospital) or valspodar.

[0389] In some embodiments, the anti-cancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors such as gefitinib (Iressa®), erlotinib (Tarceva®), piritinib, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, and JNJ-26483327.

[0390] The compounds of the present invention can also be used in combination with VEGFR inhibitors. Other compounds described in the following patents and patent applications can be used in combination therapy: US 6,258,812, US 2003 / 0105091, WO 01 / 37820, US 6,235,764, WO 01 / 32651, US 6,630,500, US 6,515,004, US 6,713,485, US 5,521,184, US 5,770,599, US 5 ,747,498, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, US5,990,141, WO00 / 12089, and WO00 / 02871.

[0391] In some embodiments, the combination comprises a composition of the present invention combined with at least one anti-angiogenic agent. Agents include, but are not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. The agent may be an agonist, antagonist, allosteric modulator, toxin, or more generally, may act to inhibit or stimulate its target (e.g., activate or inhibit a receptor or enzyme), thereby promoting cell death or arresting cell proliferation.

[0392] Exemplary anti-angiogenic agents include ERBITUX® (IMC-C225), KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen-binding regions that specifically bind to VEGF (e.g., bevacizumab), or a soluble VEGF receptor or ligand-binding region thereof), such as AVASTIN® or VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind thereto), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto), such as Vectibix (panitumumab), IRESSA® (gefitinib), TARCEVA® (erlotinib), anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind thereto or their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto). The pharmaceutical compositions of the invention can also include one or more agents (e.g., antibodies, antigen-binding regions, or soluble receptors) that specifically bind and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), as well as antibodies or antigen-binding regions that specifically bind to its receptor, "c-met."

[0393] Other anti-angiogenic agents include Cambus, IL-8, B-FGF, Tek antagonists (US2003 / 0162712, US6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen-binding regions, or soluble TWEAK receptor antagonists, see US6,727,225), ADAM distointegrin domains that antagonize the binding of integrins to their ligands (US2002 / 0042368), specifically binding anti-eph receptor or anti-ephrin antibodies or antigen-binding regions. (U.S. Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124, and patent family members thereof), and anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind), 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 thereto).

[0394] Additional antiangiogenic / antineoplastic agents include SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 770622); pegaptanib octasodium (Gilead Sciences, USA); alphastatin (BioActa, UK), M-PGA (Celgene, USA, US5712291), ilomastat (Arriva, USA, US5892112), emaxanib (Pfizer, USA, US5792783), vatalanib (Novartis, Switzerland), 2-methoxyestradiol (EntreMed, USA), TLC ELL-12 (Elan, Ireland), anecortave acetate (Alcon, USA), alpha-D148 Mab (Amgen, USA), CEP-7055 (Cephalon, USA), anti-Vn Mab (Crucell, Netherlands), DAC antiangiogenic agent (ConjuChem, Canada), angiocidin (InKine Pharmaceutical, USA), KM-2550 (Kyowa Hakko, Japan), SU-0879 (Pfizer, USA), CGP-79787 (Novartis, Switzerland, EP970070), 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), angiogenesis inhibitor (Tripep, Sweden), maspin (Sosei, Japan), 2-methoxyestradiol (Oncology Sciences Corporation, USA), ER-68203-00 (IV AX, USA), Benefin (LaneLabs, USA), Tz-93 (Tsumura, Japan), TAN-1120 (Takeda, Japan), FR-111142 (Fujisawa, Japan, JP02233610), platelet factor 4 (RepliGen, USA, EP407122), vascular endothelial growth factor antagonist (Borean, Denmark), bevacizumab (pINN) (Genentech, USA), angiogenesis inhibitor (SUGEN, USA), XL 784 (Exelixis, USA), XL 647 (Exelixis, USA), MAb, alpha 5 beta 3 integrin, second generation (Applied Molecular Evolution, USA and MediImmune, USA), retinopathy gene therapy (Oxford BioMedica, UK); enzastaurin hydrochloride (USAN) (Lilly, USA), CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France), BC 1 (Genoa Institute of Cancer Research, Italy), angiogenesis inhibitors (Alchemia, Australia), VEGF antagonists (Regeneron, USA), rBPI 21 and BPI-derived antiangiogenic agents (XOMA, USA), PI 88 (Progen, Australia), cilengitide (pINN) (Merck KGaA, Germany, Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA), cetuximab (INN) (Aventis, France), 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), angiostatin (Boston Children's Hospital, USA), 2-methoxyestradiol (Boston Children's Hospital, USA), ZD 6474 (AstraZeneca, UK), ZD 6126 (Angiogene Pharmaceuticals, UK), PPI2458 (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), xanthorrhizol (Yonsei University, 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), motuporamine C (British Columbia University, Canada), CDP 791 (Celltech Group, UK), atiprimod (pINN) (GlaxoSmithKline, UK), E 7820 (Eisai, Japan), CYC 381 (Harvard University, USA), AE 941 (Aeterna, Canada), vaccines, angiogenic agents (EntreMed, USA), urokinase plasminogen activator inhibitors (Dendreon, USA), oglufanide (pINN) (Melmotte, USA), HIF-lalfa 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, Korea), GW 2286 (GlaxoSmithKline, UK), EHT 0101 (ExonHit, France), CP 868596 (Pfizer, USA), CP 564959 (OSI, USA), CP547632 (Pfizer, USA), 786034 (GlaxoSmithKline, UK), KRN 633 (Kirin Brewery, Japan), drug delivery system, intraocular, 2-methoxyestradiol (EntreMed, USA), Anginex (Maastricht University, The Netherlands and University of Minnesota, USA), ABT 510 (Abbott, USA), AAL 993 (Novartis, Switzerland), VEGI (ProteomTech, USA), tumor necrosis factor-alpha inhibitor (National Institute on Aging, USA), 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, alpha5beta (Protein Design, USA), KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA), GFB 116 (University of South Florida, 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, Korea), MAb vascular endothelial growth factor (Xenova, UK), irsogladine (INN) (Nippon Shinyaku, Japan), RG 13577 (Aventis, France), WX360 (Wilex, Germany), squalamine (pINN) (Genaera, USA), RPI 4610 (Sirna, USA), cancer therapy (Marinova, Australia), heparanase inhibitor (InSight, Israel), KL 3106 (Kolon, 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), VEGF receptor regulator (Pharmacopeia, USA), VE-cadherin-2 antagonist (ImClone Systems, USA), vasostatin (National Institutes of Health, USA), vaccine, Flk-1 (ImClone Systems, USA), TZ 93 (Tsumura, Japan), tumstatin (Beth Israel Hospital, USA), truncated soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA), Tie-2 ligand (Regeneron, USA), and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0395] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil®), bafilomycin Al, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, analogs of cAMP, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, antisense or siRNA inhibitors that inhibit the expression of proteins, including but not limited to ATG5 (involved in autophagy), can also be used.

[0396] Additional pharmaceutically active compounds / agents that can be used to treat cancer and that can be used in combination with one or more compounds of the invention include epoetin alfa, darbepoetin alfa, panitumumab, pegfilgrastim, palifermin, filgrastim, denosumab, ancestim, AMG 102, AMG 386, AMG 479, AMG 655, AMG 745, AMG 951, and AMG 706, or pharmaceutically acceptable salts thereof.

[0397] In certain embodiments, the compositions provided herein are administered in combination with a chemotherapeutic agent.Suitable chemotherapeutic agents include vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., enzymes that metabolize L-asparagine systemically and promote its own metabolism), and chemotherapeutic agents (e.g., steroids, anti-inflammatory drugs ... L-asparaginase, which deprives cells of the ability to synthesize asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., ribociclib, abemaciclib, palbociclib, seliciclib, UCN-01, P1446A-05, PD-0332), 991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), trazeneth-dacarbazine (DTIC), folate analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs, and related inhibitors agents (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoylanilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., temsirolimus, everolimus, ridaforolimus, and sirolimus (see also below).)), KSP (Eg5) inhibitors (e.g., Array 520), DNA binders (e.g., Zalipsis), PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g., CAL-130); multikinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen), and hormonal 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., Zarnestra™ ), anti-CD138 (e.g., BT062), Torcl / 2-specific kinase inhibitors (e.g., INK128), kinase inhibitors (e.g., GS-1101), 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 natural products such as BCL-2 antagonists. Other chemotherapeutic agents may include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or any analog or derivative variant of the foregoing.

[0398] Other mTOR inhibitors that can be combined with the compounds of the present invention include ATP-competitive mTORC1 / mTORC2 inhibitors, such as PI-103, PP242, PP30; 1; FKBP12 potentiators; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and its derivatives, such as temsirolimus (Torisel®); everolimus (Afinitor®, WO 94 / 09010); ridaforolimus (also known as deforolimus or AP23573); rapalogs, such as those disclosed in WO 98 / 02441 and WO 01 / 14387, for example, 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-pentynyloxy-32(S)-dihydrorapamycin; derivatives disclosed in WO 05 / 005434; U.S. Patent Nos. 5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, and WO 94 / 090101, WO 92 / 051 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 diastereomeric inhibitor (see, e.g., WO2018 / 204416, WO2019 / 212990, and WO2019 / 212991), such as RMC-5552.

[0399] The compounds of the present invention can be used in combination with radiation therapy, hormone therapy, surgery, and immunotherapy, which are well known to those skilled in the art. In certain embodiments, the pharmaceutical compositions provided herein are administered in combination with a steroid. Suitable steroids include 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, flucortine butyl, flucortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, and flurandrenolide. , fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof. In certain embodiments, the compounds of the present invention can also be used in combination with an additional pharmaceutically active agent to treat nausea. Examples of drugs that can be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0400] The compounds of the present invention can also be used in combination with an additional pharmaceutically active compound that disrupts or inhibits the RAS-RAF-ERK or PI3K-AKT-TOR signaling pathway. In some combinations, the additional pharmaceutically active compound is a PD-1 or PD-L1 antagonist. The compounds or pharmaceutical compositions of the present disclosure can also be used in combination with an amount of one or more substances selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, Mcl-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapies, including monoclonal antibodies, immunomodulatory imids (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs.

[0401] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva®), osimertinib (Tagrisso®), and lapatinib (TykerB®). See, for example, Yan L, et al., Pharmacogenetics and Pharmacogenomics In: See Oncology Therapeutic Antibody Development, BioTechniques 2005;39(4):565-8, and Paez JG, et.al, EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004;304(5676):1497-500.

[0402] Non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, and all pharmaceutically acceptable salts and solvates of said EGFR inhibitors: European Patent Application No. EP 520722 (published December 30, 1992), European Patent Application No. EP 566226 (published October 20, 1993), PCT International Publication No. WO 96 / 33980 (published October 31, 1996), U.S. Patent No. 5,747,498 (issued May 5, 1998), PCT International Publication No. WO 96 / 30347 (issued October 3, 1996), and the like. Publication No. WO97 / 30044 (published August 21, 1997), PCT International Publication No. WO97 / 38994 (published October 23, 1997), PCT International Publication No. WO97 / 49688 (published December 31, 1997), European Patent Application No. EP837063 (published April 22, 1998), PCT International Publication No. WO98 / 02434 (published January 22, 1998), PCT International Publication No. WO9 PCT International Publication No. 7 / 38983 (published October 23, 1997), PCT International Publication No. WO95 / 19774 (published July 27, 1995), PCT International Publication No. WO95 / 19970 (published July 27, 1995), PCT International Publication No. WO97 / 13771 (published April 17, 1997), PCT International Publication No. WO98 / 02437 (published January 22, 1998), PCT International Publication No. WO98 / 02438 (published January 22, 1998), PCT International Publication No. WO97 / 32881 (published September 12, 1997), German Application No. DE19629652 (published September 12, 1997), PCT International Publication No. WO98 / 33798 (published January 29, 1998), PCT International Publication No. WO97 / 32880 (published September 12, 1997), PCT International Publication No. WO97 / 32880 (published September 12, 1997), European Patent Application No. EP682027 (published November 15, 1995), PCT International Publication No. WO97 / 02266 (published January 23, 1997), PCT International Publication No. WO97 / 27199 (published July 31, 1997), PCT International Publication No. WO98 / 97726 (published February 26, 1998),PCT International Publication No. WO97 / 34895 (published September 25, 1997), PCT International Publication No. WO96 / 31510 (published October 10, 1996), PCT International Publication No. WO98 / 14449 (published April 9, 1998), PCT International Publication No. WO98 / 14450 (published April 9, 1998), PCT International Publication No. WO98 / 14451 (published April 9, 1998), PCT International Publication No. WO95 / 09847 (published April 13, 1995), PCT International Publication No. WO97 / 19065 (published May 29, 1997), PCT International Publication No. WO98 / No. 17662 (published April 30, 1998), U.S. Pat. No. 5,789,427 (issued August 4, 1998), U.S. Pat. No. 5,650,415 (issued July 22, 1997), U.S. Pat. No. 5,656,643 (issued August 12, 1997), PCT International Publication No. WO99 / 35146 (published July 15, 1999), PCT International Publication No. WO99 / 35132 (published July 15, 1999), PCT International Publication No. WO99 / 07701 (published February 18, 1999), and PCT International Publication No. WO92 / 20642 (published November 26, 1992). Further non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12):1599-1625. In some embodiments, the EGFR inhibitor is an ERBB inhibitor. In humans, the ERBB family contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).

[0403] Antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin. Cancer Res. 1:1311-1318; Huang, S. M., et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang, X., et al., 1999, Cancer Res. 59:1236-1243. Thus, the EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

[0404] MEK inhibitors include, but are not limited to, cobimetinib, trametinib, and binimetinib. PI3K inhibitors include wortmannin, a 17-hydroxywortmannin analog described in WO 06 / 044453, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC 0941 and described in PCT Publication Nos. WO 09 / 036082 and WO 09 / 055730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (BEZ 235 or NVP-BEZ 235 and described in PCT Publication No. WO06 / 122806), (S)-1-(4-((2-(2-aminopyrinddin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyriiTddin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in PCT Publication No. WO2008 / 070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, available from Axon Medchem), PI 103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride, available from Axon Medchem), Medchem), PIK 75 (N'-[(1E)-(6-bromoindazo[l,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfono-hydrazide hydrochloride, available from Axon Medchem), PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide, available from Axon Medchem), GDC-0941 bismesylate (2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine bismesylate, available from Axon Medchem), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione, available from Axon Medchem), and TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrinidin-4-one, available from Axon Medchem), XL-765, and XL-147. Other PI3K inhibitors include demethoxyviridine, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0405] AKT inhibitors include Akt-1-1 (inhibits Akt1) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1,2 (inhibits Akt1 and 2) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05011700); indole-3-carbinol and its derivatives (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li (2004) J. Nutr. 134 (12 Suppl), 3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al. (2004) Cancer Res. 64, 4394-9).

[0406] TOR inhibitors include, but are not limited to, inhibitors (including AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus), ATP-competitive TORC1 / TORC2 inhibitors (including PI-103, PP242, PP30, and Torin1). Other TOR inhibitors in the FKBP12 enhancer, rapamycin, and their derivatives include CCI-779 (temsirolimus), RAD001 (everolimus; WO 9409010), and AP23573; rapalogs (e.g., those disclosed in WO 98 / 02441 and WO 01 / 14387, e.g., AP23573, AP23464, or AP23841); 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779), 40-epi(tetrazolito)-rapamycin (also known as ABT578), 32-deoxorapamycin, 16-pentynyloxy-32(S)-dihydrorapamycin, and other derivatives disclosed in WO 05005434; U.S. Pat. No. 5,258,389, WO 9 Nos. 4 / 090101, WO92 / 05179, U.S. Pat. Nos. 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, WO93 / 111130, WO94 / 02136, WO94 / 02485, WO95 / 14023, WO94 / 02136, WO95 / 16691, WO96 / 41807, WO96 / 41807, and U.S. Pat. No. 5,256,790; phosphorus-containing rapamycin derivatives (e.g., WO05016252), and 4H-1-benzopyran-4-one derivatives (e.g., WO2005 / 056014).

[0407] Optional BRAF inhibitors that can be used in combination include, for example, vemurafenib, dabrafenib, and encorafenib. MCl-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the major anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression and resistance to not only conventional chemotherapy but also targeted therapeutic agents, including BCL-2 inhibitors such as ABT-263.

[0408] Proteasome inhibitors include, but are not limited to, Kyprolis® (carfilzomib), Velcade® (bortezomib), and oprozomib.

[0409] Immunotherapies include, but are not limited to, anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA-4 agents, anti-LAG1 agents, and anti-OX40 agents. Monoclonal antibodies include, but are not limited to, Darzalex® (daratumumab), Herceptin® (trastuzumab), Avastin® (bevacizumab), Rituxan® (rituximab), Lucentis® (ranibizumab), and Eylea™ (aflibercept).

[0410] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that modify the immune response) that contain an imide group. The IMiD class includes thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0411] Exemplary anti-PD-1 antibodies and their methods of use are described by Goldberg et al., Blood 110(1):186-192 (2007), Thompson et al., Clin. Cancer Res. 13(6):1757-1761 (2007), and Korman et al., International Application No. PCT / JP2006 / 309606 (Publication No. WO2006 / 121168A1), each of which is expressly incorporated by reference herein, and include Yervoy® (ipilimumab) or tremelimumab (against CTLA-4), galiximab (against B7.1), BMS-936558 (against PD-1), MK-3475 (against PD-1) (pembrolizumab), AMP224 (against B7DC), BMS-936559 (against B7-H1), MPDL3280A (against B7-H1), MEDI-570 (against ICOS), AMG557 (against B7H2), MGA271 (against B7H3), IMP321 (against LAG-3), BMS-663513 (against CD137), PF-05082566 (against CD137), CDX-1127 (against CD27), anti-OX40 (Providence Health Services), huMAbOX40L (against OX40L), atacicept (against TACI), CP-870893 (against CD40), lucatumumab (against CD40), dacetuzumab (against CD40), muromonab-CD3 (against CD3), ipilimumab (against CTLA-4). Immunotherapies also include genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTEs).

[0412] GITR agonists include GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as those described in U.S. Pat. No. 6,111,090, European Patent No. 090505B1, U.S. Pat. No. 8,586,023, PCT Publication Nos. WO 2010 / 003118 and 2011 / 090754, or those described in, for example, U.S. Pat. Patent No. 7,025,962, European Patent No. 1947183B1, U.S. Patent No. 7,812,135, U.S. Patent No. 8,388,967, U.S. Patent No. 8,591,886, European Patent No. EP1866339, PCT Publication No. WO2011 / 028683, PCT Publication No. WO2013 / 039954, PCT Publication No. WO2005 / 007190, PCT Publication No. WO PCT Publication No. WO2007 / 133822, PCT Publication No. WO2005 / 055808, PCT Publication No. WO99 / 40196, PCT Publication No. WO2001 / 03720, PCT Publication No. WO99 / 20758, PCT Publication No. WO2006 / 083289, PCT Publication No. 2005 / 115451, U.S. Patent No. 7,618,632, and PCT Publication No. WO2011 / 051726.

[0413] In some embodiments, the additional therapeutic agent is an SHP2 inhibitor. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene and contributes to multiple cellular functions, such as proliferation, differentiation, cell cycle maintenance, and migration. SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the intracellular localization and functional regulation of SHP2. This molecule exists in an inactive, autoinhibited conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. For example, stimulation by cytokines or growth factors acting through receptor tyrosine kinases (RTKs) leads to exposure of the catalytic site, resulting in enzymatic activation of SHP2.

[0414] SHP2 is involved in signal transduction 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, such as Noonan syndrome and Leopard syndrome, as well as human cancers such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancer. Some of these mutations destabilize the autoinhibitory conformation of SHP2, promoting its self-activation or enhanced growth factor-driven activation. Therefore, SHP2 is a highly attractive target for the development of novel therapies for the treatment of various diseases, including cancer. SHP2 inhibitors (e.g., RMC-4550 or SHP099) in combination with RAS pathway inhibitors (e.g., MEK inhibitors) have been shown to inhibit the growth of multiple cancer cell lines (e.g., pancreatic, lung, ovarian, and breast cancer) in vitro. Therefore, combination therapy using SHP2 inhibitors and RAS pathway inhibitors together may be a general strategy to prevent tumor resistance in a wide range of malignancies.

[0415] Non-limiting examples of such SHP2 inhibitors are known in the art and are described in Chen et al. Mol Pharmacol. 2006, 70, 562; Sarver et al., J. Med. Chem. 2017, 62, 1793; Xie et al., J. Med. Chem. 2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734; and PCT applications WO2015107493; WO2015107494; WO201507495; WO2016203404; WO2016203405; WO2016203406; WO2011022440; WO2017156397; 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 WO2018013597; WO2018129402; WO2018130928; WO20181309928; WO2018136264; WO2018136265; WO2018160731; WO2018172984; and WO2010121212, each of which is incorporated herein by reference.

[0416] In some embodiments, the SHP2 inhibitor binds to the active site. In some embodiments, the SHP2 inhibitor is a mixed, irreversible inhibitor. In some embodiments, the SHP2 inhibitor binds to an allosteric site, e.g., 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.

[0417] In some embodiments, the additional therapeutic agent is selected from the group consisting of a HER2 inhibitor, an SHP2 inhibitor, a CDK4 / 6 inhibitor, an mTOR inhibitor, an SOS1 inhibitor, or a PD-L1 inhibitor. See, e.g., 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 additional therapeutic agent is selected from the group consisting of an EGFR inhibitor, a second Ras inhibitor, an SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, and a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof. In some embodiments, the additional therapeutic agent is a second Ras inhibitor and a PD-L1 inhibitor (i.e., triplet therapy).

[0418] The compounds described herein can be used in combination with other suitable agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure are co-administered with other agents, such as those described above. When used in combination therapy, the compounds described herein are administered simultaneously with the second agent or separately. This combined administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the aforementioned agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present disclosure and any of the aforementioned agents can be administered simultaneously, with both agents being in separate formulations. In another alternative, the compounds of the present disclosure can be administered followed immediately by administration of any of the aforementioned agents, or vice versa. In some embodiments of the separate administration protocol, the compounds of the present disclosure and any of the aforementioned agents are administered within minutes, hours, or days of each other.

[0419] Because one aspect of the present invention contemplates treating a disease / condition using a combination of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in the form of a kit. The kit includes two separate pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit includes a container for housing the separate compositions, such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes 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 dosage intervals, or when titration of the individual components of the combination is desired by the prescribing healthcare professional.

[0420] Furthermore, it should be understood that any embodiment of the present invention within the scope of the prior art can be clearly excluded from any one or more of the claims.Such an embodiment can be excluded even if the exclusion is not explicitly stated herein, because it is considered to be known to those skilled in the art.Any embodiment of the composition of the present invention can be excluded from any one or more of the claims for any reason, regardless of whether it is related to the existence of prior art.

[0421] Numbered Embodiments [1] A compound having the structure of Formula I: ALB Formula I wherein A is a Ras-binding moiety; L is a linker, B is a selective bridging group. or a pharmaceutically acceptable salt thereof; The compound, or a pharmaceutically acceptable salt thereof, wherein when the compound, or a pharmaceutically acceptable salt thereof, contacts a sample containing Ras protein, at least 20% of the Ras protein in the sample covalently reacts with the compound, or a pharmaceutically acceptable salt thereof, to form a conjugate.

[0422] [2] The compound of paragraph [1], or a pharmaceutically acceptable salt thereof, wherein the Ras protein in the sample is human H-Ras, human N-Ras, human K-Ras, or a combination thereof.

[0423] [3] The compound according to paragraph [1] or [2], or a pharmaceutically acceptable salt thereof, wherein the Ras protein in the sample is a mutant Ras protein. [4] The compound of paragraph [1], or a pharmaceutically acceptable salt thereof, wherein the Ras-binding moiety is a human H-Ras-binding moiety, a human N-Ras-binding moiety, or a human K-Ras-binding moiety.

[0424] [5] A compound described in any one of paragraphs [2] to [4], or a pharmaceutically acceptable salt thereof, wherein the Ras binding moiety is a K-Ras binding moiety and the Ras protein in the sample is a K-Ras protein.

[0425] [6] The compound of paragraph [5], or a pharmaceutically acceptable salt thereof, wherein the K-Ras binding moiety interacts with a residue in the K-Ras Switch-II binding pocket of the K-Ras protein.

[0426] [7] The compound of paragraph [6], or a pharmaceutically acceptable salt thereof, wherein the residues of the K-Ras Switch-II binding pocket are residues of the K-Ras protein corresponding to V7, V8, V9, G10, A11, D12, K16, P34, T58, A59, G60, Q61, E62, E63, Y64, S65, R68, D69, Y71, M72, F78, I92, H95, Y96, Q99, I100, R102, or V103 of human wild-type K-Ras (SEQ ID NO: 1).

[0427] [8] A compound described in any one of paragraphs [5] to [7], or a pharmaceutically acceptable salt thereof, wherein the K-Ras binding moiety has a structure of any one of formulas II to V. [9] The compound of paragraph [8], wherein the K-Ras binding moiety has the structure of Formula II, or a pharmaceutically acceptable salt thereof:

[0428] [ka]

[0429] wherein m is 0, 1, 2, or 3; W 1 is N or C, and C is optionally attached to said linker via an optionally substituted C-C alkylene bridge or an optionally substituted C-C heteroalkylene bridge; Each R 1are independently CN, halo, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 1 is attached to the linker via a C1-C3 alkylene bridge or a C1-C3 heteroalkylene bridge, and R 2 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl.

[10] The compound of paragraph [9], wherein the K-Ras binding moiety has the structure of formula II-1, or a pharmaceutically acceptable salt thereof:

[0430] [ka]

[0431] wherein m is 0, 1, 2, or 3; Each R 1 are independently CN, halo, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 1 is attached to the linker via a C1-C3 alkylene bridge or a C1-C3 heteroalkylene bridge, and R 2 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl.

[11] The compound of paragraph

[10] , having the following structure:

[0432] [ka]

[0433] [In the formula, W 2 is hydrogen or hydroxy.

[12] The compound of paragraph [9], wherein the K-Ras binding moiety has the structure of formula II-2, or a pharmaceutically acceptable salt thereof:

[0434] [ka]

[0435] wherein m is 0, 1, 2, or 3; W 1 is C attached to the linker via an optionally substituted C-C alkylene bridge or an optionally substituted C-C heteroalkylene bridge; Each R 1 are independently CN, halo, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 1 is attached to the linker via a C1-C3 alkylene bridge or a C1-C3 heteroalkylene bridge, and R 2 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl.

[13] The compound of paragraph [8], wherein the K-Ras binding moiety has the structure of Formula III, or a pharmaceutically acceptable salt thereof:

[0436] [ka]

[0437] wherein n is 0, 1, 2, 3, 4, 5, or 6;

[0438] [ka]

[0439] represents a single or double bond, X is N or CR', and R' is hydrogen, or R' is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; V is CHR 5 , C.R. 5 R 5 , OR 5 , NHR 5 , or NR 5a R 5b and Each R 3 is independent,

[0440] [ka]

[0441] optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; or R 3 is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; R 4 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl; Each R 5 is independently an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted —C1-C6 alkyl-C2-C9 heteroaryl, or an optionally substituted —C1-C6 alkyl-C2-C9 heterocyclyl, and Each R 5a and R 5b are independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted —C1-C6 alkyl-C2-C9 heteroaryl, or optionally substituted —C1-C6 alkyl-C2-C9 heterocyclyl; or R 5a and R 5bcombine with the nitrogen atom to which they are attached to form an optionally substituted C2-C9 heterocyclyl; provided that when R' is attached to said linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, R 3 is not attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; and Furthermore, however, R 3 is attached to said linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, then R' is not attached to said linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge.

[14] The compound of paragraph

[13] , wherein the K-Ras binding moiety has the structure of formula III-1, or a pharmaceutically acceptable salt thereof:

[0442] [ka]

[0443] wherein n is 0, 1, 2, 3, 4, 5, or 6; X is N or CR', and R' is hydrogen, or R' is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; V is CHR 5 , C.R. 5 R 5 , OR 5 , NHR 5 , or NR 5a R 5b and Each R 3 are independently optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; or R 3is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; R 4 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl; Each R 5 is independently an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted —C1-C6 alkyl-C2-C9 heteroaryl, or an optionally substituted —C1-C6 alkyl-C2-C9 heterocyclyl, and Each R 5a and R 5b is independently an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted —C1-C6 alkyl-C2-C9 heteroaryl, or an optionally substituted —C1-C6 alkyl-C2-C9 heterocyclyl; provided that when R' is attached to said linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, R 3 is not attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; and Furthermore, however, R 3 is attached to said linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, then R' is not attached to said linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge.

[15] The compound of paragraph

[14] , wherein the K-Ras binding moiety has the structure of formula III-1a, or a pharmaceutically acceptable salt thereof:

[0444] [ka]

[0445] wherein n is 0, 1, 2, 3, 4, 5, or 6; V is CHR 5 , C.R. 5 R 5 , OR 5 , NHR 5 , or NR 5a R 5b and Each R 3 are independently optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; or R 3 is attached to the linker via a C1-C3 alkylene bridge or a C1-C3 heteroalkylene bridge; R 4 is an optionally substituted C6-C 10 aryl, or C2-C9 heteroaryl; Each R 5 are independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 alkyl-C2-C9 heteroaryl, or optionally substituted C1-C6 alkyl-C2-C9 heterocyclyl, and Each R 5a and R 5b are independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted -C1-C6 alkyl-C2-C9 heteroaryl, or optionally substituted -C1-C6 alkyl-C2-C9 heterocyclyl.

[16] The compound of paragraph

[13] , wherein the K-Ras binding moiety has the structure of formula III-2, or a pharmaceutically acceptable salt thereof:

[0446] [ka]

[0447] wherein n is 0, 1, 2, or 3; X is N or CR', and R' is hydrogen, or R' is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; V is CHR 5 , C.R. 5 R 5 , OR 5 , NHR 5 , or NR 5a R 5b and Each R 3 teeth

[0448] [ka]

[0449] and R 4 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl; Each R 5 is independently an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted —C1-C6 alkyl-C2-C9 heteroaryl, or an optionally substituted —C1-C6 alkyl-C2-C9 heterocyclyl, and Each R 5a and R 5b are independently optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted —C1-C6 alkyl-C2-C9 heteroaryl, or optionally substituted —C1-C6 alkyl-C2-C9 heterocyclyl; or R 5a and R 5b combine with the nitrogen atom to which they are attached to form an optionally substituted C2-C9 heterocyclyl; provided that when R' is attached to said linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, R 3is not attached to said linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge.

[17] The compound of paragraph

[13] , wherein the K-Ras binding moiety has the structure of formula III-3, or a pharmaceutically acceptable salt thereof:

[0450] [ka]

[0451] wherein n is 0, 1, 2, 3, 4, 5, or 6;

[0452] [ka]

[0453] represents a single or double bond, X is N or CR', and R' is hydrogen, or R' is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; V is NR 5a R 5b and Each R 3 is independent,

[0454] [ka]

[0455] optionally substituted C1-C6 alkyl or optionally substituted C1-C6 heteroalkyl; or R 3 is attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; R 4 is an optionally substituted C6-C 10aryl, or optionally substituted C2-C9 heteroaryl; R 5a and R 5b combine with the nitrogen atom to which they are attached to form an optionally substituted C2-C9 heterocyclyl; provided that when R' is attached to said linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, R 3 is not attached to the linker via an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge; and Furthermore, however, R 3 is attached to said linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge, then R' is not attached to said linker through an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge.

[18] R 4 but

[0456] [ka]

[0457] The compound according to any one of paragraphs

[13] to

[17] , or a pharmaceutically acceptable salt thereof.

[19] R 4 but

[0458] [ka]

[0459] The compound according to any one of paragraphs

[13] to

[17] , or a pharmaceutically acceptable salt thereof.

[20] V

[0460] [ka]

[0461] The compound according to any one of paragraphs

[13] to

[19] , or a pharmaceutically acceptable salt thereof.

[21] The compound according to any one of paragraphs

[13] to

[18] , wherein formula III has the following structure:

[0462] [ka]

[0463]

[22] The compound of paragraph [8], wherein the K-Ras binding moiety has the structure of formula IV, or a pharmaceutically acceptable salt thereof:

[0464] [ka]

[0465] wherein o is 0, 1, or 2; X 1 , X 2 , and X 3 are each independently N, CH, or CR 6 and Each R 6 are independently halo, CN, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 6 is attached to the linker via a C1-C3 alkyl bridge or a C1-C3 heteroalkyl bridge, and R 7 and R 8 are independently an optionally substituted C-C 10 aryl, or optionally substituted C2-C9 heteroaryl.

[23] X 1 , X 2 , and X 3 or a pharmaceutically acceptable salt thereof.

[0466]

[24] The compound of paragraph

[22] or

[23] , wherein Formula IV has the following structure: or a pharmaceutically acceptable salt thereof.

[0467] [ka]

[0468]

[25] The compound of paragraph [8], wherein the K-Ras binding moiety has the structure of Formula V, or a pharmaceutically acceptable salt thereof:

[0469] [ka]

[0470] wherein p is 0, 1, 2, or 3; R 9 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl; Each R 10 are independently halo, CN, hydroxy, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl, or R 10 is attached to the linker via a C1-C3 alkylene bridge or a C1-C3 heteroalkylene bridge, and R 11 is an optionally substituted C2-C9 heteroaryl or an optionally substituted C2-C9 heterocyclyl.

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

[25] , or a pharmaceutically acceptable salt thereof, wherein the linker positions the reactive atom of B at a position about 0.5 to about 1.1 nm (about 5 to about 11 angstroms) from the nearest atom of A.

[0471]

[27] The compound of any one of paragraphs 1 to 29, or a pharmaceutically acceptable salt thereof, wherein the linker positions the reactive atom of B 4 to 9 atoms from the nearest atom of A.

[0472]

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

[27] , wherein the linker has the structure of formula VI, or a pharmaceutically acceptable salt thereof: A 1 -(B 1 ) a -(C 1 ) b -(B 2 ) c -(D)-(B 3 ) d -(C 2 ) e -(B 4 ) f -A 2 Equation VI [In the formula, A 1 is the bond between the linker and the Ras binding moiety, A 2 is the bond between the selective crosslinking group and the linker; B 1 , B 2 , B 3 , and B 4 are each independently an optionally substituted C1-C2 alkylene, an optionally substituted C1-C3 heteroalkylene, O, S, and NR N Selected from R N is hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C 6-12 Aryl, or optionally substituted C 1-7 is heteroalkyl, C 1 and C 2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; a, b, c, d, e, and f are each independently 0 or 1; and D is an optionally substituted C 1-10 Alkylene, optionally substituted C 2-10 Alkenylene, optionally substituted C 2-10 Alkynylene, optionally substituted C 2-6 Heterocyclylene, optionally substituted C 2-6 Heteroarylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 6-12 Arylene, optionally substituted C-C 10 Polyethylene glycol or optionally substituted C 1-10 heteroalkylene, or A 1 -(B 1 ) a -(C 1 ) b -(B 2 ) c -(B 3 ) d -(C 2 ) e -(B 4 ) f -A 2 It is a chemical bond that connects

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

[28] , or a pharmaceutically acceptable salt thereof, wherein the linker comprises a 3- to 8-membered heterocyclyl group:

[30] The compound of paragraph

[29] , wherein ALB has the structure of formula VIIa or VIIb, or a pharmaceutically acceptable salt thereof:

[0473] [ka]

[0474] wherein q and r are independently 0, 1, or 2; X 1 is N or CH, R 12 and R 13are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, and R 14 is hydrogen, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 14 optionally includes a bond to A.

[0475]

[31] ALB,

[0476] [ka]

[0477] The compound according to paragraph

[30] , or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [In the formula, R x is an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge attached to A.

[32] -LB is

[0478] [ka]

[0479] The compound according to paragraph [1], or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[33] ALB

[0480] [ka]

[0481] The compound according to paragraph

[31] , or a pharmaceutically acceptable salt thereof.

[34] The compound of paragraph

[29] , wherein ALB has the structure of formula VIIc or VIId, or a pharmaceutically acceptable salt thereof:

[0482] [ka]

[0483] wherein s, t, u, and v are independently 0, 1, or 2; X 3 is N or CH, and R 15 and R 16 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl.

[35] ALB

[0484] [ka]

[0485] The compound according to paragraph

[34] , or a pharmaceutically acceptable salt thereof,

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

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

[0486]

[37] The compound of paragraph

[36] , wherein the linker has the structure of formula VIII, or a pharmaceutically acceptable salt thereof:

[0487] [ka]

[0488] [In the formula, R 17 is hydrogen or optionally substituted C1-C6 alkyl, and L 2 is an optionally substituted C1-C4 alkylene or an optionally substituted C3-C6 cycloalkylene.

[38] The linker is

[0489] [ka]

[0490] The compound according to paragraph

[37] , or a pharmaceutically acceptable salt thereof, selected from the group consisting of: [In the formula, R y is an optionally substituted C1-C3 alkylene bridge or an optionally substituted C1-C3 heteroalkylene bridge attached to A.

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

[38] , or a pharmaceutically acceptable salt thereof, wherein the selective crosslinking group is a CO bond-forming selective crosslinking group.

[0491]

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

[39] , or a pharmaceutically acceptable salt thereof, wherein the selective crosslinking group comprises a carbodiimide, an aminooxazoline, a chloroethylurea, an aziridine, a trifluoromethyl ketone, a boronic acid, a boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an isoEEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal.

[0492]

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

[40] , wherein the selective bridging group has a structure of formula IX, or a pharmaceutically acceptable salt thereof:

[0493] [ka]

[0494] [In the formula, R 18 is an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl.

[42] The selective crosslinking group

[0495] [ka]

[0496] The compound according to paragraph

[31] , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

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

[40] , wherein the selective bridging group has a structure of formula Xa or Xb, or a pharmaceutically acceptable salt thereof:

[0497] [ka]

[0498] [In the formula, X 5 is O or S, X 5’ is O or S, X 5a is not present or NR 19 and X 5a’ is N, said N being a ring atom of an optionally substituted C2-C9 heterocyclyl group; R 19 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; and R 20 , R 21 , R 22 , R 23 , R 20’ , R 21’ , R 22’ , and R 23’ are independently hydrogen or optionally substituted C1-C6 alkyl.

[44] The selective crosslinking group

[0499] [ka]

[0500] The compound according to paragraph

[43] , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

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

[40] , wherein the selective bridging group has a structure of formula XIa or formula XIb, or a pharmaceutically acceptable salt thereof:

[0501] [ka]

[0502] [In the formula, X 6 is O or S, X 6’ is O or S, X 6a is not present or NR 24 and X 6a’ is N, said N being a ring atom of an optionally substituted C2-C9 heterocyclyl group; X 7 and X 7’ are O, S, or NR, respectively. 29 and R 24 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; and R 25 , R 26 , R 27 , R 28 , R 29 , R 25’ , R 26’ , R 27’ , and R 28’ are independently hydrogen or optionally substituted C1-C6 alkyl.

[46] The selective crosslinking group

[0503] [ka]

[0504] The compound according to paragraph

[45] , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

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

[40] , wherein the selective bridging group has a structure of formula XIIa, XIIb, XIIc, XIId, or XIIe, or a pharmaceutically acceptable salt thereof:

[0505] [ka]

[0506] wherein X is absent or NR 30 and X' is N, said N being a ring atom of an optionally substituted C2-C9 heterocyclyl group; Y is C(O), C(S), SO, or optionally substituted C-C alkyl; Z' is C(O) or SO2; Z'' is -CH2- or C(O), q is 0, 1, or 2; Each R x are independently hydrogen, CN, C(O)R y , CO2R y , C(O)NR y R y , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; Each R y are independently hydrogen, optionally substituted C-C alkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; R z is hydrogen or CH3, R 30 is hydrogen or optionally substituted C1-C6 alkyl; R 31is hydrogen, -C(O)R32, -SO2R 33 , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; and R 32 and R 33 are independently hydrogen, optionally substituted C-C alkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl.

[48] ​​R31 and R x or a pharmaceutically acceptable salt thereof.

[0507]

[49] R 31 is CH3, C(O)CH3, SO2CH3, CH2-C6H5, or CH2CH2OCH3, or a pharmaceutically acceptable salt thereof.

[0508]

[50] The selective crosslinking group

[0509] [ka]

[0510] The compound according to paragraph

[47] , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[51] The selective crosslinking group

[0511] [ka]

[0512] The compound according to paragraph

[40] , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[52] The selective crosslinking group

[0513] [ka]

[0514] The compound according to paragraph

[40] , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[53] The selective crosslinking group

[0515] [ka]

[0516] The compound according to paragraph

[40] , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[54]

[0517] [ka]

[0518] The compound according to paragraph

[40] , or a pharmaceutically acceptable salt thereof, selected from:

[55] The compound of paragraph

[40] , having the structure of Formula XXIV, or a pharmaceutically acceptable salt thereof:

[0519] [ka]

[0520] [In the formula, R 31 is absent, hydrogen, C(O)CH3, SO2CH3, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C3 alkyl-C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C1-C3 alkyl-C2-C9 heterocyclyl; R 56 is CH3 or Cl, Rz is hydrogen, optionally substituted C1-C3 alkyl, Each R x are independently hydrogen, CO2CH3, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, and Z''' is N or O.]

[56] The compound of paragraph

[40] or

[55] , having the structure of formula XIII, or a pharmaceutically acceptable salt thereof:

[0521] [ka]

[0522] [In the formula, R 31 is hydrogen, CH3, C(O)CH3, SO2CH3, CH2-C6H5, or CH2CH2OCH3.]

[57] The compound of paragraph

[40] or

[55] , having the structure of Formula XXV, or a pharmaceutically acceptable salt thereof:

[0523] [ka]

[0524] [In the formula, R 31 is absent, hydrogen, C(O)CH3, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C 10 Aryl, optionally substituted C1-C3 alkyl-C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C1-C3 alkyl-C2-C9 heterocyclyl; R zis hydrogen, optionally substituted C1-C3 alkyl, R x is hydrogen, CO2CH3, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, optionally substituted C2-C6 alkenyl, or optionally substituted C2-C6 alkynyl, and Z''' is N or O.]

[58] The selective crosslinking group

[0525] [ka]

[0526] [ka]

[0527] The compound according to any one of paragraphs [1] to

[40] , or a pharmaceutically acceptable salt thereof.

[59] The selective crosslinking group

[0528] [ka]

[0529] The compound according to any one of paragraphs [1] to

[40] , or a pharmaceutically acceptable salt thereof.

[60] Selective crosslinking

[0530] [ka]

[0531] The compound according to any one of paragraphs [1] to

[40] , or a pharmaceutically acceptable salt thereof.

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

[40] , wherein the selective bridging group has the structure of formula XIV, or a pharmaceutically acceptable salt thereof:

[0532] [ka]

[0533] [In the formula, R 34 and R 35 is independently an optionally substituted C1-C6 alkyl, or R 34 and R 35 combine with the boron to which they are attached to form an optionally substituted heterocyclyl.

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

[40] , wherein the selective bridging group has a structure of formula XV, or a pharmaceutically acceptable salt thereof:

[0534] [ka]

[0535] wherein w is 1 or 2; R 36 is hydrogen or optionally substituted C1-C6 alkyl, and Each R 37 and R 38 are independently hydrogen or optionally substituted C1-C6 alkyl.

[63] The selective crosslinking group

[0536] [ka]

[0537] The compound according to paragraph

[61] or

[62] , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

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

[40] , wherein the selective bridging group has the structure of formula XVI, or a pharmaceutically acceptable salt thereof:

[0538] [ka]

[0539] [In the formula, X 8 Does not exist or is O, S, NR 40 , or CH2, X 9 O, NR 41 , S, S(O), or S(O)2; R 39 is an optionally substituted C1-C6 alkyl, and R 40 and R 41 are independently hydrogen or optionally substituted C1-C6 alkyl.

[65] The selective crosslinking group

[0540] [ka]

[0541] The compound according to paragraph

[64] , or a pharmaceutically acceptable salt thereof,

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

[40] , wherein the selective bridging group has a structure of formula XVII, or a pharmaceutically acceptable salt thereof:

[0542] [ka]

[0543] [In the formula, X 10 Does not exist or is O, S, NR 43 , or CH2, X 11 O, NR 44 , S, S(O), or S(O)2; R 42 is an optionally substituted C1-C6 alkyl, and R 43 and R 44are independently hydrogen or optionally substituted C1-C6 alkyl.

[67] The selective crosslinking group

[0544] [ka]

[0545] The compound according to paragraph

[66] , or a pharmaceutically acceptable salt thereof,

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

[40] , wherein the selective bridging group has a structure of formula XVIII, or a pharmaceutically acceptable salt thereof:

[0546] [ka]

[0547] [In the formula, R 45 is hydrogen or optionally substituted C1-C6 alkyl.

[69] The selective crosslinking group

[0548] [ka]

[0549] The compound according to paragraph

[68] , or a pharmaceutically acceptable salt thereof,

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

[40] , wherein the selective bridging group has a structure of formula XIX, or a pharmaceutically acceptable salt thereof:

[0550] [ka]

[0551] [In the formula, R 46 and R 47 are independently hydrogen, optionally substituted C-C alkyl, optionally substituted C-C 10aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl.

[71] The compound of paragraph [1] having the structure of formula XX or XXI, or a pharmaceutically acceptable salt thereof:

[0552] [ka]

[0553] wherein Y is C(O), C(S), SO, or optionally substituted C-C alkyl; Z' is C(O) or SO2; q is 0, 1, or 2; x is 0, 1, 2, or 3, Each R X are independently hydrogen, CN, C(O)R y , CO2R y , C(O)NR y R y , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; Each R y are independently hydrogen, optionally substituted C-C alkyl, optionally substituted C-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; Each R 48 are independently CN, halo, hydroxy, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 49 is an optionally substituted C6-C 10 aryl, or optionally substituted C2-C9 heteroaryl; R 50is hydrogen or C1-C6 alkyl, R 51 is hydrogen, CN, or C1-C6 alkyl; R 54 is hydrogen, —C(O)R32, —SO2R33, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C6-C 10 aryl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl; and R 55 is hydrogen or optionally substituted C1-C6 alkyl.

[72] R 51 , R 54 , and R x

[71] The compound of paragraph

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

[0554]

[73] The compound of paragraph

[71] or

[72] , having the structure of Formula XXII or Formula XXIII, or a pharmaceutically acceptable salt thereof:

[0555] [ka]

[0556] wherein X is hydrogen or hydroxy.

[74] A compound having the following structure:

[0557] [ka]

[0558] [ka]

[0559] [ka]

[0560] [ka]

[0561] [ka]

[0562] [ka]

[0563] [ka]

[0564] [ka]

[0565] [ka]

[0566] [ka]

[0567]

[75] A compound having the structure set forth in any one of Examples 63-95 of Table 2b, or a pharmaceutically acceptable salt thereof.

[76] A compound having the structure set forth in any one of Examples 96-104 of Table 2c, or a pharmaceutically acceptable salt thereof.

[0568]

[77] A compound having the structure set forth in any one of Examples 105-180 of Table 2d, or a pharmaceutically acceptable salt thereof.

[78] A compound having the structure set forth in any one of Examples 181-216 of Table 2e, or a pharmaceutically acceptable salt thereof.

[0569]

[79] A compound having the structure set forth in any one of Examples 217-300 in Table 2f, or a pharmaceutically acceptable salt thereof.

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

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

[0570]

[81] A conjugate or salt thereof comprising a Ras protein covalently bound to a selective cross-linking group, wherein the selective cross-linking group is attached to a Ras binding moiety via a linker, and the selective cross-linking group is a carbodiimide, aminooxazoline, chloroethylurea, aziridine, trifluoromethyl ketone, boronic acid, boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, epoxide, oxazolium, or glycal.

[0571]

[82] The conjugate of paragraph

[81] , or a salt thereof, comprising the linker selected from the group consisting of: (a) -A 1 -(B 1 ) a -(C 1 ) b -(B 2 ) c -(D)-(B 3 ) d -(C 2 ) e -(B 4 ) f -A 2 - Equation VI [In the formula, A 1 is the bond between the linker and the Ras binding moiety; A 2 is the bond between the selective crosslinking group and the linker; B 1 , B 2 , B 3 , and B 4 are each independently an optionally substituted C1-C2 alkylene, an optionally substituted C1-C3 heteroalkylene, O, S, and NRN Selected from;R N is hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 2-6 Heterocyclyl, optionally substituted C6- 12 Aryl or optionally substituted C 1-7 Heteroalkyl; C 1 and C 2 are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; a, b, c, d, e, and f are each independently 0 or 1; D is an optionally substituted C1- 10 Alkylene, optionally substituted C 2-10 Alkenylene, optionally substituted C 2-10 Alkynylene, optionally substituted C 2-6 Heterocyclylene, optionally substituted C 2-6 Heteroarylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 6-12 Arylene, optionally substituted C-C 10 Polyethylene glycol or optionally substituted C 1-10 Heteroalkyl, or A 1 -(B 1 ) a -(C 1 ) b -(B 2 ) c A-(B 3 ) d -(C 2 ) e -(B 4 ) f -A 2 It is a chemical bond that connects (b)

[0572] [ka]

[0573] wherein q and r are independently 0, 1, or 2; X 1 and X 2 are independently N or CH; R 12 and R 13 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl, and R 14 is hydrogen, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 14 optionally includes a bond to A. (c)

[0574] [ka]

[0575] wherein s, t, u, and v are independently 0, 1, or 2; X 3 and X 4 are independently N or CH, and R 15 and R 16 are independently hydrogen, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; and (d)

[0576] [ka]

[0577] [In the formula, R 17 is hydrogen or optionally substituted C1-C6 alkyl, and L 2 is an optionally substituted C1-C4 alkylene.

[83] The conjugate or salt according to paragraph

[81] or

[82] , wherein the Ras protein is K-Ras G12D, K-Ras G13D, or K-Ras G12S.

[0578]

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

[81] to

[82] , wherein the linker is attached to the Ras protein via a bond to a carboxyl group of a residue of the Ras protein.

[0579]

[85] The conjugate of paragraph

[83] , or a salt thereof, wherein the carboxyl group of the residue of the Ras protein is the carboxyl group of an aspartic acid residue at a mutated position corresponding to position 12 or 13 of human wild-type K-Ras (SEQ ID NO: 1).

[0580]

[86] A method for producing a conjugate, comprising contacting a Ras protein with a compound described in any one of paragraphs [1] to

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

[80] , under conditions sufficient to covalently react the compound with the Ras protein.

[0581]

[87] The method of paragraph

[86] , wherein the Ras protein is K-Ras G12D, K-Ras G13D, or K-Ras G12S.

[88] A conjugate produced by the method of paragraph

[86] or

[87] .

[0582]

[89] A method for producing a conjugate, the method comprising contacting a Ras protein with a compound described in any one of paragraphs [1] to

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

[80] , under conditions suitable for allowing conjugate formation.

[0583]

[90] The method of paragraph

[89] , wherein the Ras protein is K-Ras G12D, K-Ras G13D, or K-Ras G12S.

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

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

[80] .

[0584]

[92] The method of paragraph

[91] , wherein the cancer is colorectal cancer, non-small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small intestine cancer, ampullary cancer, germ cell cancer, 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.

[0585]

[93] The method of paragraph

[91] or

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

[94] The method of paragraph

[93] , wherein the Ras mutation is K-Ras G12D, K-Ras G13D, or K-Ras G12S.

[0586]

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

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

[80] .

[0587]

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

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

[80] .

[0588]

[97] The method of paragraph

[95] or

[96] , wherein the Ras protein is K-Ras G12D, K-Ras G13D, or K-Ras G12S.

[98] The method of paragraph

[96] or

[97] , wherein the cells are cancer cells.

[0589]

[99] The method of paragraph

[98] , wherein the cancer cells are colorectal cancer cells, non-small cell lung cancer cells, pancreatic cancer cells, appendix cancer cells, melanoma cells, acute myeloid leukemia cells, small intestine cancer cells, ampullary cancer cells, germ cell cancer cells, cervical cancer cells, cancer cells of unknown primary origin, endometrial cancer cells, esophagogastric cancer cells, GI neuroendocrine cancer cells, ovarian cancer cells, sex cord stromal tumor cancer cells, hepatobiliary cancer cells, or bladder cancer cells.

[0590]

[0100] The method or use according to any one of paragraphs

[91] to

[99] , wherein the method further comprises administering an additional anti-cancer therapy.

[0101] The method described in paragraph

[0100] , wherein the additional anticancer treatment is an EGFR inhibitor, a second Ras inhibitor, an SHP2 inhibitor, an SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, or a combination thereof.

[0591]

[0102] The method described in paragraph

[0101] or

[0101] , wherein the additional anti-cancer treatment is an SHP2 inhibitor. [Example]

[0592] The following examples are intended to illustrate the synthesis and use of a representative number of compounds, or pharmaceutically acceptable salts thereof. Accordingly, the examples are intended to illustrate, but not limit, the invention. Additional compounds not specifically exemplified can be synthesized using conventional methods in combination with the methods described herein.

[0593] Shorthand: Ac Acetyl BnNCS Benzyl isothiocyanate Boc tert-butyloxycarbonyl Cbz benzyloxycarbonyl CbzOSu Benzyl (2,5-dioxopyrrolidin-1-yl) carbonate COMU (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholino-carbenium hexafluorophosphate DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DMA N,N-dimethylacetamide DMAP N,N-dimethylamine-4-pyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDC N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide Et Ethyl HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HOBt 1-hydroxybenzotriazole KHMDS Potassium bis(trimethylsilyl)amide m-CPBA meta-chloroperoxybenzoic acid Me methyl MsCl Mesyl chloride MTBE Methyl tert-butyl ether NCS N-chlorosuccinimide NMM N-methylmorpholine n-PrNCS 1-propyl isothiocyanate Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Ph2NTf N-phenyl-bis(trifluoromethanesulfonimide) Pr Propyl RuPhos Dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane T3P Propanephosphonic Anhydride TBAF Tetrabutylammonium fluoride TBDPSCl tert-butyl(chloro)diphenylsilane Tf triflate TFA trifluoroacetic acid THF tetrahydrofuran Trt Trityl TsOH Toluenesulfonic acid Synthesis of intermediate 1-(2S,3S)-1-((S)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylic acid

[0594] [ka]

[0595] Step 1: Synthesis of (S,E)-N-benzylidene-2-methylpropane-2-sulfinamide A solution of (S)-2-methylpropane-2-sulfinamide (2.50 g, 20.6 mmol), titanium ethoxide (9.41 g, 41.25 mmol), and benzaldehyde (2.19 g, 20.7 mmol) was heated at 70 °C for 1 h, cooled, and diluted with HO (250 mL). The aqueous layer was extracted with EtOAc (3 × 80 mL), and the combined organic layers were washed with brine (2 × 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired product (4.3 g, crude), which was used without further purification. LCMS (ESI) m / z: [M+H]C 11 H 15 Calculated value for NOS: 210.10; Measured value 210.2.

[0596] Step 2: Synthesis of ethyl (2S,3S)-1-((S)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylate To a solution of ethyl bromoacetate (798 mg, 4.78 mmol) in THF (15 mL) was added LiHMDS (1 M in THF, 4.78 mL, 4.78 mmol) at −78° C. After 1 h, a solution of (S,E)-N-benzylidene-2-methylpropane-2-sulfinamide (500 mg, 2.39 mmol) in THF (5 mL) was added in small portions over 20 min. The reaction mixture was stirred at −78° C. for 2 h and then quenched by the addition of saturated NH4Cl. The aqueous layer was extracted with EtOAc (3 × 40 mL), and the combined organic layers were washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by reverse-phase chromatography (30→60% MeCN / HO, 0.1% HC02H) gave the desired product (480 mg, 61% yield). LCMS(ESI) m / z:[M+H]C 15 H 21 Calculated value for NO3S: 296.13; Found 296.2.

[0597] Step 3: Synthesis of (2S,3S)-1-((S)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylic acid To a solution of ethyl (2S,3S)-1-((S)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylate (600 mg, 2.03 mmol) in THF (4.0 mL) was added a solution of LiOH (97.2 mg, 4.06 mmol) in HO (4.0 mL) at 0° C. The resulting mixture was stirred for 2 h at 0° C. and then acidified to pH 5 with 1 M HCl. The aqueous layer was extracted with EtOAc (3×40 mL), and the combined organic layers were washed with brine (2×20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired compound (450 mg, crude), which was used without further purification. LCMS (ESI) m / z: [M+H]C 13 H 17 Calculated value for NO3S: 268.10; Found value 268.1.

[0598] Synthesis of intermediate 2-(2R,3R)-1-((R)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylic acid

[0599] [ka]

[0600] Step 1: Synthesis of (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide A solution of (R)-2-methylpropane-2-sulfinamide (2.50 g, 20.6 mmol), titanium tetraethoxide (9.41 g, 41.3 mmol), and benzaldehyde (2.19 g, 20.6 mmol) was heated at 70 °C for 1 h, cooled, and diluted with HO (250 mL). The aqueous layer was extracted with EtOAc (3 × 90 mL), and the combined organic layers were washed with brine (2 × 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired product (4.2 g, crude), which was used without further purification. LCMS (ESI) m / z: [M+H]C 11 H 15 Calculated value for NOS: 210.10; Measured value 210.1.

[0601] Step 2: Synthesis of ethyl (2R,3R)-1-((R)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylate To a solution of ethyl bromoacetate (6.38 g, 38.2 mmol) in THF (150 mL) was added LiHMDS (1 M in THF, 7.19 mL, 42.9 mmol) at −78° C. After 1 h, a solution of (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide (4.0 g, 19.1 mmol) in THF (50 mL) was added in small portions over 20 min. The reaction mixture was stirred at −78° C. for 2 h and then quenched by the addition of saturated NH4Cl. The aqueous layer was extracted with EtOAc (3 × 80 mL), and the combined organic layers were washed with brine (2 × 60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by reverse-phase chromatography (30→60% MeCN / HO, 0.1% HC02H) gave the desired product (3.9 g, 62% yield). LCMS(ESI) m / z:[M+H]C 15H 21 Calculated value for NO3S: 296.13; Found 296.2.

[0602] Step 3: Synthesis of (2R,3R)-1-((R)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylic acid To a solution of ethyl (2R,3R)-1-((R)-tert-butylsulfinyl)-3-phenylaziridine-2-carboxylate (200 mg, 0.677 mmol) in THF (1.5 mL) was added a solution of LiOH (32.4 mg, 1.35 mmol) in HO (1.3 mL) at 0° C. The resulting mixture was stirred for 2 h at 0° C. and then acidified to pH 5 with 1 M HCl. The aqueous layer was extracted with EtOAc (3×20 mL), and the combined organic layers were washed with brine (2×10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired compound (220 mg, crude), which was used without further purification. LCMS (ESI) m / z: [M+H]C 13 H 17 Calculated value for NO3S: 268.10; Found 268.4.

[0603] Synthesis of intermediate 3-(2R,3S)-3-phenylaziridine-2-carboxylic acid

[0604] [ka]

[0605] Step 1: Synthesis of ethyl (2S,3R)-2,3-dihydroxy-3-phenylpropanoate To a solution of ethyl cinnamate (2.0 g, 11.4 mmol) in t-BuOH (35.0 mL) and HO (35.0 mL) at 0 °C, AD-mix-β (15.83 g, 20.32 mmol) and methanesulfonamide (1.08 g, 11.3 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction was cooled to 0 °C and quenched with aqueous KHSO solution. The resulting mixture was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with brine (2 × 90 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography (50% EtOAc / petroleum ether) to give the desired product (2.2 g, 82% yield) as a solid.

[0606] Step 2: Synthesis of ethyl (2S,3R)-3-hydroxy-2-(((4-nitrophenyl)sulfonyl)oxy)-3-phenylpropanoate To a solution of ethyl (2S,3R)-2,3-dihydroxy-3-phenylpropanoate (2.0 g, 9.5 mmol) and EtN (3.97 mL, 28.5 mmol) in DCM (30.0 mL) was added 4-nitrobenzenesulfonyl chloride (2.11 g, 9.51 mmol) at 0 °C. The resulting mixture was stirred for 1 h and then diluted with HO (300 mL). The mixture was extracted with DCM (3 × 100 mL), and the combined organic layers were washed with brine (2 × 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc / petroleum ether) to give the desired product (2.8 g, 67% yield) as a solid.

[0607] Step 3: Synthesis of ethyl (2R,3R)-2-azido-3-hydroxy-3-phenylpropanoate To a solution of ethyl (2S,3R)-3-hydroxy-2-(((4-nitrophenyl)sulfonyl)oxy)-3-phenylpropanoate (2.80 g, 7.08 mmol) in THF (30 mL) at room temperature, trimethylsilyl azide (1.63 g, 14.2 mmol) and TBAF (1 M in THF, 14.16 mL, 14.16 mmol) were added. The reaction mixture was heated to 60 °C and stirred for 16 h. The reaction mixture was then cooled to room temperature, diluted with HO (150 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine. (2×30 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography (50% EtOAc / petroleum ether) to give the desired product (1.2 g, 64% yield) as an oil.

[0608] Step 4: Synthesis of ethyl (2R,3S)-3-phenylaziridine-2-carboxylate To a solution of ethyl (2R,3R)-2-azido-3-hydroxy-3-phenylpropanoate (1.20 g, 5.10 mmol) in DMF (15.0 mL) was added PPh3 (1.61 g, 6.12 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then heated to 80 °C for an additional 16 hours. The reaction mixture was then cooled to room temperature, diluted with HO (100 mL), and extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography (16% EtOAc / petroleum ether) to give the desired product (620 mg, 57% yield) as an oil. LCMS (ESI) m / z: [M+H]C 11 H 13 Calculated value for NO2: 192.10; Measured value 192.0.

[0609] Step 5: Synthesis of (2R,3S)-3-phenylaziridine-2-carboxylic acid To a solution of ethyl (2R,3S)-3-phenylaziridine-2-carboxylate (0.100 g, 0.523 mmol) in MeOH (0.70 mL) was added a solution of LiOH (18.8 mg, 0.784 mmol) in HO (0.70 mL) at 0 °C. The reaction mixture was stirred for 1 h. The mixture was then diluted with MeCN (10 mL), and the resulting precipitate was collected by filtration and washed with MeCN (2 × 10 mL) to give the crude desired product (70 mg) as a solid. LCMS (ESI) m / z: calculated for [M+H]C9H9NO2: 164.07; found 164.0.

[0610] Synthesis of intermediate 4-(2S,3R)-3-phenylaziridine-2-carboxylic acid

[0611] [ka]

[0612] Step 1: Synthesis of ethyl (2R,3S)-2,3-dihydroxy-3-phenylpropanoate To a solution of ethyl cinnamate (2.0 g, 11.4 mmol) in t-BuOH (35.0 mL) and HO (35.0 mL) at 0 °C, AD-mix-α (15.83 g, 20.32 mmol) and methanesulfonamide (1.08 g, 11.3 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction was cooled to 0 °C and quenched with aqueous KHSO solution. The resulting mixture was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with brine (2 × 80 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography (50% EtOAc / petroleum ether) to give the desired product (2.2 g, 82% yield) as a solid.

[0613] Step 2: Synthesis of ethyl (2R,3S)-3-hydroxy-2-(((4-nitrophenyl)sulfonyl)oxy)-3-phenylpropanoate To a solution of ethyl (2R,3S)-2,3-dihydroxy-3-phenylpropanoate (2.10 g, 9.99 mmol) and EtN (4.18 mL, 29.9 mmol) in DCM (30.0 mL) was added 4-nitrobenzenesulfonyl chloride (2.21 g, 9.99 mmol) at 0 °C. The resulting mixture was stirred for 1 h and then diluted with HO (200 mL). The mixture was extracted with DCM (3 × 80 mL), and the combined organic layers were washed with brine (2 × 80 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (50% EtOAc / petroleum ether) to give the desired product (3.0 g, 68% yield) as a solid.

[0614] Step 3: Synthesis of ethyl (2S,3S)-2-azido-3-hydroxy-3-phenylpropanoate To a solution of ethyl (2R,3S)-3-hydroxy-2-(((4-nitrophenyl)sulfonyl)oxy)-3-phenylpropanoate (3.0 g, 7.59 mmol) in THF (30 mL) at room temperature, trimethylsilyl azide (1.75 g, 15.2 mmol) and TBAF (1 M in THF, 15.18 mL, 15.18 mmol) were added. The reaction mixture was heated to 60 °C and stirred for 16 h. The reaction mixture was then cooled to room temperature, diluted with HO (150 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography (50% EtOAc / petroleum ether) to give the desired product (1.4 g, 70% yield) as an oil.

[0615] Step 4: Synthesis of ethyl (2S,3R)-3-phenylaziridine-2-carboxylate To a solution of ethyl (2S,3S)-2-azido-3-hydroxy-3-phenylpropanoate (1.40 g, 5.95 mmol) in DMF (20.0 mL) was added PPh3 (1.87 g, 7.14 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then heated to 80 °C for an additional 16 hours. The reaction mixture was then cooled to room temperature, diluted with HO (150 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (40 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by normal phase chromatography (16% EtOAc / petroleum ether) to give the desired product (720 mg, 56% yield) as an oil. LCMS (ESI) m / z: [M+H]C 11 H 13 Calculated value for NO2: 192.10; Measured value 192.0.

[0616] Step 5: Synthesis of (2S,3R)-3-phenylaziridine-2-carboxylic acid To a solution of ethyl (2S,3R)-3-phenylaziridine-2-carboxylate (0.100 g, 0.523 mmol) in MeOH (0.70 mL) was added a solution of LiOH (18.8 mg, 0.784 mmol) in HO (0.70 mL) at 0 °C. The reaction mixture was stirred for 1 h. The mixture was then diluted with MeCN (10 mL), and the resulting precipitate was collected by filtration and washed with MeCN (2 × 10 mL) to give the crude desired product (68 mg) as a solid. LCMS (ESI) m / z: calculated for [M+H]C9H9NO2: 164.07; found 164.0.

[0617] Synthesis of intermediate 5-(2R,3R)-1-((R)-tert-butylsulfinyl)-3-methylaziridine-2-carboxylic acid

[0618] [ka]

[0619] Step 1: Synthesis of (R,E)-N-ethylidene-2-methylpropane-2-sulfinamide To a solution of (R)-2-methylpropane-2-sulfinamide (3.0 g, 24.75 mmol) and tetraethoxytitanium (1.7 g, 7.43 mmol) in THF (30 mL) was added acetaldehyde (218.1 mg, 4.95 mmol) at 0 °C. The resulting mixture was stirred for 20 min and then quenched with HO (100 mL). The suspension was filtered, and the filter cake was washed with EtOAc (3 × 100 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with brine (3 × 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by normal phase chromatography (9% EtOAc / petroleum ether) afforded the desired product (3 g, 82% yield). LCMS (ESI) m / z: [M+H]CH 13 Calculated value for NOS: 148.08; Found 148.0.

[0620] Step 2: Synthesis of ethyl (2R,3R)-1-((R)-tert-butylsulfinyl)-3-methylaziridine-2-carboxylate Ethyl bromoacetate (6.80 g, 40.75 mmol) was added to a solution of 1 M LiHMDS (40.75 mL, 40.75 mmol) in THF (30.0 mL) at −78° C. The resulting mixture was stirred for 1 h. Next, (R,E)-N-ethylidene-2-methylpropane-2-sulfinamide (3.0 g, 20.38 mmol) was added to the reaction mixture. The resulting mixture was stirred at −78° C. for 2 h and then quenched with HO (300 mL). The aqueous layer was extracted with EtOAc (3 × 300 mL), and the combined organic layers were washed with brine (3 × 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (10→50% MeCN / HO) to give the desired product (1.4 g, 29.5% yield). LCMS(ESI) m / z:[M+H]C 10 H 19 Calculated value for NO3S: 234.12; Found 234.1.

[0621] Step 3: Synthesis of (2R,3R)-1-((R)-tert-butylsulfinyl)-3-methylaziridine-2-carboxylic acid To a solution of ethyl (2R,3R)-1-((R)-tert-butylsulfinyl)-3-methylaziridine-2-carboxylate (1.0 g, 4.29 mmol) in THF (6.4 mL) and HO (6.4 mL) at 0 °C was added LiOH·HO (539.5 mg, 12.86 mmol). The resulting mixture was warmed to room temperature and stirred for 2 h, then neutralized to pH 5 with HCl (aq) and saturated NH4Cl (aq). The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude desired product (489 mg, 55.6% yield). LCMS (ESI) m / z: [M+H]CH 15 Calculated value for NO3S: 206.09; Found value 206.0.

[0622] Synthesis of intermediate 6-(2S,3S)-1-((S)-tert-butylsulfinyl)-3-methylaziridine-2-carboxylic acid

[0623] [ka]

[0624] Step 1: Synthesis of (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide Acetaldehyde (3.63 g, 82.51 mmol) was added to a mixture of (S)-2-methylpropane-2-sulfinamide (5.0 g, 41.25 mmol) and tetraethoxytitanium (18.82 g, 82.51 mmol) at 0 °C. The resulting mixture was warmed to room temperature and stirred for 30 min before being quenched with HO (100 mL). The suspension was filtered and the filter cake was washed with EtOAc (3 × 100 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with brine (3 × 100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired crude product (3.9 g, 64% yield). LCMS (ESI) m / z: [M+H]CH13 Calculated value for NOS: 148.08; Found 148.2.

[0625] Step 2: Synthesis of ethyl (2S,3S)-1-((S)-tert-butylsulfinyl)-3-methylaziridine-2-carboxylate Ethyl bromoacetate (6.80 g, 40.75 mmol) was added to a solution of 1 M LiHMDS (40.75 mL, 40.75 mmol) in THF (30.0 mL) at −78° C. The resulting mixture was stirred for 1 h. Next, (S,E)-N-ethylidene-2-methylpropane-2-sulfinamide (3.0 g, 20.38 mmol) was added to the reaction mixture. The resulting mixture was stirred at −78° C. for 2 h and then quenched with HO. The aqueous layer was extracted with EtOAc (3×200 mL), and the combined organic layers were washed with brine (3×300 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (10→50% MeCN / HO) to give the desired product (2 g, 42% yield). LCMS (ESI) m / z: [M+H]C 10 H 19 Calculated value for NO3S: 234.12; Found 234.0.

[0626] Step 3: Synthesis of (2S,3S)-1-((S)-tert-butylsulfinyl)-3-methylaziridine-2-carboxylic acid To a solution of ethyl (2S,3S)-1-((S)-tert-butylsulfinyl)-3-methylaziridine-2-carboxylate (80.0 mg, 0.34 mmol) in THF (1.0 mL) and HO (0.2 mL) at 0 °C was added LiOH·HO (32.9 mg, 1.37 mmol). The resulting mixture was warmed to room temperature and stirred for 4 h before being acidified to pH 3 with HCl (aq). The aqueous layer was extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give the crude desired product (70 mg, 99% yield). LCMS (ESI) m / z: [M+H]CH 15 Calculated value for NO3S: 206.09; Found value 206.0.

[0627] Synthesis of intermediate 7-(2R,3R)-3-isopropyl-1-tritylaziridine-2-carboxylic acid

[0628] [ka]

[0629] Step 1: Synthesis of (E)-4-methylpent-2-enoic acid Two batches of malonic acid (25.0 mL, 240 mmol), isobutyraldehyde (34.7 mL, 380 mmol), and pyridine (380 μL, 4.32 mmol) in pyridine (75 mL) were stirred for 24 h, then heated to 115 °C and stirred for 12 h. The combined reaction mixture was poured into H2SO4 (1 M, 800 mL) and extracted into EtOAc (3 × 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in NaOH (1 M, 500 mL), washed with EtOAc (2 × 200 mL), acidified with HCl (4 M) to pH 4-2, and extracted into EtOAc (3 × 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the product (54 g, 98% yield).

[0630] Step 2: Synthesis of benzyl (E)-4-methylpent-2-enoate To a solution of two batches of (£)-4-methylpent-2-enoic acid (6.25 mL, 52.6 mmol) in acetone (90 mL), K2CO3 (13.8 g, 100 mmol) was added, and the mixture was stirred for 30 min. Next, a solution of benzyl bromide (6.31 mL, 53.1 mmol) in acetone (10 mL) was added, and the mixture was heated to 75 °C for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and HO (200 mL) and then extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 → 10% EtOAc / petroleum ether) gave the product (9.0 g, 42% yield).

[0631] Step 3: Synthesis of benzyl (2R,3S)-2,3-dihydroxy-4-methylpentanoate To a solution of AD-mix-α (61.7 g) and methanesulfonamide (4.19 g, 44.1 mmol) in tert-BuOH (225 mL) and HO (225 mL) was added benzyl (E)-4-methylpent-2-enoate (9 g, 44.1 mmol). The mixture was stirred at room temperature for 12 h, after which NaSO (67.5 g) was added and stirred for 30 min. The reaction mixture was diluted with EtOAc (300 mL) and HO (300 mL), extracted into EtOAc (3 × 300 mL), washed with brine (300 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 → 25% EtOAc / petroleum ether) gave the product (8.3 g, 79% yield). LCMS (ESI) m / z: [M+Na]C 13 H 18 Calculated value for O4: 261.11; Measured value 261.0.

[0632] Step 4: Synthesis of benzyl (4R,5S)-5-isopropyl-1,3,2-dioxathiolane-4-carboxylate 2-oxide To a solution of benzyl (2R,3S)-2,3-dihydroxy-4-methylpentanoate (10 g, 42.0 mmol) in DCM (100 mL) was added EtN (17.5 mL, 126 mmol) and SOCl (4.26 mL, 58.8 mmol) at 0° C. The reaction mixture was stirred for 30 min, then diluted with DCM (30 mL) and HO (100 mL), extracted with DCM (3 × 50 mL), washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the product (11.0 g, 92% yield).

[0633] Step 5: Synthesis of benzyl (4R,5S)-5-isopropyl-1,3,2-dioxathiolane-4-carboxylate 2,2-dioxide To a solution of benzyl (4R,5S)-5-isopropyl-1,3,2-dioxathiolane-4-carboxylate 2-oxide (11 g, 38.7 mmol) in HO (250 mL), MeCN (125 mL), and CCl (125 mL) was added NaIO (3.22 mL, 58.0 mmol) and RuCl·HO (872 mg, 3.87 mmol). The mixture was stirred at room temperature for 1 h, then diluted with EtOAc (200 mL) and HO (50 mL), filtered, and the filtrate was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed successively with brine (200 mL) and saturated aqueous NaCO (300 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 → 17% EtOAc / petroleum ether) gave the product (11 g, 95% yield).

[0634] Step 6: Synthesis of benzyl (2S,3S)-2-bromo-3-hydroxy-4-methylpentanoate To a solution of benzyl (4R,5S)-5-isopropyl-1,3,2-dioxathiolane-4-carboxylate 2,2-dioxide (11 g, 36.6 mmol) in THF (520 mL) was added LiBr (3.49 mL, 139 mmol). The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. The residue was diluted in THF (130 mL) and HO (65 mL) and cooled to 0 °C. HSO solution (20% aqueous, 1.3 L) was added, and the mixture was allowed to warm to room temperature and stirred for 24 h. The mixture was diluted with EtOAc (1.0 L), extracted into EtOAc (2 × 300 mL), washed successively with NaCO (saturated aqueous, 300 mL) and brine (300 mL), and then concentrated under reduced pressure. Purification by silica gel chromatography (0 → 17% EtOAc / petroleum ether) gave the product (10 g, 81% yield).

[0635] Step 7: Synthesis of benzyl (2R,3S)-2-azido-3-hydroxy-4-methylpentanoate To a solution of benzyl (2S,3S)-2-bromo-3-hydroxy-4-methylpentanoate (10 g, 33.2 mmol) in DMSO (100 mL) was added NaN (4.32 g, 66.4 mmol). The reaction mixture was stirred at room temperature for 12 h and then diluted with EtOAc (300 mL) and HO (200 mL). The aqueous phase was extracted with EtOAc (2 × 200 mL), washed with brine (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 → 17% EtOAc / petroleum ether) gave the product (7.5 g, 79% yield).

[0636] Step 8: Synthesis of benzyl (2R,3R)-3-isopropylaziridine-2-carboxylate To a solution of benzyl (2R,3S)-2-azido-3-hydroxy-4-methylpentanoate (7.5 g, 28.5 mmol) in MeCN (150 mL) was added PPh3 (7.70 g, 29.3 mmol). The reaction mixture was stirred at room temperature for 1 hour, then heated to 70 °C and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (0 → 17% EtOAc / petroleum ether) to give the product (4.5 g, 66% yield). LCMS (ESI) m / z: [M+H] C 13 H 17 Calculated value for NO2: 220.13; Measured value 220.0.

[0637] Step 9: Synthesis of benzyl (2R,3R)-3-isopropyl-1-tritylaziridine-2-carboxylate To a solution of benzyl (2R,3R)-3-isopropylaziridine-2-carboxylate (2 g, 9.12 mmol) in DCM (30 mL) at 0 °C, EtN (3.81 mL, 27.4 mmol) and trityl chloride (3.05 g, 10.9 mmol) were added, followed by DMAP (111 mg, 912 μmol). The reaction mixture was stirred at 0 °C for 1 h, then diluted with DCM (50 mL) and HO (50 mL), and then extracted into DCM (2 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 → 25% DCM / petroleum ether) afforded the product (3.1, 72% yield).

[0638] Step 10: Synthesis of (2R,3R)-3-isopropyl-1-tritylaziridine-2-carboxylic acid A solution of two benzyl (2R,3R)-3-isopropyl-1-tritylaziridine-2-carboxylates (200 mg, 430 μmol) and Pd / C (100 mg) in THF (4 mL) was stirred for 1 h at room temperature under an H atmosphere. The combined reaction mixtures were filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0→50% EtOAc / petroleum ether) afforded the product (160 mg, 51% yield).

[0639] Synthesis of intermediate 8-(2S,3S)-1-benzyl-3-isopropylaziridine-2-carboxylic acid

[0640] [ka]

[0641] Step 1: Synthesis of benzyl (2S,3R)-2,3-dihydroxy-4-methylpentanoate To a solution of AD-mix-β (61.7 g) and methanesulfonamide (4.19 g, 44.1 mmol) in tert-BuOH (225 mL) and HO (225 mL) was added benzyl (E)-4-methylpent-2-enoate (9 g, 44.1 mmol). The mixture was stirred at room temperature for 12 h, after which NaSO (67.5 g) was added and stirred for 30 min. The reaction mixture was diluted with EtOAc (300 mL) and HO (300 mL), extracted into EtOAc (3 × 300 mL), washed with brine (300 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 → 25% EtOAc / petroleum ether) gave the product (8.8 g, 84% yield). LCMS (ESI) m / z: [M+Na]C 13 H 18 Calculated value for O4: 261.11; Measured value 261.0.

[0642] Step 2: Synthesis of benzyl (4S,5R)-5-isopropyl-1,3,2-dioxathiolane-4-carboxylate 2-oxide To a solution of benzyl (2S,3R)-2,3-dihydroxy-4-methylpentanoate (11.6 g, 48.7 mmol) in DCM (116 mL) was added EtN (20.3 mL, 146 mmol) and SOCl (4.94 mL, 68.2 mmol) at 0° C. The reaction mixture was stirred for 30 min, then diluted with DCM (100 mL) and HO (100 mL), extracted with DCM (3 × 100 mL), washed with brine (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the product (13.0 g, 94% yield).

[0643] Step 3: Synthesis of benzyl (4S,5R)-5-isopropyl-1,3,2-dioxathiolane-4-carboxylate 2,2-dioxide To a solution of benzyl (4S,5R)-5-isopropyl-1,3,2-dioxathiolane-4-carboxylate 2-oxide (13 g, 45.7 mmol) in HO (290 mL), MeCN (145 mL), and CCl (145 mL) was added NaIO (3.80 mL, 68.6 mmol) and RuCl·HO (1.03 g, 4.57 mmol). The mixture was stirred at room temperature for 1 h, then diluted with DCM (500 mL) and HO (300 mL), filtered, and the filtrate was extracted into DCM (3 × 200 mL). The combined organic layers were washed successively with brine (500 mL) and saturated aqueous NaCO (300 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0→17% EtOAc / petroleum ether) gave the product (11.5 g, 80% yield).

[0644] Step 4: Synthesis of benzyl (2R,3R)-2-bromo-3-hydroxy-4-methylpentanoate To a solution of benzyl (4S,5R)-5-isopropyl-1,3,2-dioxathiolane-4-carboxylate 2,2-dioxide (11.5 g, 38.3 mmol) in THF (520 mL) was added LiBr (3.65 mL, 146 mmol). The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. The residue was diluted with THF (130 mL) and HO (65 mL) and cooled to 0 °C. HSO solution (20% aqueous, 1.3 L) was added, and the mixture was allowed to warm to room temperature and stirred for 24 h. The mixture was diluted with EtOAc (1.0 L), washed with NaCO (saturated aqueous, 300 mL), and then concentrated under reduced pressure. Purification by silica gel chromatography (0 → 17% EtOAc / petroleum ether) gave the product (10 g, 83% yield).

[0645] Step 5: Synthesis of benzyl (2S,3R)-2-azido-3-hydroxy-4-methylpentanoate To a solution of benzyl (2R,3R)-2-bromo-3-hydroxy-4-methylpentanoate (10 g, 33.2 mmol) in DMSO (100 mL) was added NaN (4.33 g, 66.6 mmol). The reaction mixture was stirred at room temperature for 12 h and then diluted with EtOAc (300 mL) and HO (200 mL). The mixture was extracted with EtOAc (2 × 200 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 → 17% EtOAc / petroleum ether) gave the product (7.5 g, 76% yield).

[0646] Step 6: Synthesis of benzyl (2S,3S)-3-isopropylaziridine-2-carboxylate To a solution of benzyl (2S,3R)-2-azido-3-hydroxy-4-methylpentanoate (7.5 g, 28.5 mmol) in MeCN (150 mL) was added PPh3 (7.70 g, 29.3 mmol). The reaction mixture was stirred at room temperature for 1 hour, then heated to 70 °C and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (0 → 17% EtOAc / petroleum ether) to give the product (4.5 g, 64% yield). LCMS (ESI) m / z: [M+H]C 13 H 17 Calculated value for NO2: 220.13; Found value 220.1.

[0647] Step 7: Synthesis of benzyl (2S,3S)-1-benzyl-3-isopropylaziridine-2-carboxylate To a solution of benzyl (2S,3S)-3-isopropylaziridine-2-carboxylate (1 g, 4.56 mmol) in MeCN (10 mL) was added KCO (3.15 g, 22.8 mmol) and benzyl bromide (812 μL, 6.84 mmol). The reaction mixture was stirred at room temperature for 6 h, then diluted with EtOAc (30 mL) and HO (30 mL), extracted into EtOAc (2 × 30 mL), washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0 → 17% EtOAc / petroleum ether) gave the product (1.3 g, 89% yield). LCMS (ESI) m / z: [M+H]C 20 H 23 Calculated value for NO2: 310.18; Measured value 310.1.

[0648] Step 8: Synthesis of (2S,3S)-1-benzyl-3-isopropylaziridine-2-carboxylic acid To a solution of benzyl (2S,3S)-1-benzyl-3-isopropylaziridine-2-carboxylate (600 mg, 1.94 mmol) in THF (6 mL), MeCN (3 mL), and HO (6 mL) was added LiOH·HO (163 mg, 3.88 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h and adjusted to pH 7-8 with HCl (0.5 M). Lyophilization afforded the product (750 mg, crude). LCMS (ESI) m / z: [M+H] C 13 H 17 Calculated value for NO2: 220.13; Found value 220.1.

[0649] Synthesis of intermediate 9-(2R,3R)-1-((R)-tert-butylsulfinyl)-3-cyclopropylaziridine-2-carboxylic acid

[0650] [ka]

[0651] Step 1: Synthesis of (R,E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide To a solution of (R)-2-methylpropane-2-sulfinamide (1.0 g, 8.25 mmol) and cyclopropanecarbaldehyde (1.16 g, 16.55 mmol) in DCM (50 mL) at room temperature, CuSO4 (3.95 g, 24.75 mmol) was added. The resulting mixture was stirred overnight. The reaction mixture was then filtered, the filter cake was washed with EtOAc, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (17% EtOAc / petroleum ether) to give the desired product (1.4 g, 97.9% yield). LCMS (ESI) m / z:[M+H]CH 15 Calculated value for NOS: 174.10; Found 174.1.

[0652] Step 2: Synthesis of ethyl (2R,3R)-1-((R)-tert-butylsulfinyl)-3-cyclopropylaziridine-2-carboxylate To a solution of 1 M LiHMDS (23 mL, 23 mmol) in THF (50.0 mL) was added ethyl bromoacetate (3.83 g, 22.95 mmol) at −78° C. The resulting mixture was warmed to −70° C. and stirred for 1 h. Next, (R,E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide (2.0 g, 11.48 mmol) was added to the reaction mixture. The resulting mixture was stirred at −70° C. for 1 h. The reaction mixture was warmed to 0° C. and quenched with H2O. The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (25% EtOAc / petroleum ether) to give the desired product (1.8 g, 60.5% yield). LCMS (ESI) m / z: [M+H]C 12 H 21 Calculated value for NO3S: 306.14; Found value 260.13.

[0653] Step 3: Synthesis of (2R,3R)-1-((R)-tert-butylsulfinyl)-3-cyclopropylaziridine-2-carboxylic acid To a solution of ethyl (2R,3R)-1-((R)-tert-butylsulfinyl)-3-cyclopropylaziridine-2-carboxylate (900.0 mg, 3.47 mmol) in THF (3.0 mL) and HO (3.0 mL) at 0 °C was added LiOH·HO (218.4 mg, 5.21 mmol). The resulting mixture was stirred for 1 h and then quenched with HO. The aqueous layer was extracted with EtOAc (3 × 50), and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give the desired crude product (400 mg, 29.9% yield). LCMS (ESI) m / z: [M+H]C 10 H 17 Calculated value for NO3S: 232.10; Found value 232.1.

[0654] Synthesis of intermediate 10-(2S,3S)-1-(tert-butylsulfinyl)-3-cyclopropylaziridine-2-carboxylic acid

[0655] [ka]

[0656] Step 1: Synthesis of (E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide To a suspension of (S)-2-methylpropane-2-sulfinamide (4.0 g, 33.0 mmol) and CuSO (15.80 g, 99.01 mmol) in DCM (200.0 mL) was added cyclopropanecarbaldehyde (4.63 g, 66.0 mmol). The resulting mixture was stirred overnight, filtered, the filter cake washed with DCM (3 × 100 mL), and the filtrate concentrated under reduced pressure to give the desired product (3.5 g, 61.2% yield). LCMS (ESI) m / z: [M+H]CH 15 Calculated value for NOS: 174.10; Found 174.1.

[0657] Step 2: Synthesis of ethyl (2S,3S)-1-(tert-butylsulfinyl)-3-cyclopropylaziridine-2-carboxylate To a solution of ethyl bromoacetate (481.91 mg, 2.886 mmol) in THF (5.0 mL) was added LiHMDS (2.90 mL, 2.90 mmol) at −78° C. After stirring the resulting mixture for 2 h at −78° C., a solution of (E)-N-(cyclopropylmethylene)-2-methylpropane-2-sulfinamide (250.0 mg, 1.443 mmol) was added. After stirring the resulting mixture for 2 h at −78° C., it was quenched with HO at 0° C. The aqueous layer was extracted with EtOAc (3×50 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (17% EtOAc / petroleum ether) to give the desired product (250 mg, 66.8% yield). LCMS (ESI) m / z: [M+H]C 12 H 21 Calculated value for NO3S: 260.13; Found value 260.1.

[0658] Step 3: Synthesis of (2S,3S)-1-(tert-butylsulfinyl)-3-cyclopropylaziridine-2-carboxylic acid To a solution of ethyl (2S,3S)-1-(tert-butylsulfinyl)-3-cyclopropylaziridine-2-carboxylate (500.0 mg, 1.928 mmol) in THF (2.0 mL) and HO (2.0 mL) was added LiOH·HO (121.34 mg, 2.89 mmol) at 0 °C. The reaction mixture was stirred for 1 h and then acidified to pH 6 with 1 M HCl (aq). The resulting mixture was extracted with EtOAc (2 × 10 mL), and the combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give the desired product (400 mg, 89.7%). LCMS (ESI) m / z: [M+H]C 10 H 17 Calculated value for NO3S: 232.10; Found 232.0.

[0659] Synthesis of intermediate 11-(2R,3S)-3-cyclopropylaziridine-2-carboxylic acid

[0660] [ka]

[0661] Step 1: Synthesis of ethyl (2S,3R)-3-cyclopropyl-2,3-dihydroxypropanoate A solution of ethyl (E)-3-cyclopropylacrylate (10.4 mL, 71 mmol) in tert-BuOH (270 mL) and HO (270 mL) was stirred at 0 °C. After 5 min, MsNH (6.8 g, 71 mmol) and (DHQD)PHAL (100 g, 130 mmol) were added, and the reaction mixture was allowed to warm to room temperature. After stirring overnight, saturated NaSO was added, and the mixture was stirred for 30 min. The mixture was acidified to pH 6 with KHPO. Purification by silica gel column chromatography (33% EtOAc / petroleum ether) gave the desired product (5.5 g, 44% yield).

[0662] Step 2: Synthesis of ethyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-(((4-nitrophenyl)sulfonyl)oxy)propanoate A solution of ethyl (2S,3R)-3-cyclopropyl-2,3-dihydroxypropanoate (5.40 g, 31.0 mmol) and EtN (13.0 mL, 93.0 mmol) in DCM (20 mL) was stirred at 0 °C, and a solution of 4-nitrobenzenesulfonyl chloride (6.53 g, 29.5 mmol) in DCM (10 mL) was added. The reaction mixture was stirred for 1.5 h and then extracted with DCM (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (33% EtOAc / petroleum ether) gave the desired product (6.9 g, 62% yield).

[0663] Step 3: Synthesis of ethyl (2R,3R)-2-azido-3-cyclopropyl-3-hydroxypropanoate A mixture of ethyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-(((4-nitrophenyl)sulfonyl)oxy)propanoate (6.90 g, 19.2 mmol) and NaN (6.24 g, 96.0 mmol) in DMF (70.0 mL) was heated to 50 °C. The reaction mixture was stirred for 5 h and then extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (20% EtOAc / petroleum ether) gave the desired product (2.8 g, 73% yield).

[0664] Step 4: Synthesis of ethyl (2R,3S)-3-cyclopropylaziridine-2-carboxylate A mixture of triphenylphosphine (1.84 g, 7.02 mmol) and DMF (5 mL) was stirred at 0 °C. After 5 min, ethyl (2R,3R)-2-azido-3-cyclopropyl-3-hydroxypropanoate (1.40 g, 7.03 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was heated to 80 °C and stirred for 1 h. The mixture was then cooled to room temperature and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (20% EtOAc / petroleum ether) gave the desired product (230 mg, 46% yield). LCMS (ESI) m / z: [M+H]CH 13 Calculated value for NO2: 156.10; Found value 156.2.

[0665] Step 5: Synthesis of lithium (2R,3S)-3-cyclopropylaziridine-2-carboxylate To a mixture of ethyl (2R,3S)-3-cyclopropylaziridine-2-carboxylate (230 mg, 1.5 mmol) and MeOH (3.0 mL) was added LiOH·HO (125 mg, 3.0 mmol). The reaction was stirred for 3 h and then filtered. The filtrate was concentrated under reduced pressure to give the desired product (150 mg, crude). LCMS (ESI) m / z: calculated for [M+H]C6H9NO2: 128.07; found 128.2.

[0666] Synthesis of intermediate 12-(2S,3R)-3-cyclopropylaziridine-2-carboxylic acid

[0667] [ka]

[0668] Step 1: Synthesis of ethyl (2S,3R)-3-cyclopropylaziridine-2-carboxylate A mixture of PPh3 (1.4 g, 5.4 mmol) and DMF (15.0 mL) was stirred at 0 °C. After 30 min, ethyl (2S,3S)-2-azido-3-cyclopropyl-3-hydroxypropanoate (980 mg, 4.92 mmol) was added. The reaction mixture was heated to 80 °C. After 2 h, the reaction was quenched by adding HO (20 mL) and extracted with EtOAc (3 × 30 mL). Purification by silica gel column chromatography (17% EtOAc / petroleum ether) gave the desired product (500 mg, 65% yield).

[0669] Step 2: Synthesis of lithium (2S,3R)-3-cyclopropylaziridine-2-carboxylate To a solution of ethyl (2S,3R)-3-cyclopropylaziridine-2-carboxylate (450 mg, 2.9 mmol) in THF (6.0 mL) and HO (2.0 mL) was added LiOH (90 mg, 3.8 mmol). The reaction was stirred for 2 hours and then filtered. The filtrate was concentrated under reduced pressure to give the desired product (300 mg, crude).

[0670] Synthesis of intermediate 13-(2S,3S)-1-((S)-tert-butylsulfinyl)-3-cyclobutylaziridine-2-carboxylic acid

[0671] [ka]

[0672] Step 1: Synthesis of (S,E)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide To a solution of cyclobutanecarbaldehyde (0.5 g, 5.94 mmol) in THF (10 mL) was added (S)-2-methylpropane-2-sulfinamide (792.48 mg, 6.54 mmol) and Ti(OEt) (2.47 mL, 11.89 mmol). The mixture was stirred at 75 °C for 3 h. The reaction mixture was cooled to room temperature, quenched with additional brine (30 mL), and filtered to remove solids. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (2% → 10% EtOAc / petroleum ether) to give the desired product (907.3 mg, 39.9% yield). LCMS (ESI) m / z: [M+H]CH 17 Calculated value for NOS: 188.1; Found 188.3.

[0673] Step 2: Synthesis of ethyl (2S,3S)-1-((S)-tert-butylsulfinyl)-3-cyclobutylaziridine-2-carboxylate To a solution of ethyl 2-bromoacetate (1.60 g, 9.61 mmol, 1.06 mL) in THF (9 mL) was added LiHMDS (1 M, 9.61 mL) at −78° C., and after 2 minutes, (S,E)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide (0.9 g, 4.81 mmol) was added. The mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with additional HO (25 mL) at −78° C., and after warming to room temperature, the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (10% to 20% EtOAc / petroleum ether) to give the desired product (426 mg, crude). LCMS (ESI) m / z: [M+H]C 13 H 23 Calculated for NO3S: 274.14; Found 274.3.

[0674] Step 3: Synthesis of (2S,3S)-1-((S)-tert-butylsulfinyl)-3-cyclobutylaziridine-2-carboxylic acid To a solution of (2S,3S)-1-((S)-tert-butylsulfinyl)-3-cyclobutylaziridine-2-carboxylate (100 mg, 365.78 μmol) in MeCN (0.5 mL) and HO (0.5 mL) at 0° C., NaOH (21.95 mg, 548.67 μmol) was added, and the mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was adjusted to pH 5 by adding 10% aqueous citric acid (ca. 10 mL) and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired product (92.6 mg, crude). LCMS (ESI) m / z: [M+H]C 11 H 19 Calculated value for NO3S: 246.11; Found 246.3.

[0675] Synthesis of intermediate 14-(2R,3R)-1-((R)-tert-butylsulfinyl)-3-cyclobutylaziridine-2-carboxylic acid

[0676] [ka]

[0677] Step 1: Synthesis of (R,E)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide To a solution of cyclobutanecarbaldehyde (0.25 g, 2.97 mmol) in THF (5 mL) was added (R)-2-methylpropane-2-sulfinamide (396.24 mg, 3.27 mmol) and Ti(OEt) (1.36 g, 5.94 mmol, 1.23 mL). The mixture was stirred in two batches at 75 °C for 3 h. The two batches were combined, and the reaction mixture was quenched by the addition of brine (15 mL). The solution was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine (2 × 5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (10% → 20% EtOAc / petroleum ether) to give the desired product (786.7 mg, 70.7% yield). LCMS (ESI) m / z: [M+H]CH 17 Calculated value for NOS: 188.1; Found 188.3.

[0678] Step 2: Synthesis of ethyl (2R,3R)-1-((R)-tert-butylsulfinyl)-3-cyclobutylaziridine-2-carboxylate To a solution of ethyl 2-bromoacetate (236.19 μL, 2.14 mmol) in THF (2 mL) was added LiHMDS (1 M, 2.14 mL) at −78° C. After 30 min, (R,E)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide (0.2 g, 1.07 mmol) was added. The mixture was warmed to −40° C. and stirred for 4 h. The reaction mixture was quenched by the addition of HO (18 mL) at −40° C. and allowed to warm to room temperature. The mixture was extracted with EtOAc (3 × 15 mL), and the combined organic layers were washed with brine (2 × 5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. This was purified by preparative TLC (20% EtOAc / petroleum ether) to give the desired product (0.1 g, crude). LCMS (ESI) m / z: [M+H]C 13 H 23 Calculated for NO3S: 274.14; Found 274.3.

[0679] Step 3: Synthesis of (2R,3R)-1-((R)-tert-butylsulfinyl)-3-cyclobutylaziridine-2-carboxylic acid In two batches, to a solution of ethyl (2R,3R)-1-((R)-tert-butylsulfinyl)-3-cyclobutylaziridine-2-carboxylate (25 mg, 91.44 μmol) in MeCN (0.25 mL) and HO (0.25 mL) at 0° C., NaOH (5.49 mg, 137.17 μmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The reaction mixtures were combined, the pH adjusted to 5 with 10% aqueous citric acid (10 mL), and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired product (53 mg, crude). LCMS (ESI) m / z: [M+H]C 11 H 19 Calculated value for NO3S: 246.11; Found 246.2.

[0680] Synthesis of intermediates 15, 16, 17, and 18-ethyl (2R,3R)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (15), ethyl (2S,3S)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (16), ethyl (2R,3S)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (17), and ethyl (2S,3R)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (18)

[0681] [ka]

[0682] Intermediates 15, 16, 17, and 18 are used to make the following intermediates 19, 20, 21, and 22. Step 1: Synthesis of N-benzhydryl-1-(oxetan-3-yl)methanimine Diphenylmethanamine (12.1 mL, 69.7 mmol) was added to a solution of oxetane-3-carbaldehyde (5.0 g, 58 mmol) and MgSO (6.99 g, 58.1 mmol) in DCM (120 mL) at 0° C. The mixture was stirred at room temperature for 12 h, then filtered and concentrated under reduced pressure to give the desired compound (14 g, 95.9% yield), which was used without further purification.

[0683] Step 2: Synthesis of ethyl cis-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate and ethyl trans-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate To a solution of N-benzhydryl-1-(oxetan-3-yl)methanimine (10 g, 39.79 mmol) in MeCN (150 mL) was added TfOH (878 mL, 9.95 mmol), followed 5 min later by the addition of ethyl diazoacetate (5.0 mL, 47.8 mmol). The reaction mixture was stirred at room temperature for 12 h, then cooled to 0 °C and quenched by the addition of saturated NaHCO (300 mL). The aqueous layer was extracted with EtOAc (3 × 200 mL), and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. Purification by reverse-phase chromatography (50→65% MeCN / HO, 10 mM NHHCO) gave racemic ethyl cis-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (1.1 g, 8.2% yield) and racemic ethyl trans-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (780 mg, 5.8% yield).

[0684] Step 3: Separation of racemic ethyl cis-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate: ethyl (2R,3R)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate, and ethyl (2S,3S)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate Racemic ethyl cis-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (800 mg, 2.37 mmol) was separated by chiral preparative SFC (25% MeOH / CO) to give ethyl (2R,3R)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (320 mg, 40% yield) and ethyl (2S,3S)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (320 mg, 40% yield).

[0685] Step 4: Separation of racemic ethyl trans-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate: ethyl (2R,3S)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate, and ethyl (2S,3R)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate Racemic ethyl trans-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (700 mg, 2.07 mmol) was separated by chiral preparative SFC (25% EtOH, 0.1% NHOH / CO) to give ethyl (2R,3S)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (300 mg, 42% yield) and ethyl (2S,3R)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (320 mg, 43% yield).

[0686] Synthesis of Intermediates 19 and 20-(2R,3R)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylic acid (19) and (2S,3S)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylic acid (20)

[0687] [ka]

[0688] Intermediates 19 and 20 are derived from intermediates 15 and 16 above. Step 1: Synthesis of (2R,3R)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylic acid (19) To a solution of ethyl (2R,3R)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (15) (156 mg, 463 mmol) in EtOH (3 mL) was added 2 M NaOH (347 mL, 696 mmol). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The concentrate was acidified to pH 5 with 1 M HCl and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give the desired compound (110 mg, 72.6% yield).

[0689] Step 2: Synthesis of (2S,3S)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylic acid (20) To a solution of ethyl (2S,3S)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (16) (150 mg, 444 mmol) in EtOH (5 mL) was added 2 M NaOH (333 mL, 666 mmol). The reaction mixture was stirred at room temperature for 3 h and then acidified to pH 5 with 1 M HCl. The aqueous layer was extracted with DCM (3 × 10 mL), and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give the desired compound (120 mg, 86.1% yield).

[0690] Intermediates 21 and 22—Synthesis of sodium (2R,3S)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (21) and sodium (2S,3R)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (22)

[0691] [ka]

[0692] Intermediates 21 and 22 are derived from intermediates 17 and 18 above. Step 1: Synthesis of sodium (2R,3S)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (21) To a solution of ethyl (2R,3S)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (17) (150 mg, 444 mmol) in EtOH (3 mL) was added 2 M NaOH (333.42 mL, 666 mmol). The reaction mixture was stirred at room temperature for 3 h, and then the pH was adjusted to pH 8 with 1 M HCl. The resulting solution was lyophilized to give the desired compound (165 mg, crude), which was used without further purification. LCMS (ESI) m / z: [M]C 19 H 18 Calculated for NO3: 308.13; Found 308.0.

[0693] Step 2: Synthesis of sodium (2S,3R)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (22) To a solution of ethyl (2S,3R)-1-benzhydryl-3-(oxetan-3-yl)aziridine-2-carboxylate (18) (170 mg, 503 mmol) in EtOH (3 mL) was added 2 M NaOH (378 mL, 754 mmol). The reaction mixture was stirred at room temperature for 3 h, and then the pH was adjusted to pH 8 with 1 M HCl. The resulting solution was lyophilized to give the desired compound (230 mg, crude), which was used without further purification. LCMS (ESI) m / z: [M]C 19 H 18 Calculated for NO3: 308.13; Found 308.0.

[0694] Synthesis of intermediate 23-(2R,3S)-1-((R)-tert-butylsulfinyl)-3-(methoxycarbonyl)aziridine-2-carboxylic acid

[0695] [ka]

[0696] Step 1: Synthesis of methyl (R,E)-2-((tert-butylsulfinyl)imino)acetate To a solution of (R)-2-methylpropane-2-sulfinamide (13.21 g, 109.01 mmol) and methyl 2-oxoacetate (8.0 g, 90.85 mmol) in DCM (130 mL) at room temperature was added MgSO (54.67 g, 454.23 mmol). The resulting mixture was heated to 35 °C and stirred for 16 h. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 × 50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase chromatography (25% EtOAc / petroleum ether) to give the desired product (5.8 g, 33.4% yield). LCMS (ESI) m / z: [M+H]CH 13 Calculated value for NO3S: 192.07; Found 191.9.

[0697] Step 2: Synthesis of 2-(tert-butyl) 3-methyl (2R,3S)-1-((R)-tert-butylsulfinyl)aziridine-2,3-dicarboxylate To a solution of 1 M LiHMDS (61.40 mL, 61.40 mmol) in THF (300.0 mL) was added tert-butyl 2-bromoacetate (11.83 g, 60.65 mmol) at −78° C. The resulting mixture was stirred for 30 minutes. Next, methyl (R,E)-2-((tert-butylsulfinyl)imino)acetate (5.8 g, 30.33 mmol) was added to the reaction mixture. The resulting mixture was warmed to −60° C. and stirred for 2.5 hours. The reaction was warmed to 0° C. and quenched with saturated NH4Cl (aq). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (10->50% MeCN / HO) to give the desired product (1.34 g, 4.5% yield). LCMS (ESI) m / z: [M+H]C 13 H 23 Calculated value for NO5S: 306.14; Found value 306.2.

[0698] Step 3: Synthesis of (2R,3S)-1-((R)-tert-butylsulfinyl)-3-(methoxycarbonyl)aziridine-2-carboxylic acid To a solution of 2-(tert-butyl) 3-methyl(2R,3S)-1-((R)-tert-butylsulfinyl)aziridine-2,3-dicarboxylate (302.0 mg, 0.99 mmol) in DCM (3.0 mL) was added TFA (1.50 mL) at 0° C. The resulting mixture was stirred for 1 h and then concentrated under reduced pressure to give the desired crude product (300 mg). LCMS (ESI) m / z: [M+H]CH 15 Calculated value for NO5S: 250.07; Found value 250.1.

[0699] Synthesis of intermediate 24-(2R,3S)-1-((S)-tert-butylsulfinyl)-3-(methoxycarbonyl)aziridine-2-carboxylic acid

[0700] [ka]

[0701] Step 1: Synthesis of methyl (S,E)-2-((tert-butylsulfinyl)imino)acetate To a solution of (S)-2-methylpropane-2-sulfinamide (9.81 g, 80.94 mmol) and methyl 2-oxoacetate (5.94 g, 67.45 mmol) in DCM (100 mL) was added MgSO (40.60 g, 337.26 mmol) at room temperature. The resulting mixture was heated to 35 °C and stirred for 16 h. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 × 50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase chromatography (25% EtOAc / petroleum ether) to give the desired product (5.68 g, 44.0% yield). LCMS (ESI) m / z: [M+H]CH 13 Calculated value for NO3S: 192.07; Found value 191.1.

[0702] Step 2: Synthesis of 2-(tert-butyl) 3-methyl (2R,3S)-1-((S)-tert-butylsulfinyl)aziridine-2,3-dicarboxylate To a solution of 1 M LiHMDS (59.40 mL, 59.40 mmol) in THF (300.0 mL) was added tert-butyl 2-bromoacetate (11.59 g, 59.40 mmol) at −78° C. The resulting mixture was stirred for 30 minutes. Next, methyl (S,E)-2-((tert-butylsulfinyl)imino)acetate (5.68 g, 29.70 mmol) was added to the reaction mixture. The resulting mixture was warmed to −60° C. and stirred for 2.5 hours. The reaction was warmed to 0° C. and quenched with saturated NH4Cl (aq). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (10->50% MeCN / HO) to give the desired product (1.26 g, 13.9% yield). LCMS (ESI) m / z: [M+H]C 13 H 23 Calculated value for NO5S: 306.14; Found value 306.1.

[0703] Step 3: Synthesis of (2R,3S)-1-((S)-tert-butylsulfinyl)-3-(methoxycarbonyl)aziridine-2-carboxylic acid To a solution of 2-(tert-butyl) 3-methyl(2R,3S)-1-((S)-tert-butylsulfinyl)aziridine-2,3-dicarboxylate (457.0 mg, 1.50 mmol) in DCM (6.0 mL) was added TFA (3.0 mL) at 0° C. The resulting mixture was stirred for 1 hour and then concentrated under reduced pressure to give the desired crude product. (450 mg) was obtained. LCMS (ESI) m / z: [M+H]CH 15 Calculated value for NO5S: 250.07; Found value 250.1.

[0704] Synthesis of Intermediates 25 and 26-(2R,3S)-1-(4-Methoxybenzyl)-3-(trifluoromethyl)aziridine-2-carboxylic Acid and (2S,3R)-1-(4-Methoxybenzyl)-3-(trifluoromethyl)aziridine-2-carboxylic Acid

[0705] [ka]

[0706] Step 1: Synthesis of ethyl 1-(4-methoxybenzyl)-3-(trifluoromethyl)aziridine-2-carboxylate A solution of 1-ethoxy-2,2,2-trifluoroethan-1-ol (2.17 mL, 18.37 mmol) and p-methoxybenzylamine (1.89 mL, 14.58 mmol) in toluene (46 mL) was refluxed under Dean-Stark conditions for 16 h. The reaction was concentrated under reduced pressure, and the resulting residue was dissolved in THF (80 mL) and cooled to −78 °C. BF EtO (0.360 mL, 2.92 mmol) was added to the solution, followed by dropwise addition of ethyl diazoacetate (1.83 mL, 17.50 mmol). The reaction was stirred for 4 h at room temperature. The reaction mixture was quenched by the addition of saturated aqueous NaHCO (5 mL), and the resulting solution was extracted with DCM (3 × 50 mL). The combined organic layers were washed with HO (20 mL) and brine (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1->10% EtOAc / petroleum ether) to give the desired product (2 g, 45.2% yield).

[0707] Step 2: Synthesis of ethyl (2R,3S)-1-(4-methoxybenzyl)-3-(trifluoromethyl)aziridine-2-carboxylate and ethyl (2S,3R)-1-(4-methoxybenzyl)-3-(trifluoromethyl)aziridine-2-carboxylate Ethyl 1-(4-methoxybenzyl)-3-(trifluoromethyl)aziridine-2-carboxylate (1 g) was purified by SFC separation (column: REGIS(S,S)WHELK-O1 (250 mm*25 mm, 10 μm); mobile phase: [Neu-IPA]; B%: 13%-13%, min) to give ethyl (2R,3S)-1-(4-methoxybenzyl)-3-(trifluoromethyl)aziridine-2-carboxylate (530 mg) and ethyl (2S,3R)-1-(4-methoxybenzyl)-3-(trifluoromethyl)aziridine-2-carboxylate (470 mg).

[0708] Step 3: Synthesis of (2R,3S)-1-(4-methoxybenzyl)-3-(trifluoromethyl)aziridine-2-carboxylic acid To a solution of ethyl (2R,3S)-1-(4-methoxybenzyl)-3-(trifluoromethyl)aziridine-2-carboxylate (430 mg, 1.42 mmol) in EtOH (4 mL) and HO (6 mL) was added NaOH (113.42 mg, 2.84 mmol). The mixture was stirred at room temperature for 5 h. The mixture was acidified to pH 1-2 with 2 M hydrochloric acid. The reaction mixture was poured into HO (3 mL), and the aqueous phase was extracted with EtOAc (3 × 3 mL). The combined organic phases were washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired product (350 mg, 89.1% yield). LCMS (ESI) m / z: [M+H]C 12 H 11 Calculated value for FNO3: 274.08; measured value 274.1.

[0709] Step 4: Synthesis of (2S,3R)-1-(4-methoxybenzyl)-3-(trifluoromethyl)aziridine-2-carboxylic acid To a solution of ethyl (2S,3R)-1-(4-methoxybenzyl)-3-(trifluoromethyl)aziridine-2-carboxylate (370 mg, 1.22 mmol) in HO (2 mL) and EtOH (4 mL) was added NaOH (97.59 mg, 2.44 mmol). The mixture was stirred at room temperature for 5 hours. Hydrochloric acid (2 M) was added to bring the mixture to pH = 1-2. The reaction mixture was poured into HO (3 mL), and the aqueous phase was extracted with EtOAc (3 × 3 mL). The combined organic phases were washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired product (300 mg, 89.0% yield). LCMS (ESI) m / z: [M+H]C 12 H 11 Calculated value for FNO3: 234.08; measured value 234.2.

[0710] Synthesis of Intermediates 27 and 28-(2S,3S)-1-benzyl-3-(trifluoromethyl)aziridine-2-carboxylic acid and (2R,3R)-1-benzyl-3-(trifluoromethyl)aziridine-2-carboxylic acid

[0711] [ka]

[0712] Step 1: Synthesis of ethyl (2S,3R)-2,3-dibromo-4,4,4-trifluorobutanoate To a solution of ethyl (E)-4,4,4-trifluorobut-2-enoate (5 g, 29.74 mmol, 4.42 mL) in CCl (90 mL) was added Br (1.69 mL, 37.72 mmol), and the solution was stirred at 75° C. for 5 h. The reaction mixture was concentrated under reduced pressure to give the desired product (10.72 g, crude).

[0713] Step 2: Synthesis of ethyl (2S,3S)-1-benzyl-3-(trifluoromethyl)aziridine-2-carboxylate To a solution of ethyl (2S,3R)-2,3-dibromo-4,4,4-trifluorobutanoate (10.72 g, 32.69 mmol) in EtOH (30 mL) was slowly added a solution of BnNH (12.47 mL, 114.42 mmol) in EtOH (120 mL) at −5° C. under N. The mixture was warmed to room temperature and stirred for 15 h. The mixture was concentrated under reduced pressure, and EtOAc (120 mL) was added to the residue. The precipitate was filtered, and the filtrate was washed with hydrochloric acid (3%, 180 mL) and HO (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% EtOAc / petroleum ether) to give the desired product (6.02 g, 67.4% yield).

[0714] Step 3: Synthesis of ethyl (2R,3R)-1-benzyl-3-(trifluoromethyl)aziridine-2-carboxylate and (2S,3S)-1-benzyl-3-(trifluoromethyl)aziridine-2-carboxylic acid Ethyl (2R,3R)-1-benzyl-3-(trifluoromethyl)aziridine-2-carboxylate and (2S,3S)-1-benzyl-3-(trifluoromethyl)aziridine-2-carboxylic acid were synthesized on an enzyme screening platform based on the procedure in Tetrahedron Asymmetry 1999, 10, 2361.

[0715] Step 4: Synthesis of (2R,3R)-1-benzyl-3-(trifluoromethyl)aziridine-2-carboxylic acid To a solution of ethyl (2R,3R)-1-benzyl-3-(trifluoromethyl)aziridine-2-carboxylate (200 mg, 731.93 μmol) in EtOH (5 mL) was added NaOH (2 M, 548.95 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove EtOH. The mixture was then adjusted to pH 1 by adding HCl (1 M) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the desired product (138 mg, 76.9% yield). LCMS (ESI) m / z: [M+H]C 11 H 10 Calculated value for F3NO2: 246.07; Measured value 245.9.

[0716] Synthesis of intermediate 29-(R)-1-((benzyloxy)carbonyl)-2-methylaziridine-2-carboxylic acid

[0717] [ka]

[0718] Step 1: Synthesis of benzyl (2S,4S)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a mixture of ((benzyloxy)carbonyl)-L-alanine (25 g, 111.99 mmol) and (dimethoxymethyl)benzene (71.38 mL, 115.35 mmol) in THF (180 mL) was added SOCl (8.94 g, 123.19 mmol) in one portion at 0 °C. After the mixture was stirred for 10 min, ZnCl (5.77 mL, 123.26 mmol) was added to the solution, and the mixture was then stirred at 0 °C for 4 h. The reaction mixture was quenched by the dropwise addition of cold HO, adjusted to pH 5 with saturated NaHCO, and extracted with EtOAc (2 × 100 mL). The organic phase was washed with saturated aqueous NaHCO (30 mL) and brine (30 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1→10% EtOAc / petroleum ether) to give the product (15 g, 43% yield).

[0719] Step 2: Synthesis of benzyl (2S,4S)-4-(iodomethyl)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate HMPA (5.22 mL, 29.74 mmol) and LHMDS (1 M, 6.62 mL) were mixed in THF (45 mL) at 20 °C under a N atmosphere. This solution was cooled to -78 °C and added dropwise with stirring to a solution of benzyl (2S,4S)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate (2.0 g, 6.42 mmol) in THF (12 mL). After stirring for an additional 30 min, a solution of CHCl (1.55 mL, 19.27 mmol) in THF (6 mL) was added dropwise. The mixture was stirred at -78 °C for 90 min. The mixture was warmed to 0 °C and quenched with saturated aqueous NHCl (70 mL). The mixture was extracted with EtOAc (2 × 30 mL), and the combined organic layers were washed with saturated aqueous NH4Cl (20 mL), HO (2 × 20 mL), and brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (1 → 20% EtOAc / petroleum ether) to give the product (1.2 g, 41.4% yield).

[0720] Step 3: Synthesis of methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-iodo-2-methylpropanoate To a mixture of benzyl (2S,4S)-4-(iodomethyl)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate (1.2 g, 2.66 mmol) and THF (20 mL), a solution of NaOMe (957.69 mg, 5.32 mmol, 30% purity) in MeOH (9 mL) was added dropwise over 10 min at −40° C. under N2. The mixture was stirred at −40° C. for 2 h, then warmed to −20° C. and stirred for 1 h. The reaction was quenched by the addition of HO (20 mL), and the resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1→20% EtOAc / petroleum ether) to give the product (870 mg, 2.24 mmol, 84.4% yield).

[0721] Step 4: Synthesis of 1-benzyl 2-methyl (R)-2-methylaziridine-1,2-dicarboxylate To a mixture of methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-iodo-2-methylpropanoate (0.87 g, 2.31 mmol) and MeCN (125 mL) at room temperature, AgO (1.60 g, 6.92 mmol) was added in one portion. The mixture was stirred at 90 °C for 30 min. The mixture was filtered and concentrated under reduced pressure to give the product (500 mg, 2.01 mmol, 86.9% yield).

[0722] Step 5: Synthesis of 1-benzyl 2-methyl (R)-2-methylaziridine-1,2-dicarboxylate To a mixture of 1-benzyl 2-methyl (R)-2-methylaziridine-1,2-dicarboxylate (250 mg, 1.0 mmol) in MeCN (2.5 mL) and HO (2.5 mL) was added NaOH (40.12 mg, 1.0 mmol) in one portion at 0 °C under N. The mixture was stirred at 0 °C for 30 min. The mixture was concentrated under reduced pressure to give the crude product (256 mg, crude). LCMS (ESI) m / z: [M+H]C 12 H 12 Calculated for NO4: 234.1; Found 234.1.

[0723] Synthesis of intermediate 30-potassium (S)-1-isopropylaziridine-2-carboxylate

[0724] [ka]

[0725] Step 1: Synthesis of benzyl isopropyl-L-serinate To a solution of benzyl L-serinate (3.65 g, 18.69 mmol), KOAc (1.83 g, 18.69 mmol), and acetone (2.5 mL, 33.66 mmol) in DCM (60.0 mL) was added NaBH(AcO) (4.76 g, 22.436 mmol) in small portions at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched by adding saturated aqueous NaHCO (50 mL) at room temperature. The resulting mixture was extracted with DCM (3 × 80 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (67% EtOAc / hexanes) to give the desired product (2.7 g, 60.9% yield) as an off-white solid. LCMS (ESI) m / z: [M+H]C 13 H 19 Calculated for NO3: 238.14; Found 238.2.

[0726] Step 2: Synthesis of benzyl (S)-1-isopropylaziridine-2-carboxylate To a solution of benzyl isopropyl-L-serinate (2.70 g, 11.378 mmol), EtN (4.75 mL, 34.134 mmol), and DMAP (2.57 mg, 0.021 mmol) in DCM (50.0 mL) was added dropwise a solution of TsCl (2.60 g, 13.65 mmol) in DCM at 0 °C. The resulting mixture was stirred overnight at room temperature and then at 40 °C for 4 h. The reaction mixture was diluted with HO (80 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% EtOAc / hexanes) to give the desired product (2.3 g, 93.2% yield). LCMS (ESI) m / z: [M+H] C 13 H 17 Calculated value for NO2: 220.13; Found value 220.1.

[0727] Step 3: Synthesis of potassium (S)-1-isopropylaziridine-2-carboxylate To a solution of benzyl (S)-1-isopropylaziridine-2-carboxylate (800.0 mg, 3.65 mmol) in HO (6.0 mL) and THF (8.0 mL) was added dropwise a solution of KOH (245.62 mg, 4.378 mmol) in HO (2.0 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with HO (10 mL), and the aqueous layer was washed with MTBE (3 × 8 mL). The aqueous layer was dried by lyophilization to give the desired product (400 mg, crude). LCMS (ESI) m / z: [M+H]CH 11 Calculated value for NO2: 130.09; Measured value 130.0.

[0728] Synthesis of intermediate 31-potassium (R)-1-isopropylaziridine-2-carboxylate

[0729] [ka]

[0730] Step 1: Synthesis of benzyl isopropyl-D-serinate To a solution of benzyl D-serinate (2.10 g, 10.757 mmol), KOAc (1.06 g, 10.757 mmol), and acetone (1.2 mL, 16.136 mmol) in DCM (40.0 mL) was added a solution of NaBH(AcO) (2.96 g, 13.984 mmol) in portions at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO (50 mL), and the mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (67% EtOAc / hexanes) to give the desired product (1.7 g, 66.6% yield). LCMS (ESI) m / z: [M+H]C 13 H 19 Calculated for NO3: 238.14; Found 238.0.

[0731] Step 2: Synthesis of benzyl (R)-1-isopropylaziridine-2-carboxylate At 0°C, a DCM solution of TsCl (1.69 g, 8.850 mmol) was added dropwise to a DCM solution of benzyl isopropyl-D-serinate (1.75 g, 7.375 mmol), EtN (2.58 mL, 18.437 mmol), and DMAP (90.09 mg, 0.737 mmol) in 30.0 mL of DCM. The resulting mixture was stirred overnight at room temperature and then at 40°C for 4 hours. The mixture was diluted with HO (80 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was puri...

Claims

1. A compound having the structure of Formula I: A-L-B Formula I wherein A is a Ras binding moiety; L is a linker, B is a selective bridging group. or a pharmaceutically acceptable salt thereof; The compound, or a pharmaceutically acceptable salt thereof, wherein when the compound, or a pharmaceutically acceptable salt thereof, contacts a sample containing a Ras protein, at least 20% of the Ras protein in the sample covalently reacts with the compound, or a pharmaceutically acceptable salt thereof, to form a conjugate.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the Ras protein in the sample is a mutant Ras protein.

3. 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the Ras-binding moiety is a K-Ras-binding moiety, and the Ras protein in the sample is a K-Ras protein.

4. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein the K-Ras binding moiety interacts with a residue in the K-Ras Switch-II binding pocket of the K-Ras protein.

5. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the residues in the K-Ras Switch-II binding pocket are residues in the K-Ras protein corresponding to V7, V8, V9, G10, A11, D12, K16, P34, T58, A59, G60, Q61, E62, E63, Y64, S65, R68, D69, Y71, M72, F78, I92, H95, Y96, Q99, I100, R102, or V103 of human wild-type K-Ras (SEQ ID NO: 1).

6. 6. The compound of any one of claims 3 to 5, or a pharmaceutically acceptable salt thereof, wherein the K-Ras binding moiety has a structure of any one of formulas II to V:

7. 7. The compound of claim 6, wherein the K-Ras binding moiety has the structure of Formula II, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 wherein m is 0, 1, 2, or 3; W １ is N or C, and C is optionally substituted C １ -C ３ an alkylene bridge or an optionally substituted C １ -C ３ is optionally attached to said linker via a heteroalkylene bridge; Each R １ are independently CN, halo, hydroxy, optionally substituted C １ -C ６ alkyl, or optionally substituted C １ -C ６ heteroalkyl; or R １ is C １ -C ３ Alkylene bridge, or C １ -C ３ is attached to the linker via a heteroalkylene bridge, and R ２ is an optionally substituted C ６ -C １０ aryl, or optionally substituted C ２ -C ９ is heteroaryl.

8. 7. The compound of claim 6, wherein the K-Ras binding moiety has the structure of Formula III, or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 wherein n is 0, 1, 2, 3, 4, 5, or 6; 【Transformation 3】 represents a single or double bond, X is N or CR', where R' is hydrogen, or R' is an optionally substituted C １ -C ３ Alkylene bridge or optionally substituted C １ -C ３ is attached to the linker via a heteroalkylene bridge; V is CHR ５ , C.R. ５ R ５ , OR ５ , N.H.R. ５ , or NR ５ａ R ５ｂ and Each R ３ is independent, 【Chemistry 4】 , optionally substituted C １ -C ６ alkyl, or optionally substituted C １ -C ６ heteroalkyl; or R ３ is an optionally substituted C １ -C ３ an alkylene bridge or an optionally substituted C １ -C ３ is attached to the linker via a heteroalkylene bridge; R ４ is an optionally substituted C ６ -C １０ aryl, or optionally substituted C ２ -C ９ is heteroaryl, Each R ５ are independently optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted -C １ -C ６ Alkyl-C ２ -C ９ heteroaryl, or optionally substituted —C １ -C ６ Alkyl-C ２ -C ９ heterocyclyl, and Each R ５ａ and R ５ｂ are independently optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted -C １ -C ６ Alkyl-C ２ -C ９ heteroaryl, or optionally substituted —C １ -C ６ Alkyl-C ２ -C ９ heterocyclyl, or R ５ａ and R ５ｂ are combined with the nitrogen atom to which they are attached to form an optionally substituted C ２ -C ９ forming a heterocyclyl, wherein R' is an optionally substituted C １ -C ３ an alkylene bridge, or an optionally substituted C １ -C ３ When attached to the linker via a heteroalkylene bridge, R ３ is an optionally substituted C １ -C ３ an alkylene bridge or an optionally substituted C １ -C ３ is not attached to the linker via a heteroalkylene bridge, and Furthermore, however, R ３ is optionally substituted C １ -C ３ an alkylene bridge, or an optionally substituted C １ -C ３ When attached to the linker via a heteroalkylene bridge, R' is an optionally substituted C １ -C ３ an alkylene bridge or an optionally substituted C １ -C ３ is not attached to the linker via a heteroalkylene bridge.

9. 7. The compound of claim 6, wherein the K-Ras binding moiety has the structure of Formula IV, or a pharmaceutically acceptable salt thereof: 【Transformation 5】 wherein o is 0, 1, or 2; X １ , X ２ , and X ３ are each independently N, CH, or CR ６ and Each R ６ are independently halo, CN, hydroxy, optionally substituted C １ -C ６ alkyl, or optionally substituted C １ -C ６ heteroalkyl; or R ６ is C １ -C ３ Alkyl bridge or C １ -C ３ is attached to the linker via a heteroalkyl bridge, and R ７ and R ８ are independently optionally substituted C ６ -C １０ aryl or optionally substituted C ２ -C ９ is heteroaryl.

10. X １ , X ２ , and X ３ 10. The compound of claim 9, wherein only one of is N, or a pharmaceutically acceptable salt thereof.

11. 7. The compound of claim 6, wherein the K-Ras binding moiety has the structure of Formula V, or a pharmaceutically acceptable salt thereof: 【Transformation 6】 wherein p is 0, 1, 2, or 3; W ４ is NH or O, R ９ is an optionally substituted C ６ -C １０ aryl, or optionally substituted C ２ -C ９ is heteroaryl, Each R １０ are independently halo, CN, hydroxy, optionally substituted C １ -C ６ Alkyl or optionally substituted C １ -C ６ heteroalkyl, or R １０ is C １ -C ３ Alkylene bridge or C １ -C ３ is attached to the linker via a heteroalkylene bridge, and R １１ is an optionally substituted —C １ -C ６ Alkyl-C ２ -C ９ Heteroaryl, optionally substituted -C １ -C ６ Alkyl-C ２ -C ９ Heterocyclyl, optionally substituted C ２ -C ９ Heteroaryl, or optionally substituted C ２ -C ９ heterocyclyl].

12. 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein the linker positions the reactive atom of B about 0.5 to about 1.1 nm (about 5 to about 11 angstroms) from the nearest atom of A.

13. 13. The compound of any one of claims 1 to 12, wherein the linker has the structure of Formula VI, or a pharmaceutically acceptable salt thereof: A １ -(B １ ) ａ -(C １ ) ｂ -(B ２ ) ｃ -(D)-(B ３ ) ｄ -(C ２ ) ｅ -(B ４ ) ｆ -A ２ Formula VI [In the formula, A １ is the bond between the linker and the Ras binding moiety, A ２ is the bond between the selective crosslinking group and the linker; B １ , B ２ , B ３ , and B ４ each independently represents an optionally substituted C １ -C ２ Alkylene, optionally substituted C １ -C ３ Heteroalkylene, O, S, and NR Ｎ and R Ｎ is hydrogen, optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, optionally substituted C ２－６ Heterocyclyl, optionally substituted C ６－１２ aryl, or optionally substituted C １－７ is heteroalkyl, C １ and C ２ are each independently selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl; a, b, c, d, e, and f are each independently 0 or 1; and D is an optionally substituted C １－１０ Alkylene, optionally substituted C ２－１０ Alkenylene, optionally substituted C ２－１０ Alkynylene, optionally substituted C ２－６ Heterocyclylene, optionally substituted C ２－６ Heteroarylene, optionally substituted C ３－８ Cycloalkylene, optionally substituted C ６－１２ Arylene, optionally substituted C ２ -C １０ Polyethylene glycol or optionally substituted C １－１０ heteroalkylene, or A １ - (B １ ) ａ -(C １ ) ｂ - (B ２ ) ｃ - (B ３ ) ｄ -(C ２ ) ｅ - (B ４ ) ｆ -A ２ [This is a chemical bond that connects the two molecules together.]

14. 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein the linker comprises a 3- to 8-membered heterocyclyl group.

15. 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein the linker is acyclic.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the selective crosslinking group is a CO bond-forming selective crosslinking group.

17. 17. The compound of claim 16 having the structure of Formula XXIV, or a pharmaceutically acceptable salt thereof: 【Transformation 7】 [In the formula, R ３１ is absent or hydrogen, C(O)CH ３ , S.O. ２ CH ３ , optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ６ -C １０ aryl, optionally substituted C １ -C ３ Alkyl-C ６ -C １０ aryl, optionally substituted C ２ -C ９ heterocyclyl or optionally substituted C １ -C ３ Alkyl-C ２ -C ９ is heterocyclyl, R ５６ is CH ３ or Cl, Rz is hydrogen, optionally substituted C １ -C ３ is alkyl, Each R ｘ are independently hydrogen, CO ２ CH ３ , optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ６ -C １０ aryl, optionally substituted C ２ -C ９ Heterocyclyl, optionally substituted C ２ -C ６ alkenyl, or optionally substituted C ２ -C ６ alkynyl, and Z''' is N or O].

18. 18. The compound of claim 16 or 17, having the structure of Formula XIII, or a pharmaceutically acceptable salt thereof: 【Transformation 8】 [In the formula, R ３１ is hydrogen, CH ３ , C(O)CH ３ , S.O. ２ CH ３ , C.H. ２ -C ６ H ５ , or C.H. ２ CH ２ OCH ３ is.

19. 2. The compound of claim 1 having the structure of Formula XX or XXI, or a pharmaceutically acceptable salt thereof: 【Chemistry 9】 [wherein Y is C(O), C(S), SO ２ or optionally substituted C １ -C ６ is alkyl, Z' is C(O) or SO ２ and q is 0, 1, or 2; x is 0, 1, 2, or 3; Each R Ｘ are independently hydrogen, CN, C(O)R ｙ , CO ２ R ｙ , C(O)NR ｙ R ｙ , optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ６ -C １０ aryl, optionally substituted C ２ -C ９ heterocyclyl, or optionally substituted C ２ -C ９ is heteroaryl, Each R ｙ are independently hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ６ -C １０ aryl, optionally substituted C ２ -C ９ heterocyclyl, or optionally substituted C ２ -C ９ is heteroaryl, Each R ４８ are independently CN, halo, hydroxy, optionally substituted C １ -C ６ alkyl, or optionally substituted C １ -C ６ heteroalkyl; or R ４９ is an optionally substituted C ６ -C １０ aryl, or optionally substituted C ２ -C ９ is heteroaryl, R ５０ is hydrogen, or C １ -C ６ is alkyl, R ５１ is hydrogen, CN, or C １ -C ６ is alkyl, R ５４ is hydrogen, -C(O)R ３２ , -SO ２ R ３３ , optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ６ -C １０ aryl, optionally substituted C ２ -C ９ heterocyclyl, or optionally substituted C ２ -C ９ is heteroaryl, and R ５５ is hydrogen or an optionally substituted C １ -C ６ alkyl].

20. 20. The compound of claim 19 having the structure of Formula XXII or Formula XXIII, or a pharmaceutically acceptable salt thereof: 【Chemistry 10】 wherein X is hydrogen or hydroxy.

21. A compound having the structure set forth in any one of Examples 63-95 in Table 2b, or a pharmaceutically acceptable salt thereof.

22. A compound having the structure set forth in any one of Examples 96-104 in Table 2c, or a pharmaceutically acceptable salt thereof.

23. A compound having the structure set forth in any one of Examples 105-180 in Table 2d, or a pharmaceutically acceptable salt thereof.

24. A compound having the structure set forth in any one of Examples 181-216 in Table 2e, or a pharmaceutically acceptable salt thereof.

25. A compound having the structure set forth in any one of Examples 217-300 in Table 2f, or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. 1. A conjugate, or a salt thereof, comprising a Ras protein covalently bound to a selective cross-linking group, wherein the selective cross-linking group is attached to a Ras binding moiety via a linker, and the selective cross-linking group is a carbodiimide, an aminooxazoline, a chloroethylurea, an aziridine, a trifluoromethyl ketone, a boronic acid, a boronic acid ester, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isoEEDQ or other EEDQ derivatives, an epoxide, an oxazolium, or a glycal.

28. 27. A method of making a conjugate, comprising contacting a Ras protein with a compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 26, under conditions sufficient to covalently react said compound with said Ras protein.

29. 29. A conjugate produced by the method of claim 28.

30. 27. A method of treating cancer in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26.

31. A method for treating a Ras protein-associated disease in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26.

32. A method for inhibiting Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26.

33. 33. The method of claim 32, wherein the cell is a cancer cell.

34. 34. The method or use of any one of claims 30 to 33, wherein the method further comprises administering an additional anti-cancer therapy.

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